Review of Organic Chemistry Functional Group Solutions Manual

Robin M.
Zavod, PhD
Editor-in-Chief, Currents in Pharmacy Teaching

and Learning
Professor of Pharmaceutical Sciences
Midwestern University Chicago College of
Pharmacy
Downers Grove, Illinois
Marc W. Harrold, PhD

Professor of Medicinal Chemistry
Duquesne University Mylan School of Pharmacy
Pittsburgh, Pennsylvania
Purchased by palm beach atlantic university, Ed Nordine

From: ASHP eBooks (digital.ashp.org)
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ISBN: 978-1-58528-464-1

10 9 8 7 6 5 4 3 2 1
DEDICATION
To our students, whose
creative problem solving
has not only taunted and
teased us, but has also
inspired us to develop
review questions that
provide meaningful
guidance during the
structure evaluation
journey.


TABLE OF CONTENTS
Preface .......................................................................................................................................................................................... vii
Acknowledgments.......................................................................................................................................................................... ix
PART I QUESTIONS
Section 1 General Self Assessment
1.1
1.2
1.3
1.4
1.5
1.6
1.7
Functional Group Characteristics and Roles........................................................................................................................ 1

Identifying Acidic and Basic Functional Groups................................................................................................................... 7
Solving pH/pKa Problems................................................................................................................................................... 11
Salts and Solubility............................................................................................................................................................ 13
Drug Binding Interactions.................................................................................................................................................. 17
Stereochemistry and Drug Action...................................................................................................................................... 21
Drug Metabolism............................................................................................................................................................... 23
Section 2 Whole Molecule Drug Evaluation

1.8
1.9
1.10
1.11
1.12
1.13
1.14
1.15
1.16
1.17
1.18
1.19
1.20
1.21
1.22
1.23
1.24
1.25
1.26
1.27
Aliskiren............................................................................................................................................................................ 27
Aripiprazole....................................................................................................................................................................... 31
Cefprozil............................................................................................................................................................................ 35
Cetirizine........................................................................................................................................................................... 39
Chlorpropamide and Other Sulfonylureas ......................................................................................................................... 41
Dabigatran Etexilate.......................................................................................................................................................... 43
Fenofibrate and Gemfibrozil.............................................................................................................................................. 47
Fluvoxamine...................................................................................................................................................................... 51
Haloperidol........................................................................................................................................................................ 55
Hydrocortisone.................................................................................................................................................................. 57
Levothyroxine.................................................................................................................................................................... 61
Lidocaine........................................................................................................................................................................... 65
Montelukast and Zafirlukast.............................................................................................................................................. 69
Phenobarbital and Other Barbiturates............................................................................................................................... 71
Pravastatin and Fluvastatin............................................................................................................................................... 73
Quinapril........................................................................................................................................................................... 75
Rivastigmine...................................................................................................................................................................... 79
Sitagliptin.......................................................................................................................................................................... 83
Sorafenib........................................................................................................................................................................... 87
Zanamivir and Oseltamivir ............................................................................................................................................... 91
PART 2 ANSWERS
2.1 Functional Group Characteristics and Roles...................................................................................................................... 95
2.2 Identifying Acidic and Basic Functional Groups................................................................................................................. 99
TABLE OF CONTENTS
2.3
2.4
2.5
2.6
2.7
Solving pH/pKa Problems................................................................................................................................................ 105

Salts and Solubility......................................................................................................................................................... 109
Drug Binding Interactions............................................................................................................................................... 113
Stereochemistry and Drug Action................................................................................................................................... 117
Drug Metabolism ........................................................................................................................................................... 123

2.8
2.9
2.10
2.11
2.12
2.13
2.14
2.15
2.16
2.17
2.18
2.19
2.20
2.21
2.22
2.23
2.24
2.25
2.26
2.27
Aliskiren......................................................................................................................................................................... 129
Aripiprazole.................................................................................................................................................................... 137
Cefprozil......................................................................................................................................................................... 143
Cetirizine........................................................................................................................................................................ 149
Chlorpropamide and Other Sulfonylureas ...................................................................................................................... 153
Dabigatran Etexilate....................................................................................................................................................... 159
Fenofibrate and Gemfibrozil........................................................................................................................................... 165
Fluvoxamine................................................................................................................................................................... 169
Haloperidol..................................................................................................................................................................... 173
Hydrocortisone............................................................................................................................................................... 177
Levothyroxine................................................................................................................................................................. 183
Lidocaine........................................................................................................................................................................ 189
Montelukast and Zafirlukast........................................................................................................................................... 193
Phenobarbital and Other Barbiturates............................................................................................................................ 199
Pravastatin and Fluvastatin............................................................................................................................................ 205
Quinapril........................................................................................................................................................................ 211
Rivastigmine................................................................................................................................................................... 217
Sitagliptin....................................................................................................................................................................... 223
Sorafenib........................................................................................................................................................................ 227
Zanamivir and Oseltamivir ............................................................................................................................................ 233
INDEX .................................................................................................................................................................................... 239

vii
PREFACE
If our suspicions are correct, youve heard the phrases, Keep up the good workyoull get better with
practice! and Keep practicing and youll see that it gets easier. Regardless of whether it is a coach,
teacher, clergy member, scout leader, friend, or family member providing this encouragement, the person
receiving this advice is likely learning a new skill, technique, or language. With practice, soccer goals
are scored, training wheels are removed, piano and ballet recitals are executed, and tents are pitched.
Through self assessment, one is able to both relish the victory, as well as consider how he or she could
have improved.
When learning a new language, another common expression is, If you dont use it, youll lose it. The
Basic Concepts in Medicinal Chemistry textbook served to lay the language foundation for drug structure evaluation. Whereas written/spoken language is based on phonemic awareness and phonetics, the
language of medicinal chemistry is based on functional group identification and evaluation. These functional groups speak to biological targets via key binding interactions, with stimulation or inhibition of
key physiological and biochemical processes as the response. Mastery of this language will help facilitate
a learners journey into understanding structure activity relationshipsthe next level of structure evaluation.
The Basic Concepts in Medicinal Chemistry chapters discussed physicochemical properties, provided clinically relevant examples and, through the review problems, offered an opportunity to practice new structure evaluation skills. With all of the variations of practice makes perfect ringing in our ears, Marc and I
agreed that one way to help cement the concepts in the textbook chapters is to offer learners a chance
to engage in self assessment. Better yet, we knew that the next step was to put all of the functional
group pieces together to support whole molecule evaluation.
This workbook is split into two sections with two goals in mind. Our first goal is to help the learner
reinforce his or her foundational knowledge. Additional practice problems focus on the following eight
fundamental types of evaluation:
1. Identification of functional groups that contribute to water solubility and those that contribute
to lipid solubility and the need for a balance between the two
2. The role of electron withdrawing and donating functional groups on adjacent atoms and functional groups
3. Identification of acidic and basic functional groups and related ionization under physiologically
relevant conditions
4. Use of the Henderson-Hasselbalch equation to solve both qualitative and quantitative pH and pKa
problems
5. Formation of inorganic and organic salts of specific functional groups and the value of those salts
6. Interaction chemistry between a drug molecule and its biological target for drug action
7. Spatial orientation of functional groups
8. Metabolic routes of drug activation, inactivation, and/or elimination
Our second goal, and the natural next step in the learning process, is to have the learner put all of his or
her evaluation skills together and fully assess all of the functional groups within a given drug molecule.
Twenty contemporary drugs that span an equivalent number of drug classes were selected as representative models for whole molecule evaluation. Section questions challenge the learner to anticipate what
could happen to a drug molecule (e.g., what metabolites could form), as well as to provide an explanation for an observed pharmacodynamic (e.g., mechanism of action) or pharmacokinetic parameter (e.g.,
percent orally bioavailability) based on the information gleaned from the structure evaluation process.
viii
PREFACE
(contd)
Although the workbook and associated on-line content (available to instructors only) are designed to
allow learners to conduct a self assessment of their knowledge, other audiences are also likely to derive
benefit. Those individuals who teach organic chemistry to pre-health profession students may find the
use of clinically relevant agents in these problems valuable in enhancing student engagement. Pharmacy
faculty tasked with dusting the rust off of prerequisite course content may find the workbook a valuable alternative to graded homework assignments. For those pharmacy faculty who contribute to an
integrated sequence and have precious little time to review these fundamental concepts, we offer this
workbook (and previous textbook) as a solution to quickly, but thoroughly translate organic chemistry
concepts into chemistry meaningful for the pharmacy practitioner. We hope that you find the format of
the workbook amenable to modification and that you enjoy solving a variety of problems for which drug
structure evaluation can contribute.
We are thankful to have had the opportunity to contribute to learner self assessment and for those
faculty who appreciate the absolute need for practice prior to mastery.
Robin M. Zavod
Marc W. Harrold

ix
ACKNOWLEDGMENTS
The writing and publishing of this text could not have been accomplished without the hard work and
the support of others. We would like to thank the following individuals from ASHP who provided us with
this opportunity and who were extremely valuable in answering our many queries: Ruth Bloom, Robin
Coleman, and Johnna Hershey. Your thoughtful edits and suggestions were exceptionally helpful.
Over my lifetime several individuals have asked me if I think that fast or accurate is more important. My
response has always been, Who cares about fast, if it isnt accurate? A slow, methodical approach to
problem solving has always served me well. Working through practice problems is one method to cement
problem solving skills. I would like to acknowledge both my eighth grade chemistry teacher GH and my
parents for instilling the value of accurate. I would also like to thank Marc for putting up with all of
my varied challenges through this self-assessment book and our former textbook projects.RZ
I am thankful for the opportunity to enhance our initial text and to expand its potential use. I would like
to thank Robin for her original idea for this self-assessment text; my colleagues at Duquesne University
who have provided valuable suggestions; my wife Barbara and my family for their love and support; and
God for His many blessings.MH


Part 1 QUESTIONS
Section 1 - General Self Assessment

1.1
1.2
1.3
1.4
1.5
1.6
1.7

Functional Group Characteristics and Roles.................... 3

Identifying Acidic and Basic Functional Groups............... 7
Solving pH/pKa Problems............................................... 11
Salts and Solubility........................................................ 13
Drug Binding Interactions.............................................. 17
Stereochemistry and Drug Action.................................. 21
Drug Metabolism........................................................... 23

Structures for 1.1 and 2.1

The bold has been removed.
1.1 Functional Group Characteristics

and
Roles
The exact same structures are in both of these chapters, but I have
provided
two
copies in the event you wanted that.

1. Shown below are the structures of warfarin, phenytoin, bromfenac, and salmeterol.
a. Identify each of the boxed functional groups.
A
F
C
E
D
Warfarin
Bromfenac
Phenytoin
H
J
Salmeterol
Box
Functional Group Name
A
B
C
D
E
OH
G
H
I
H 2N
S
O
C H3
N
H
Sulfamethoxazole
Ibuprofen
J
K
L

Medicinal Chemistry Self Assessment
The bold has been removed. The exact same structures are in both of these chapters, but I have provided two
b. For each of the functional groups you identified, indicate if it is hydrophilic or hydrophobic in
character.
Also
provide
a brief explanation for your response.
copies in the
event you
wanted
that.
Box
Hydrophilic or Hydrophobic
A
B
C
D
F
G
H
Warfarin
Bromfenac
Phenytoin
J
K
L
H
J
Salmeterol
2. Shown below are the structures of ibuprofen and sulfamethoxazole. Four functional groups have
been highlighted. Based on their electronic properties AND their relative positions in the molecule,
identify if they are electron withdrawing or electron donating. Additionally, identify if this effect is
due to resonance or induction.
D
O
OH
Ibuprofen

From: ASHP
eBooks (digital.ashp.org)
H 2N
S
O
C H3
N
H
Sulfamethoxazole
Page1of2
overall evaluation of how each change will affect the chemical properties of imipramine.
1.1 Functional Group Characteristics and Roles
3. Shown below is the structure of imipramine as well

as three analogs. Evaluate each analog and
N
provide an overall evaluation of how each change will affect the chemical properties of imipramine.
Imipramine
C H3
C H3
Imipramine
N
Analog A
Cl
CH3
C H3
Analog B
C H3
Analog A
C H3
Analog C
C H3
Analog B
C H3
C H3
Analog C
4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side chains of the
four amino acids have been boxed.
4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side
chains of the four amino acids have been boxed.
O
R1
H
N
OH
N
H
N
H
O
N H2
O
N
H
R2
O
HO
a. Identify the four amino acids that comprise this tetrapeptide sequence.
b. For each amino acid, identify the key chemical properties of its highlighted side chain.
Answers can be found in Section 2.1
Page2of2
Note: The questions in this chapter are related to Chapter 2 in Harrold MW and Zavod RM, Basic Concepts in
Medicinal Chemistry, American Society of Health-System Pharmacists, 2013.


1.2 Identifying Acidic and Basic

Functional Groups
1.2
1. For each of the drugs or experimental drugs shown below, identify all of the acidic and basic functional
groups.
groups.
Experimental oral anticoagulant
Bromfenac
Sorbinil
Experimental antidiabetic agent
5. Shown below is the structure of clonidine, an D adrenergic agonist that can be used to treat hypertension.
Drug Name
Acidic Functional Groups
Basic Functional Groups
Clonidine contains a guanidine functional group (highlighted in bold) that has a pKa of 8.3. Other guanidine
Experimental Oral Anticoagulant
functional
Bromfenac groups, such as that seen with arginine are much more basic with a pKa of 12.5. Provide a chemical
Sorbinil
explanation
for this difference.
Experimental Antidiabetic Agent
pKa = 12.5
pKa = 8.3
Clonidine
Arginine
7
1.2
8
groups.
2. Using any one of the acidic functional groups that you identified in question 1, provide an explanation as to why the functional group is acidic. Also provide a similar type of analysis for any one of the
basic functional groups that you identified in question 1.
3. Using the structures from question 1, modify all of the acidic functional groups to show their ionized
forms and in the table below identify the normal pKa range for the specific functional group.
Drug Name Experimental oral anticoagulant
Acidic Functional Group
NormalBromfenac
pKa Range

Bromfenac
Sorbinil
4. Using the structures from question 1, modify all basic functional groups to show their ionized forms
and in the table below
identify the normal pKa range for the specific functional group.
Sorbinil
Drug Name
Basic Functional Group
Experimental
antidiabetic agent
Normal
pKa Range

Bromfenac
Sorbinil below is the structure of clonidine, an D adrenergic agonist that can be used to treat hypertension.
5. Shown
functional groups, such as that seen with arginine are much more basic with a pKa of 12.5. Provide a chemical
5. Shown below is the structure of clonidine, an 2 adrenergic agonist that can be used to treat hypertension. Clonidine contains a guanidine functional group (highlighted in bold) that has a pKa=8.3.
explanation for this difference.
Other guanidine functional groups, such as that seen with arginine, are much more basic with a
pKa=12.5. Provide a chemical explanation for this difference.
pKa = 12.5
pKa = 8.3
Clonidine

Arginine
Page1of2
1.2 Identifying Acidic and Basic Functional Groups
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug molecule,
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug
an amphoteric
molecule, or drug
a nonelectrolyte.
molecule, drug
an amphoteric
molecule, or a nonelectrolyte.
O
N
H
H 2N
N
H
N
N
H
Lomitapide
COOH
NH
CF3
N
O
NH
C H3
H
N
CF3
C H3
Argatroban
HO
OH
C H3
NH
H
O
H3C
OCH3
COOH
Cl
C H3
H 2N
N
N
N
H
N H2
N H2
Amiloride
HO
Pravastatin
S
O
N
C H3
O
CH2 N(CH3 )2
Diltiazem
Drug Molecule
Acid/Base Character of Drug Molecule
Lomitapide
Argatroban
Pravastatin
Amiloride
Diltiazem
Page2of2


1.3 Solving pH/pKa Problems

1. Shown below are the structures of cefotaxime, nitrofurantoin, atenolol, and ezetimibe. Each of these drug
moleculescontains
contains
one
ionizable
functional
group.
The
pKa values
provided.
molecules
one
ionizable
functional
group.
The pK
havehave
beenbeen
provided.
a values
a. Match the pKa values provided with the appropriate functional groups. For each functional group,
b. For the
each
functional
indicate
whetherititiswould
identify
name
of thegroup
group
and whether
acidicbeorprimarily
basic. ionized or primarily unionized at a
b. Forfor
each
functional
indicate
whether
it would
primarily
primarily
at a
cefotaxime
at agroup
plasma
pH of 7.4,
nitrofurantoin
atbe
a urinary
pH ionized
of 6.1, aor
stomach
pH unionized
of 1.8.
stomach pH=1.8, a urinary pH=6.1, or a plasma pH=7.4. Provide an explanation for your responses for
cefotaxime
at a plasma pH=7.4, nitrofurantoin at a urinary pH=6.1, and atenolol at a stomach pH=1.8.
Cefotaxime
pKa = 3.4
Nitrofurantoin
Nitrofurantion
pKa = 7.1
Atenolol
pKa = 9.6
Drug (pKa Value)
Ezetimibe
pKa = 10.2
Stomach (pH=1.8)
Urine (pH=6.1)
Plasma (pH=7.4)
Cefotaxime
(3.4)
3. Shown
below is the structure of natamycin. It contains two functional groups that could be potentially ionized.
Nitrofurantoin (7.1)
The pKa values for natamycin are 4.6 and 8.4.
Atenolol (9.6)
Ezetimibe (10.2)
H3C
OH
O
O
OH
OH
COOH
11
C H3
12
Atenolol
pKa = 9.6
Ezetimibe
pKa = 10.2
2. In the previous question, we examined four pKa values in three different environments for a total
of 12 different scenarios. Which of these 12 scenarios allow you to use the Rule of Nines to calculate
the percent of ionization of the functional group in the specific environment? Identify the specific
scenarios and use the Rule of Nines to calculate the percent of the functional group that would be
ionized.
3. Shown
below is the structure of natamycin. It contains two functional groups that could be potentially ionized.

3. Shown below is the structure of natamycin. It contains two functional groups that could be potentially ionized. The pKa values for natamycin are 4.6 and 8.4.
H3C
OH
O
O
OH
OH
COOH
C H3
Natamycin
HO
OH
N H2
a. Match the pKa values provided to the appropriate functional groups and identify if the functional
group is acidic or basic.
b. Using the Henderson-Hasselbalch equation, calculate the percent ionization that occurs for each
of these functional groups at an intestinal pH=6.2.
4. The most basic functional group present within the structure of ranitidine has a pKa value of 8.2. Identify this
functional group and calculate the pH that is necessary for this functional group to be 70% ionized.
Page1of2
4. The most basic functional group present within the structure of ranitidine has a pKa=8.2. Identify this
Ranitidine

1.4 Salts and Solubility
1.4 molecules
Author Query
1. Some drug
can beResponse
formulated as either a potassium salt or hydrochloride salt. Evaluate all of
the acidic and basic functional groups in each of the drug molecules drawn below and fill in the grid with
the appropriate information.
OH
H
N
H 2N
CH 3
HO
H
OCH3
OH
N
O
Cl
Arformoterol
Baclofen
O
N
H 3C
F
N
O
H N
N N
CO2 H
HN
Irbesartan
Ciprofloxacin
H 3C
HO
CH 3
CH 3
OH
NH 2
OH
OH
OH O
Tetracycline


13
14
Name of Drug
Molecule
Is the Potassium
Name of Functional
Group That Can Form Salt Acidic, Basic, or
Neutral?
a Potassium Salt
Is the Hydrochloride
Salt Acidic, Basic, or
Neutral?
Name of Functional
Group That Can Form a
Hydrochloride Salt
2. Each of these drug molecules will treat a particular ailment by either managing a symptom or
modulating a biochemical pathway. In either case, the drug has to get to its biological target. Using your
knowledge about functional group character, describe how both of the drugs get to their respective
2. Eachtargets.
of theseConsider
drug molecules
will treat
a particular
ailment
by either managing
a symptom
or modubiological
the concepts
of solubility,
absorption,
distribution,
and route of
administration
lating a biochemical pathway. In either case, the drug has to get to its biological target. Using your
knowledge
about
functional
group
character,
describe
how
in your
answer. [pH
(stomach)
= 1; pH
(intestine)
= 8; pH
(plasma)
= both
7.4] of the drugs get to their respective
biological targets. Consider the concepts of solubility, absorption, distribution, and route of administration in your answer. [pH (stomach)=1; pH (intestine)=8; pH (plasma)=7.4]
NCH3
Cl
OH
CH2OH
CONH2
Scopolamine
Loperamide
Biological Targets and Routes of Administration

3. Based
on your structural
evaluation,
provide
a rationale
for whyoral
each
of these drugs cannot be
Loperamide:
opioid receptors
located
in the
large intestine;
administration
delivered
via an oralmuscarinic
route of administration,
or why there
limited in
absorption
of thenervous
drug when
it is
Scopolamine:
acetylcholine receptors
(M1)islocated
the peripheral
systems;
transdermal administration
administered orally.
3. Based on your structural evaluation, provide a rationale for why each of these drugs cannot be delivered via an oral route of administration, or why there is limited absorption of the drug when it is
Insulin Structure
PO3Na2
S
PO3Na2
H2N
A Chain
O H Asn Tyr Cys Asn COOH

H2N Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu
S
H2 N Phe Val Asn Gln His
Insulin
Alendronate
Leu Cys Gly Ser His
Leu Val Glu Ala Leu Tyr

Leu Val Cys
B chain
Gly Glu Arg
Gly
HOOC
Thr30
Lys29 Pro28
Thr27
Tyr
Phe Phe
nistered orally.
PO3Na2
PO3Na2
H2N
OH
Alendronate
Insulin
4. Based on your structural evaluation of embeconazole, answer the following questions:
Embeconazole
Can this be formulated as

a. a topical ointment or cream?
YES NO
b. an aqueous solution?
YES NO
c. Which structural features and corresponding characteristics did you consider when answering
each of these questions?

15

1.5 Drug Binding Interactions
1. Both delapril and lisinopril are inhibitors of angiotensin converting enzyme (biological target) and as such
are valuable drugs used in the management of hypertension. The active form of these drugs requires the
presence of two carboxylic acids or two functional groups that can participate in similar types of interactions
at physiological pH. One of the carboxylic acids interacts with an active site arginine residue, and the other
interacts with a Zn+2 atom. Both of these interactions are critical for drug action. Do the following:
a. Modify the molecules below to show the form of the active drug at physiological pH (pH=7.4).
b. Identify the type1.5
ofAnswer
interaction
possible
between the carboxylic acids and the residues present within
to Author
Queries
the biological target.
Zn+2
Delapril
Delapril

Zn+2
Lisinopril
Lisinopril

17
18
2. Tolterodine (Detrol), fesoterodine (Toviaz), and oxybutynin (Ditropan) are anticholinergic agents
used
inin
thethe
treatment
of overactive
bladder.
Based
on the
evaluation
process
described
in
used
treatment
of overactive
bladder.
Based
onstructure
the structure
evaluation
process
described
in
Chapter 6* and previous chapters,* read each of these drug molecules and determine how each
of these drug molecules interact via hydrogen bonding with the muscarinic receptor. Fill in the grid
provided with your answers.
Tolterodine
Fesoterodine
Oxybutynin
Function
Function
Name of
Functional Group
Name of ALL Anticholinergics

That Contain Functional Group

One amino acid that interacts (via side

chain) with the functional group via a
H-bond donor,
H-bond acceptor, complementary H-bonding interaction;
NONE is a possible answer
both or neither
19
3. Each
of the
three
odorant
molecules
drawn
below
produces
a unique
scent
interaction
with
the
3. Each
of the
three
odorant
molecules
drawn
below
produces
a unique
scent
on on
interaction
with
the
olfactory receptors. Unlike most biological targets for drug action, olfactory receptors typically have
olfactory
Unlike
most
biologicalmolecules
targets forand
drug
receptors typically
have an
an
affinityreceptors.
for a wide
variety
of odorant
canaction,
adoptolfactory
unique conformations
to enhance
the affinity of a given odorant for the receptor. Based on the structural features found in each molephysiological pH? Indicate which functional group(s) can participate in each of the interactions identified.
cule, what type of interactions are possible with the olfactory receptors at physiological pH? Indicate
which functional group(s) can participate in each of the interactions identified.
Sclareol
(herbal scent)
Sclareol
Interaction Type
Nerolidol
(green
(greenwoody
woody scent)
scent)
Vanillin
Vanillin
Functional Group
Nerolidol
Interaction Type
Functional Group
Interaction Type
Functional Group
van der
Waals,
van der
Waals,sweet, bitter, and umami
4. Waals,
There are five basic flavors van
thatderour
taste receptors detect: salty,
sour,
Hydrophobic
Hydrophobic
Hydrophobic
(savory).
locatedbond
on taste buds that are on our
tongue,
soft palate, epiglottis, and
Hydrogen
bond The taste receptors areHydrogen
Hydrogen
bond
(acceptor and donor)
(acceptor)
Iondipole
(as the dipole)
Hydrogen bond
(donor)
CO2 HIondipole
(as the dipole)
H 2N
CO2 H
Cucumber flavor
Glutamic Acid
Green Pepper Flavor

O
O
HO
HO
P
O
HO
OH
Shitaki Mushrooms
Inosinic Acid

Sclareol
(herbal
scent)
Vanillin

20
Medicinal
Chemistry
Self Assessment
Nerolidol
(green woody scent)
4. There are five basic flavors that our taste receptors detect: salty, sour, sweet, bitter, and umami
(savory). The taste receptors are located on taste buds that are on our tongue, soft palate, epiglottis,
and are
upper
Sour
andour
salty
flavors
are mediated
by ionsour,
channels,
sweet,
bitter,
4. There
fiveesophagus.
basic flavors
that
taste
receptors
detect: salty,
sweet,whereas
bitter, and
umami
and umami flavors are derived from activation of the respective G-protein coupled receptor. The
umami
is activated
by L-amino
acids,
interactions
(savory).
The receptor
taste receptors
are located
on taste
budsspecifically
that are onglutamate.
our tongue,Determine
soft palate,which
epiglottis,
and
are possible with the side chain of glutamate (at physiological pH) and then determine if any of the
following flavor molecules can interact with and activate this receptor.
CO2 H
H 2N
CO2 H
Cucumber flavor
Glutamic Acid
Green Pepper Flavor

O
O
HO
HO
P
O
HO
OH
Shitaki Mushrooms
Inosinic Acid

Note: References to chapters are to Chapter 6 in Harrold MW and Zavod RM, Basic Concepts in Medicinal
Chemistry, American Society of Health-System Pharmacists, 2013.
1.6 Stereochemistry and Drug Action
1.6
Stereochemistry and Drug Action
1. Shown below are the structures of acebutolol, estradiol, cefamandole, and nifedipine. For each of these
compounds, identify all chiral centers.
compounds, identify all chiral centers.
OH
OH
HO
HN
Estradiol
Acebutolol
H3C
OH
N
H
O
C H3
N
N
CO2 H
H
N
H3 CO2 C
CO2 CH3
NO2
Cefamandole
Nifedipine
2. For each of the four drug molecules shown in question 1:

a. Identify if it can have an enantiomer. Provide an explanation for your response.
b. Identify if it can have a diastereomer. Provide an explanation for your response.
c. Identify if it can have a geometric isomer. Provide an explanation for your response.

21
C H3

22 2.

Thesamestructurefonterroralsoappearsinquestion3withfluvastatinonpages32and129.Compare
thefontsoffluvastatininquestion3(toolarge)withthoseinquestion4(correctfontsize).Onpage
3. Shown129,thestructuresunderAnswerarecorrect,buttheonewithintheinitialquestionistoolarge.A
below is the structure of fluvastatin, an HMG-CoA reductase inhibitor used to lower plasma LDL levels.
replacementstructureisprovidedbelow.
3. Shown
below is the structure of fluvastatin, an HMG-CoA reductase inhibitor used to lower plasma
Fluvastatin
contains
two chiralcontains
centers, designated
as A anddesignated
B. Using the
fluvastatin
and the of
Cahn
LDL levels.
Fluvastatin
two chiral centers,
asstructure
1 and 2. of
Using
the structure
fluvastatin and the Cahn-Ingold-Prelog (CIP) system, determine the R/S configurations for each of its

Ingold-Prelog
(CIP) system, determine the R/S configurations for each of its chiral centers.
chiral centers.

HO 1
A
CO2 H
2 OH
F
N
Fluvastatin
Fluvastatin
4. Shown below is the enantiomer of fluvastatin. Which of the following properties/actions would
be expected to be identical for fluvastatin and its enantiomer and which would be expected to be
4. Shown
below is the enantiomer of fluvastatin. Which of the following properties/actions would be expected to
different?
a. Hepatic
metabolism
be identical
for fluvastatin
and its enantiomer and which would be expected to be different?
b. Water solubility
a. Hepatic metabolism
c. Adverse effect profile
Waterrenal
solubility
d. b. Active
reabsorption by transport proteins
e. Potency (dosage given)
f. Percent ionization at a pH=7.4
Enantiomer of
Fluvastatin

Page2of2

1.7
1.7 Drug Metabolism
Drug Metabolism
1.7
1. Heroin is a synthetic derivative of the naturally occurring opioid analgesic morphine. Given its illicit into
Drug Metabolism
morphine.
Which phase
I transformation
is responsible
for the
conversion
of heroin
to morphine?
1. Heroin
is a synthetic
derivative
of the naturally
occurring
opioid
analgesic
morphine.
Given its illicit nature,
heroin is not subject to Food and Drug Administration (FDA) regulation; therefore, the actual composition
of1.aHeroin
given heroin
batch derivative
varies significantly.
The three
molecules
below
represent
theitsthree
is a synthetic
of the naturally
occurring
opioid drawn
analgesic
morphine.
Given
illicit major
into
components found within a batch of heroin. The users intense rush has been attributed to the conversion
of heroin
intophase
morphine.
Which phase
I transformation
is responsible
for the
morphine.
Which
I transformation
is responsible
for the conversion
of heroin
toconversion
morphine? of heroin to
morphine?
Heroin
Morphine
Heroin
Morphine
2. Estradiol, the estrogen component of many oral contraceptives, undergoes a phase
II conjugation
reabsorbed (at least in part). Consider the structure of estradiol drawn below and do the following:
2. Estradiol, the estrogen component of many oral contraceptives, undergoes a phase II conjugation reaction to produce a metabolite that is eliminated via a fecal route (at least in part). The conjugated hormone
a. Modify the structure drawn below to show the product of a sulfate conjugation (phase II
2. Estradiol,
the estrogen
component of many
oral In
contraceptives,
undergoes
a phase is
II cleaved
conjugation
undergoes
a process
called enterohepatic
recycling.
this process the
sulfate conjugate
by gut
bacteria to regenerate
the
active
drug,
which
is
then
reabsorbed
(at
least
in
part).
Consider
the
structure
of
transformation).
reabsorbed
(at least
in and
part).do
Consider
the structure of estradiol drawn below and do the following:
estradiol
drawn
below
the following:
b. the
Which
enzymedrawn
is required
toto
make
this
sulfate
conjugate?
a. Modify
structure
below
show
the
product
of aofsulfate
conjugation
a. Modify
the structure
drawn
below
to show
the product
a sulfate
conjugation(phase
(phaseIIII
transformation).
c. Which deconjugating enzyme catalyzes removal of the sulfate group thus allowing for
transformation).
b. Which enzyme
is required to make this sulfate conjugate?
enterohepatic recycling?
c. Which
catalyzes
of the
sulfate group thus allowing for
b.deconjugating
Which enzyme enzyme
is required
to makeremoval
this sulfate
conjugate?

23
Estradiol
Estradiol
24
3. Metabolites do not necessarily have the same mechanism of action as the parent drug. In the case of
chlorimipramine (a tricyclic antidepressant that inhibits serotonin uptake), a phase I transformation
produces a metabolite that is also a tricyclic antidepressant, but whose mechanism of action is via
3. Metabolites do not of action as the parent drug. In the case of I transformations are possible?
inhibition
of norepinephrine reuptake. Which phase I transformation has occurred? What additional
3. Metabolites
do not of action
as the parent drug. In the case of I transformations are possible?
phase
I transformations
are possible?
Chlorimipramine
Chlorimipramine

4. Evaluate
each of
theoffollowing
transformations
and determine which phase I metabolic
4. Evaluate
each
the phase Imetabolic
metabolic transformation
has occurred.
transformation has occurred.
4. Evaluate each of the phase I metabolic transformation has occurred.
H
N
H
CN
H3
CF3
C H3
CF3 Dexfenfluramine
Dexfenfluramine
Fluvoxamine
C H 3N H
C H3
C H3
Fluvoxamine
N H2
CF3
CF3
C H3
Baclofen
Baclofen

Part 1 QUESTIONS
Section 2 Whole Molecule Drug

Evaluation

1.8
1.9
1.10
1.11
1.12
1.13
1.14
1.15
1.16
1.17
1.18
1.19
1.20
Aliskiren....................................................................... 27
Aripiprazole.................................................................. 31
Cefprozil....................................................................... 35
Cetirizine...................................................................... 39
Chlorpropamide and Other Sulfonylureas.................... 41
Dabigatran Etexilate.................................................... 43
Fenofibrate and Gemfibrozil......................................... 47
Fluvoxamine................................................................. 51
Haloperidol.................................................................. 55
Hydrocortisone............................................................. 57
Levothyroxine (T4)........................................................ 61
Lidocaine...................................................................... 65
Montelukast and Zafirlukast........................................ 69
1.21
1.22
1.23
1.24
1.25
1.26
1.27
Phenobarbital and Other Barbiturates......................... 71

Pravastatin and Fluvastatin.......................................... 73
Quinapril...................................................................... 75
Rivastigmine................................................................ 79
Sitagliptin..................................................................... 83
Sorafenib...................................................................... 87
Zanamivir and Oseltamivir........................................... 91

1.8 Aliskiren
Aliskiren is an orally active agent used in the treatment of hypertension. This non-peptide drug acts as an inhibitor
of renin, the enzyme that converts angiotensinogen (its endogenous substrate) to angiotensin I. Biologically inactive,
angiotensin I is rapidly converted to angiotensin II by angiotensin converting enzyme. Angiotensin II is a potent
agonist when bound to its receptor and produces significant vasoconstriction, as well as an increase in blood pressure.
In the presence of aliskiren, angiotensinogen is not converted to angiotensin I so less angiotensin II is produced to
activate the angiotensin II receptor. Consequently, less vasoconstriction occurs, and a drop in blood pressure results.
Medicinal Chemistry Self-Assessment Book: Batch Two
Chapters 1.8 and 2.8
1. Conduct a structural evaluation of aliskiren, focusing on the boxed functional groups, and use the infor(removetobold
drug name
x2)
mation in the grid toChapter
inform 1.8/2.8
your answers
the from
questions
that follow.
Aliskiren
Function
Character
Name of
Functional
Group
Function
Character
Acidic, Basic,
or Neutral
Function
Hydrophilic
and/or
Hydrophobic
Provide
pKa When
Relevant
Solubility
and/or
Absorption
Aliskiren
A
B
C
D
E
F

Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
27
Amino Acids That

Can Interact with the
Functional Group via
IonDipole Interactions
at pH=7.4
None Is Acceptable
B
28
Aliskiren
2. Aliskiren is marketed as the pure 2S, 4S, 5S,C7S enantiomer. Circle all of the chiral carbon atoms and
determine if diastereomeric or geometric isomers are possible.
Aliskiren
3. Although aliskiren is administered orally, its oral bioavailability is ~2.5% and is very poorly absorbed.
Using the information in the structure evaluation grid, provide a structural rationale for this unfortunate property.
4. Approximately 25% of the absorbed dose of aliskiren is excreted in the urine unchanged. It is
unknown how much of an absorbed dose is metabolized, and several metabolites from CYP3A4
mediated transformations have been identified. Several possible metabolic products are illustrated.
Identify which metabolic transformation has occurred and whether or not it represents an oxidative
transformation.

1.8 Aliskiren
Missing diagram for Question #4 (Chapter 1.8/2.8)
Name of Metabolic Transformation

A
B
C
D
E

Oxidative or Non-Oxidative
29
30
5. Renin catalyzes the cleavage of a specific Leu-Val peptide bond within the structure of angiotensinogen. The structure of aliskiren contains functional groups that mimic the side chains for these two
amino acids. The hydrolyzable peptide bond (found between Leu-Val) has been replaced by a non1. Page 30
Question
5: font size.
hydrolyzable hydroxyethylene
group
in aliskiren.
Circle the functional groups that mimic the amino
acid side chains of these two amino acids and box the non-hydrolyzable hydroxyethylene group.
(remove bold from drug name) Chapter 2.8
2. Page 35 Introduction to 1.10 and page 143:

6. Aliskiren can be co-administered with other anti-hypertensive agents to provide better hypertension
management. Amlodipine is a second generation dihydropyridine calcium
channel blocker used in
Aliskiren
N H 2 H and amlodipine are both plasma protein bound (4751%
the treatment of hypertension. Aliskiren
and 9397%, respectively). How likely isNit H
thatHa plasma
protein binding interaction will occur if
S
these drugs are co-administered?
(remove bold from drug name) Chapter 1.8/2.8
O
HO
C H3
CO2 H
Cefprozil
3. Page 45 Question 6 and page 164:

O O
Amlodipine S
H3 C
O
O
H3 C
N
N
N H2
N
N
N
C H3
Dabigatran etexilate mesylate

O
O(CH2 )5 CH3
1.9 Aripiprazole
1.9 Aripiprazole
Shown below is the structure of aripiprazole, a serotonin receptor modulator used for the treatment of depression,
schizophrenia,
autism,
mania,
and bipolar disorder.
Shown
below is the
structure
of aripiprazole,
a serotonin receptor modulator used for the treatment of depression,
schizophrenia, autism, mania, and bipolar disorder.
H
N
Cl
Cl
N
Aripiprazole
1. Identify
of theallacidic
1. all
Identify
of theand
pH basic
of 5.6.functional groups, provide the normal pKa range for each of the identified functional groups, and identify if each functional group would be primarily ionized or unionized at a
solubility of aripiprazole.
urine 2.
pH=5.6.
3. Using yur answers previously listed.

4. all
Drug
hly aripiprazole
and either groups,
tolbutamide
losartan?
2. Identify
of the
remaining functional
andor
indicate
how each group contributes to the overall
water solubility or the overall lipid solubility of aripiprazole.
3. Using your answers from the previous two questions, provide an explanation as to why aripiprazole can be
administered orally for the indications previously listed.
Tolbutamide
Losartan
5. Assume that at a physiological pH of 7.4.

31
N
32
Aripiprazole
1. Identify all of the pH of 5.6.
Aripiprazole
2. solubility of aripiprazole.
4. 1.
Drug
molecules
that
areofpreviously
highly
3.Identify
Usingall
yurofanswers
listed.protein bound may undergo a drug interaction due to the
the pH
5.6. plasma
displacement of one drug molecule from a plasma protein by another drug molecule. Shown below
4.solubility
Drug
hlyofaripiprazole
and either
tolbutamide
or losartan?
2.
aripiprazole.
are
the
structures
of tolbutamide
and
losartan. Both
of these drugs are highly plasma protein bound.
Aripiprazole
is
also
highly
plasma
protein
bound
(>99%).
Would you expect there to be a drug inter3. Using yur answers previously listed.
action between aripiprazole and either tolbutamide or losartan?
4. Drug hly aripiprazole and either tolbutamide or losartan?
Tolbutamide
Tolbutamide
Losartan
Losartan
5. Assume
that
the
boxed
functional
groups
of
aripiprazole
form
four
key
binding interactions with
5. Assume that at a physiological pH of 7.4.
a serotonin receptor. Further assume that these binding interactions occur with the side chains of
Tyr, Asp, Ile, and Gln. Using this information, identify four possible binding interactions between
aripiprazole
andatthe
given aminopH
acids.
Assume that this binding interaction occurs at a physiological
5.
Assume that
a physiological
of 7.4.
D
pH=7.4.
A
C
B
C
B
Aripiprazole
Aripiprazole

1.9 Aripiprazole
33
6. Shown below are three known metabolites of aripiprazole. Identify the metabolic transformations that
6. Shown below are three known metabolites of aripiprazole. Identify the metabolic transformations
would be required to form each of the metabolites. For each metabolic transformation, indicate if it is
that would be required to form each of the metabolites. For each metabolic transformation, indicate
aifphase
I transformation
or a phase
transformation.
it is a phase
I transformation
or aII phase
II transformation.
O
H
N
Cl
Cl
N
HO
Metabolite A
H
N
Cl
Cl
OH
N
Metabolite B
H
N
Cl
Cl
OH
N
NH
HO
O
Metabolite C


1. Page 30 Question 5: font size.
1.10 Cefprozil
Cefprozil is a second-generation cephalosporin that exhibits good Gram (+) activity with improved Gram () activity
as compared to the first-generation cephalosporins. Effective against the majority of bacteria that cause upper and
lower respiratory infections, as well as skin infections, cefprozil was a first-line anti-infective agent until an increase in
2. Page 35ofIntroduction
to decreased
1.10 and page
143: status.
the incidence of resistance and the development
newer agents
its favored
N H2
H
N
HO
C H3
CO2 H
Cefprozil
1. Conduct a complete structural evaluation of cefprozil and use the information in the grid to inform your
answers to the questions that follow.
Character
Name of
Functional
Group
Function
Acidic, Basic,
or Neutral
H3 C
Solubility
and/or
Provide O
pKa
O
When Relevant Absorption
Hydrophilic
and/or
Hydrophobic
H3 C
Character
Function
Interaction(s)
Possible with
O Biological Target
Hat Physiological
H
pH=7.4
C H3

35
Amino Acids That

Can Interact with
H-Bonding (at pH=7.4)
N H2
None Is Acceptable
N
N
Function
O(CH2 )5 CH3
36
2. Based on the information in the structure evaluation grid, determine if cefprozil is an acidic, basic, or
amphoteric drug. Provide a brief explanation for your answer.
3. Cefprozil is administered orally as a tablet or liquid suspension. Consider each of the acidic and basic
functional groups and determine whether each group will be predominantly ionized or unionized
as it moves through the gastrointestinal (GI) tract, into systemic circulation, and then into the urine.
[The relevant pKa values=10, 1.7, and 7.2.] Complete the grid below.
Name of
Functional
Group
Acidic or
Basic
(pKa)
Ionized or
Unionized at
pH=5 (saliva)
Ionized or
Unionized
at pH=1
(stomach)
Ionized or
Unionized
at pH=7.4
(plasma)
Ionized or
Unionized at
pH=8
(intestine)
Ionized or
Unionized at
pH=6 (urine)
4. Given the predominant ionization state of these acidic and basic functional groups as they
traverse the GI tract and the information in the structure evaluation grid, determine in which GI
compartment(s) drug absorption could occur.

1.10 Cefprozil
37
5. Approximately 60% of a cefprozil dose is recovered in the urine unchanged. Because impairment in
Cefprozil
(Cefzil) the half-life of the drug by several hours, it is likely that cefprozil underhepatic function
increases
goes a variety of metabolic transformations catalyzed by liver enzymes. For each of the metabolic
transformations AF, identify which metabolic transformation has occurred and whether the product
Chpater
Corrected
(product
E transformation)
formed1.10/2.10
was the result
of a structure
phase I or
phase of
II metabolic
transformation.
N
O
HO
N
O
HO
H H
H H
CH 3
CO2 H
N H2
NH 2
HO
OH
C H3
CO2 H
HO
H 2N
H
N
H H
N
O
HO
CH 3
CO2 H
C
N H2
C H3
CO2H
NH 2
H
N
HO
H H
N
O
CH 3
N H2
N H
O
-O
OH
NH 2
H
N
HO
H H
S
O
OH
CO2 H
Name of Transformation
A
B
C
D
E
F

C H3
CO2 H
H
N
Phase I or Phase II
38
6. Like the penicillins, the cephalosporins suffer from chemical instability of the -lactam bond. Chemical hydrolysis of this bond renders the drugs in the class of anti-infective agents inactive. This bond
is also subject to cleavage by -lactamases (due to the presence of a nucleophilic serine side chain
[CH2OH] within the active site of the enzyme). Show how the -lactam bond can be hydrolyzed by
chemical and enzymatic (-lactamase) mechanisms.

1.11 Cetirizine
Cetirizine is a popular second-generation antihistamine used in the management of allergy symptoms. It is the
metabolic byproduct produced Medicinal
from the prescription
hydroxyzine.
Although
Chemistryantihistamine
Self-Assessment
Book: Batch
Twocetirizine is labeled as
non-sedating and is one of the preferred allergy medications
for long-haul
Chapters 1.11
and 2.11 drivers, hydroxyzine causes significant
drowsiness that limits its utility in the management of typical allergy symptoms. Hydroxyzine is commonly used in
the treatment of pruritus (severe itching).
Chapter 1.11 (remove bolded drug names)
Cetirizine
Hydroxyzine
1. Conduct a complete structural evaluation of hydroxyzine and use the information in the grid to inform
your answers to the questions that follow.
Function
Character E
D
Acidic, Basic, or Function

Neutral
Solubility
and/or
Provide pKa
Character
Hydrophilic
and/or
Hydrophobic
Name of
Functional
Group
Function
Hydroxyzine

39
Amino Acids That

Can Interact with
Interaction(s)
Functional Group
Possible with
Biological Target via H-Bonding (at
pH=7.4)
at Physiological
None Is Acceptable
pH=7.4
40
2. Name the phase I metabolic transformation(s) that hydroxyzine undergoes to produce cetirizine.
3. Based on your structural evaluation of both hydroxyzine and cetirizine, name ALL of the phase I
metabolic transformations possible.
4. A metabolic product from a phase II metabolic transformation has been identified. Which phase II
transformations can cetirizine undergo?
5. Review the structure of cetirizine (pKa=2.9 and 8.3) and identify all of the acidic and basic functional
groups present. Determine the predominant ionization state of each functional group as it travels
through several compartments of the body after oral administration. Complete the table below.
Name of
Functional
Group
Acidic or
Basic
(pKa)
Ionized or
Unionized at
pH=5 (saliva)
Ionized or
Unionized
at pH=1
(stomach)
Ionized or
Unionized
at pH=7.4
(plasma)
Ionized or
Unionized at
pH=8
(intestine)
Ionized or
Unionized at
pH=6 (urine)
6. Provide a structural rationale for why hydroxyzine is classified as a sedating antihistamine and cetirizine is categorized as a non-sedating antihistamine.

1.12 Chlorpropamide and

Other Sulfonylureas
1.12 Chlorpropamideand Other Sulfonylureas
Shown below are the structures of tolbutamide and chlorpropamide. These drug molecules are used in the treatment of type 2 diabetes mellitus. They stimulate the release of insulin from the pancreatic -cells by interacting with
Shown below are the structures of tolbutamide and chlorpropamid of ATP)-sensitive potassium channels.
adenosine triphosphate (ATP)-sensitive potassium channels.
Shown below are the structures of tolbutamide and chlorpropamid of ATP)-sensitive potassium channels.
Tolbutamide
Chlorpropamide
1. It is not uncommon for patients with type 2 diabetes to be dually diag and require additional occur?
1. It is not uncommon for patients with type 2 diabetes to be dually diagnosed with hypertension and
Tolbutamide
Chlorpropamide
require additional pharmacotherapy. In this scenario, it is possible for drug interactions to occur if the
prescribed combination therapy is not appropriately evaluated. Angiotensin II receptor antagonists,
commonly known as angiotensin II receptor blockers (ARBs), are often used to treat hypertension.
Losartan (shown below) is an ARB, and similar to tolbutamide and chlorpropamide, is highly plasma
1.protein
It is not
uncommon
for patients
with type
diabetes
to be dually
and require
occur?
bound.
If losartan
was selected
for2use
in a patient
who diag
is already
takingadditional
tolbutamide
or chlorpropamide, would you anticipate that a drug interaction could occur?
Losartan
Losartan
comparing the pKa values of chlorpropamide.
2. The normal pKa range for sulfonylureas is 5 to 6. When
3. Using your answer from percent of tolbutamide that will be ionized at an intestinal pH of 6.1.
sulfonylureas
is 5 to 6.groups.
When comparing the pKa values of chlorpropamide.
2. The
pKa rangeofforaction
4. normal
The mechanism
of ion functional
3. Using
your answerhas
from
percent has
of tolbutamide
thatlonger
will behalf-life
ionizedthan
at antolbutamide.
intestinal pH of 6.1.
5. Tolbutamide
a half-life
a significantly
4. The
of is
action
of ionpathways
functionalthat
groups.
6. mechanism
Shown below
a known
are required to produce this metabolite.
41
5. Tolbutamide has a half-life has a significantly longer half-life than tolbutamide.
42
Replacementstructurefortheanswertoquestion2inChapter2.9(Aripiprazole)

2. The normal pKa range for sulfonylureas
is 5 to 6.
When comparing the pKa values of chlorpropamide
Alkyl (aliphatic)
chain
and tolbutamide, it is found that the(Lipid
sulfonylurea
soluble) of one of these drug molecules has a pKa=5.4 and
the other has a pKa=4.9. Evaluate the structures of Ether
theseoxygen
two drug molecules, assign the pKa values to
soluble)
Amide
the correct molecules, andHalogens
provide an explanation(Water
for the
difference in pKa values.
(Water soluble)
(Lipid soluble)
3. Using your answer from question 2, calculate the percent of tolbutamide that will be ionized at an
Hydrocarbon portion
intestinal pH=6.1.
of bicyclic ring
(Lipid soluble)
Aromatic (phenyl) ring
soluble) of action of this class of drugs involves the ability to interact with the ATP-sensitive
4. The(Lipid
mechanism
potassium channels in the pancreas. Using the structure of tolbutamide, identify the types of binding
Aripiprazole
interactions that are possible between its functional groups
and a protein ion channel. Also identify
amino acids present within this ion channel whose side chains could participate in the interactions
identified. Assume a plasma pH=7.4 for all ionizable functional groups.
Alkyl (aliphatic) chain
(Lipid soluble)
5. Tolbutamide has a half-life of 4.5 to 6.5 hours, whereas chlorpropamide has a half-life of 36 hours.
Propose a chemical/structural reason why chlorpropamide has a significantly longer half-life than
tolbutamide.
Replacement structure for question 6 in BOTH Chapters 1.12 and 2.12 (Chlorpropamide and Other
Sulfonylureas)
6. Glyburide is a second-generation sulfonylurea that is structurally similar to chlorpropamide and
tolbutamide. Shown below are the structures of glyburide and one of its known metabolites. Identify
the metabolic pathways that are required to produce this metabolite.
Cl
S
N
H
O
H3C
N
H
N
H
Glyburide
H3C
N
H
N
H
Metabolite of glyburide

OH
N
H
1.13 Dabigatran Etexilate
Thrombin is the enzyme responsible for catalyzing the conversion of fibrinogen to fibrin. The production of fibrin is
important in the formation of sturdy blood clots. As you might expect, inhibition of thrombin prevents the formation of fibrin. As shown in the diagram below, a catalytic triad of amino acids (Asp, His, Ser) found in the active site
of thrombin is responsible for hydrolyzing a key peptide bond found within fibrinogen. Orientation of fibrinogen in
Concern
about of
His
(revised
diagram
+ removed
bolded names)
the active site ofChapters
thrombin1.13/2.13
relies on the
interaction
a key
tri-peptide
sequence
(D-Phe-Pro-Arg)
found within the
structure fibrinogen with key amino acids in the enzyme active site.
Chapters
1.13/2.13
Concern about
(revised
diagram
+ removed
boldedetexilate
names)is an orally active direct
Dabigatran
etexilate
is administered
as a His
prodrug.
In its
active form,
dabigatran
Thrombin
Activeand
Site
thrombin inhibitor used in the prevention
of stroke
blood clots in patients diagnosed with atrialThrombin
fibrillation.Active Site
Thrombin Active Site

Thrombin catalyzed
amide hydrolysis
Thrombin catalyzed
amide hydrolysis
Fibrinogen (D-Phe-Pro-Arg)
Fibrin
Chapters 1.13/2.13 (removed bold in drug name)
Fibrin
Dabigatran etexilate
Dabigatran
Chapters 1.13/2.13 (removed
bold andetexilate
centered text)
Chapters 1.13/2.13 (removed bold and centered text)

43
44
Chapters 1.13/2.13 Concern about His (revised diagram + removed bolded names)
Thrombin
Active(prodrug)
Site
1. Conduct a complete structural evaluation of dabigatran
etexilate
and use the information
in the grid to inform your answers to the questions that follow.
Function
Character
Name of
Functional
Group
Function
Character
Acidic, Basic,
or Neutral
Function
Hydrophilic
and/or
Hydrophobic
Provide pKa
When
Relevant
Solubility
and/or
Absorption
Thrombin catalyzed
amide hydrolysis
Amino Acids That
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
Can Interact with

Functional Group
via H-Bonding (at
pH=7.4)
None Is Acceptable
Fibrin

2. Dabigatran etexilate is a non-peptidomimetic prodrug. Provide a brief rationale for the value of
converting an active drug into a prodrug.
3. Dabigatran etexilate rapidly undergoes two esterase-catalyzed hydrolytic reactions to the active drug
dabigatran. Show the products from each of the esterase-catalyzed hydrolytic reactions that occur in
the plasma.
4. In its active form, dabigatran mimics the D-Phe-Pro-Arg tripeptide sequence, but does not contain a
peptide backbone (non-peptidomimetic). Review the tripeptide sequence drawn below noting that
there are numbers 13 that indicate
where
each amino
acid is
located
in the sequence.
Determine the
Chapters
1.13/2.13
(removed
bold
and centered
text)
types of interactions possible with each of the amino acid side chains.
D-Phe-Pro-Arg Tripeptide Sequence

Throm
45
5. Review the structure of dabigatran and determine which of the boxed groups will likely mimic the
interactions found within the D-Phe-Pro-Arg tripeptide sequence. Given the three-dimensional
nature of both peptides and small molecules, it is important to remember that the functional groups
within dabigatran do not need to line up in the same order. Using the table provided to guide your
Chapters
1.13/2.13
(removed
bolded
text) the functional group could mimic the
analysis, place a Yes
or No in
each box
to indicate
whether
amino acid side chain indicated.
A IntroductionBto 1.10 and page 143:

2. Page 35
D
N H2
H
N
HO
C H3
CO2 H
Cefprozil
Active form of Dabigatran
6. Dabigatran etexilate
is formulated
as(removed
a mesylate
salt.
Provide
Chapters
1.13/2.13
bold
drug
name)a brief rationale for the value of
3. the
Page
Question
6 and page 164:
administering
salt45
form
of a drug.
O
O
H3 C
O
H3 C
N H2
N
C H3
Dabigatran
etexilate
mesylate
Dabigatran
etexilate
mesylate

O
N
O(CH2 )5 CH3

1.14 Fenofibrate and Gemfibrozil
Fenofibrate is a member of the fibrate class of anti-hyperlipidemic agents. It is used as adjunct therapy to diet in the
management of dyslipidemias, including in the treatment of severe hypertriglyceridemia. The specific mechanism(s)
by which fenofibrate decreases triglyceride and total cholesterol levels, as well as increases the levels of high density
lipoproteins (HDL), is unknown. What we do know is that the decrease in very low density lipoproteins (VLDLs)
1.14 and 2.14 (drug name remove bold)
results from fenofibrate stimulation of lipoprotein lipase.
Fenofibrate
Gemfibrozil
1. Conduct a complete structural

evaluation
of bold
fenofibrate and use the information in the grid to inform
Letter
C add
Function
Character
Character
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Function
Function
Acidic, Basic, or
Neutral
Solubility
and/or
Absorption
Provide pKa
When Relevant
Interaction(s)
Possible with Biological
Target at Physiological
pH=7.4
2.14 remove bold from label
B
A
F
C
E
Fenofibrate
2.14 remove bold from

label
47
Amino Acids That

Hydrogen Bonding
Interactions at pH=7.4
None Is Acceptable
48
Fenofibrate
2. Fenofibrate is administered as a prodrug and undergoes hydrolysis to the active drug. Draw the
active drug. Provide a brief rationale for the value of administering fenofibrate as a prodrug.
1. Conduct a complete structural follow:
2. calculated
Fenofibrate
is of
administering
fenofibrate
as a prodrug.
3. The
P (drug
for
fenofibrate
is 5.24,
whereas
the calculated log P for gemfibrozil is 3.9.
1.14 andlog
2.14
name remove
bold)
Provide a structural rationale for the difference in this pharmacokinetic property.
3. The calculated in this pharmacokinetic property.
Fenofibrate
Gemfibrozil
Fenofibrate
Gemfibrozil
Letter
C addperspective,
bold
4. From an
elimination
60% of a fenofibrate dose is found
in the urine and 25% is found
1.14
and
2.14
(drug
name
remove
bold)
in the feces. The active form of fenofibrate undergoes both phase I and phase II metabolic transformations. The phase II conjugate is eliminated in the urine. Oxidative metabolism does not occur.
Evaluate
of the metabolic
products
it is the conjugate
eliminated
4. Fromeach
an elimination
perspective,
60%and
of a determine
ve phase I iftransformation
(that that
doesisNOT
occur). in the
urine (that does occur), the product of a non-oxidative phase I transformation (that does occur), or
the product of an oxidative phase I transformation (that does NOT occur).
O
HO
O
C
H3 C
Cl
OH
C Fenofibrate
H3
Gemfibrozil

ALetter C add bold
B
A
F
D
E
CC
Fenofibrate

Name
Metabolic
Transformation
Type of Product
2.14of
remove
bold
from label
BO
A
Cl
O
H3C
C H3
OC
Ester
Hydrolysis
C H3
C H3
O
H3C
Cl
Inactive
Fenofibrate
Active
OH
C H3
5. Provide a structural rationale for why oxidative O-dealkylation does not occur.
6. Fenofibrate and gemfibrozil have dramatically different elimination half-lives (2022 hours and 1.5
Identify the possible metabolic transformations for gemfibrozil and provide a
1.14 and 2.14 (drughours,
name respectively).
remove bold)
justification for the significant difference in this pharmacokinetic parameter.
Fenofibrate
Gemfibrozil
Letter C add bold
B
A
F
D
E
Fenofibrate
O
O
Cl
H3C
C H3
O
C H3
C H3
Inactive

Ester
Hydrolysis
O
O
H3C
Cl
Active
OH
C H3
49


O
O
O
H3C
Cl
OH
1.15 Fluvoxamine
C H3
Fenofibric Acid
Fluvoxamine is an inhibitor of the serotonin reuptake transporter (SERT) and prevents the reuptake of serotonin
at the presynaptic membrane in the central
nervous system. It is indicated for use in the treatment of depression.
1.15 and 2.15 remove bold from label
Fluvoxamine is structurally unique relative to the rest of the serotonin selective reuptake inhibitor class of drugs.
A
B
D
Fluvoxamine
and 2.15 remove

bold
label functional groups, and use the
1. Conduct a structural evaluation 1.15
of fluvoxamine,
focusing
onfrom
the boxed
information in the grid to inform your answers to the questions that follow.
F3 C
Function
Character
Name of
Functional
Group
Character
Acidic, Basic,
NH3
N
OFunction
or Neutral
Hydrophilic
and/or
Hydrophobic
Provide
Solubility
pKa When
and/or
Fluvoxamine
maleate
Absorption
Relevant
A
B
C
D
E

51
Function
C H3
Interaction(s)
O
Possible
Owith
Biological
Target
at Physiological
pH=7.4
Amino Acids That

O
Hydrogen
Bonding
Interactions at
OH
pH=7.4
None Is Acceptable
structures.Onpages62and180,theatomfontonfluvoxamineinquestion2seemstobetoobig.The
structureoffluvoxamineappearsinquestions2and3.Thestructuresarethesamesize,butthefonts
aredifferent.Thefontforthestructureinquestion3iscorrect,whilethefontforthestructurein
Fenofibric Acid
52 question2appearstobelarger.Ihaveprovidedareplacementstructurebelowforquestion2onpages
62and180.

2.
Fluvoxamine is marketed as a single isomer. Is the product sold as a single enantiomer, diastereomer,
or geometric isomer? Provide a brief rationale for your answer.

A
1'
2'
2'
1'
Fluvoxamine
3.
is formulated as a maleate salt. What type of salt is a maleate salt, and what type of
2. Fluvoxamine
Thesamestructurefonterroralsoappearsinquestion3withfluvastatinonpages32and129.Compare
properties does it confer to the overall properties of the drug?

129,thestructuresunderAnswerarecorrect,buttheonewithintheinitialquestionistoolarge.A
F3 C
O
N
C H3
NH3
HO 1
Fluvoxamine maleate
O
OH
CO2 H
2 OH
H
F
4. Fluvoxamine is well absorbed and has an oral bioavailability of ~50%. Using the information found in
the structure evaluation grid, provide a rationale forNthese pharmacokinetic properties.
Fluvastatin

1.15 Fluvoxamine
53
5. A number of fluvoxamine metabolites have been identified, all of which demonstrate little or no
pharmacological activity. Evaluate each of the metabolic products drawn below and identify which
metabolic transformation has occurred.

A
B
C
D
E
F
6. Fluvoxamine is a strong inhibitor of CYP1A2, CYP3A4, and CYP2C19. These enzyme isoforms catalyze
a number of the phase I oxidative metabolic transformations. Several of the benzodiazepines (used
in the treatment of anxiety), including the very popular alprazolam, rely heavily on hepatic oxidation
for metabolic inactivation and elimination. Other benzodiazepines, including the equally popular
lorazepam, rely on glucuronide conjugation for metabolic inactivation and elimination. Which
combination of drugs, fluvoxamine + alprazolam or fluvoxamine + lorazepam, is the most likely to
generate an enhanced anxiolytic effect?


1.16 Haloperidol
Shown below is the structure of haloperidol. Six of its functional groups have been identified.
E
C
1. Using1.theUsing
tablethe
below, identify the six boxed functional groups. For each of the functional groups you
identified, indicate if it is hydrophilic or hydrophobic in character. Also provide a brief explanation for
2. Based on or induction.
your response.
3. Using the.4, and 8.5.
C
D
E
F
2. Based on their electronic properties AND their
B relative positions in the molecule, identify if functional
groups
C, andbelow
E are modification
electron withdrawing
orthe
electron
donating.
Additionally, identify if this effect is
4. A,Shown
can enhance
duration
of haloperidol.
1. Using the
3. Using2.theBased
unmodified
structure of haloperidol and the table below, identify all of the acidic and basic
on or induction.
functional groups present in the structure, provide the normal pKa range for each functional group, and
3. ifUsing
and 8.5.
identify
eachthe.4,
functional
group would be primarily ionized or unionized in pH environments=1.7, 5.5,
6.0, 7.4, and 8.5.
5. Using the table below, identify the groups.

4. Shown below modification can enhance the duration of haloperidol.
C
55 B
2. Based
on or8.5.
induction.
3. Using
the.4, and

56
Functional Group
Acidic or
Basic
pKa Range
Primarily Ionized or Unionized

F
1.7
5.5
6.0
7.4
8.5
1.below
Using
the
4.
is
a structural
analog
of haloperidol.
the structural change and propose an
4. Shown
Shown
below
modification
can
enhance
the duration Evaluate
of haloperidol.
explanation
as toonhow
this structural modification can enhance the duration of haloperidol.
2.
Based
or
induction.
4. Shown below modification can enhance the duration of haloperidol.
5. Using the table below, identify the types of binding interactions that are possible between the
5. Using the table below, identify the groups.
boxed4.functional
groups
and a protein
receptor the
or enzyme.
identify amino acids present within
Shown below
modification
can enhance
duration Also
of haloperidol.
5. Using
table below,
the groups.
a receptor
orthe
enzyme
whoseidentify
side chains
could participate in the interactions that you identified.
Assume a plasma pH=7.4 for all ionizable functional groups.
C
C
B
6. Shown below is the perform with haloperidol.

6. 5.
Shown
below
is thebelow,
perform
with haloperidol.
Using
theGroup
table
identify
the groups.
Functional
Types
of Binding
Interactions
Amino Acids Capable of Forming

Specific Binding Interaction
B
C
D
D
A
6. Shown below is the structure of haloperidol and a list of five metabolic transformations. For each
metabolic transformation, indicate if it is a phase I or a phase II transformation and if haloperidol has
a functional group present that can participate in the transformation. If you answer YES, then draw
the appropriate metabolite; if you answer NO, then provide a brief explanation as to why this metabolic transformation
is not
possible
perform
with haloperidol.
6. Shown below
is the
performtowith
haloperidol.
Metabolic Pathways
A. Reduction
B. Sulfate Conjugation
C. Hydrolysis
D. Oxidative N-Dealkylation
E. Benzylic Oxidation
1.17 Hydrocortisone
Hydrocortisone is a glucocorticoid used in the management of inflammation. Derivatives of hydrocortisone are used
in the management of asthma and chronic obstructive pulmonary disease.
1.17 and 2.17
remove bold and
fromuse
label
1. Conduct a complete structural evaluation
of hydrocortisone
the information in the grid to inform
E
C
F
B
D
Hydrocortisone
Function
Question
#3 structure needs to be replaced:
Character
Name of
Functional
Group
Character
Acidic, Basic,
or Neutral
Function
Hydrophilic
and/or
Hydrophobic
Provide
pKa When
Relevant
Solubility
21
and/or
Absorption
Interaction(s)
Possible with
Biological
Target
at Physiological
pH=7.4
17
11
B
C
D
E
HO

I
O
E
OH
N H2
57
Function
Amino Acids That
at pH=7.4
None Is Acceptable
58
2. The glucocorticoids interact with residues within the glucocorticoid receptor (Arg611, Asn564, Thr739,
Gln642, and Gln570) via hydrogen bonding and iondipole interactions at physiological pH (7.4). Identify which functional groups could interact with the side chains of these amino acids.
Functional
Group
Can Interact with Arginine611

via an IonDipole Interaction
Can Interact with

Asparagine564 and Threonine739
via a Hydrogen Bonding
Interaction
Can Interact with

Glutamine642 and
Glutamine570 via a
Hydrogen Bonding
Interaction
Yes or No
Yes or No
Yes or No
A
B
D
E
3. Several of the functional groups identified in the structure evaluation grid are essential for biological
activity. There are several metabolic transformations D
that render the glucocorticoids inactive. These
A
transformations include the following:
1. Ring A ketone reduction
Hydrocortisone
2. Ring A double bond reduction

3. C-17 oxidation
4. C-11 oxidation
Question #3 structure needs to be replaced:
21
11
17
Based on this information, consider the array of products drawn in the scheme that follows. Identify each type of reaction or transformation that has occurred and evaluate each of the products to
1.18or
and
determine if each product is active
inactive.
HO
I
I
I
N H2
I
L-Thyroxine
E
OH
1.17 Hydrocortisone
F
11
17
21
E
D
Pathway
Type of Reaction or Transformation
A
B
C
D
E
F

Active or Inactive
59
60
4. The glucocorticoids
synthetic solubleare
ester
is present.
formation
an effectprodrugs.
on overall Both
drug water
solubility.
4. The synthetic
often
esterified
at C-21has
to produce
lipophilic
and
water soluble esters can be formed. Evaluate each of the four prodrugs drawn below and determine
whether a lipophilic or water soluble ester is present. Determine how prodrug formation has an
effect on overall drug water solubility.
C
Type of Ester Formed
Effect on Overall Drug Water Solubility
A
B
C
D
a. Provide a structural rationale for why prodrugs (e.g., B and D) are used in the preparation of
aqueous injectable products to be administered intramuscularly (IM) or intravenously (IV).
b. Provide a structural rationale for why prodrugs (e.g., A and C) are used in the preparation of
depot injections.
5. Lipophilic glucocorticoid esters typically do not concentrate in the urine, but rather undergo glomerular
filtration followed by tubular reabsorption. Provide a brief rationale for why lipophilic glucocorticoid
esters do not concentrate in the urine and determine what effect this has on duration of drug action.
6. Which type of prodrug, water soluble ester salts, or lipophilic esters, would you anticipate to have
greater systemic side effects?

C
F
B
D
A
Section
2 Whole Molecule Drug Evaluation
Hydrocortisone
1.18 Levothyroxine (T4)

21
17
11
Levothyroxine (T4) is a naturally produced thyroid pro-hormone.
In its active form, tri-iodo-L-thyronine (T3) is
responsible for regulating oxygen consumption and calorigenesis (think metabolism, metabolic rate, and thermogenA
molecules until it is needed. Once proteolyzed from thyroglobesis). T4 is biosynthesized and stored in thyroglobulin
ulin and transported to the desired target tissue, T4 undergoes dehalogenation catalyzed by thyroxine dehalogenase to
the active thyroid hormone T3.
1. Conduct a structural evaluation

of Tand
, focusing
on thebold
boxed
functional
groups, and use the information in
4
1.18
2.18 remove
from
label
the grid to inform your answers to the questions that follow.
HO
I
I
E
OH
N H2
L-Thyroxine
Function
Character
Name of
Functional
Group
Character
Acidic, Basic,
or Neutral
Hydrophilic
and/or
Hydrophobic
Provide
pKa When
Relevant
Function
Function
Solubility
and/or
Absorption
A
B
C
D
E

61
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
Amino Acids That

Functional Group
via H-Bonding
Interactions at pH=7.4
None Is Acceptable
HO
OH
N H2
I62 Tri-iodothyronine
O
Medicinal
Chemistry Self Assessment
2. 2.18
Hormone
replacement
1.18 and
remove
bold from
L-Thyroxine
(T4label
)therapy in the form of levothyroxine (T4) is available for those patients who
<DAVID_-change caption to Levothyroxine>
do not produce an adequate endogenous supply of T4. Evaluate the structure of levothyroxine and
determine if it is an enantiomer, diastereomer, or geometric isomer.
O
I isomer.
O
2.
Hormone
replacement therapy in the geometric
H 2N
I
OH
HO
H
OH
O
I
H NH
I
2
HO
O
I
OH
OH
H I NH
2
I
O
L-Tyrosine
Levothyroxine
I
Levothyroxine
3. Evaluate the chiral carbon atom in levothyroxine to determine if this drug is drawn as the R- or
S-enantiomer.
3. Evaluate the chiral to determine if this drug is drawn as the R- or S-enantiomer.

4. T3 is the biologically active hormone. It interacts with the thyroid hormone receptor via hydrogen
bonding,
iondipole,
hydrophobic,
and ionic interactions. Evaluate the ribbon diagram that shows
4. T3 is the
in the structure
evaluation
grid.
how T3 interacts with the surface of the thyroid receptor and identify the types of interactions
possible for each of the five functional groups identified in the structure evaluation grid.
O
I
HO
I
O H label
1.18 and 2.18 remove bold from
H N H2
O1.18 and 2.18 remove bold from label
I
Tri-iodo-L-thyronine
Tri-iodothyronine
Tri-iodothyronine
1.18 and 2.18 from

remove
bold from
label the thyroglobulin molecule and is considered an amino
5. T4 is biosynthesized
L-tyrosine
within
acidbased hormone. Other hormones in the body are steroid-based (e.g., estrogen) or peptide1.18 andEvaluate
2.18 remove
bold from
based (e.g., insulin).
the structure
oflabel
T4 and justify its classification as an amino acidbased
O
hormone by determining
which functional groups are derived from L-tyrosine.
I
O
H 2N
I
OH O
HO
I
H
OH O
H 2N
I
OH
HO
H NH
2
H
OH
O
I
H NH
OH
I
2
O
I
L-Tyrosine
Levothyroxine
OH
I
L-Tyrosine

Levothyroxine
H NH
2
1.18 Levothyroxine H
(TO
)
4
63
Levothyroxine
I
6. Interestingly, the dehalogenation transformation represents both an activation and deactivation
pathway for T4. The iodo substituents on the inner ring of T4 play a role not only in important hydrophobic binding interactions with the receptor, but also in maintaining the shape of the hormone in
a perpendicular orientation (see diagram below). This perpendicular shape is necessary to appropriately position the phenolic OH to participate in key receptor binding interactions. Evaluate the
metabolites produced from the dehalogenation
and
identify
which to
metabolite
1.18 and 2.18 transformations
structure was fixed
(pay
no attention
the colors)is
active and which is not. Provide a brief rationale for your answers.

I
1.19 and 2.19 remove bold from label.
I
HO
A
I
HO
H NH
2
D
OH
H NH
2
OH
O
I
B
Lidocaine
I
HO
O
I
OH
Levothyroxine
H NH
2
B
1.18 and 2.18 structure was fixed (pay no attention to the colors)


1.19 Lidocaine
As a sodium channel blocker, lidocaine has found therapeutic use both as a local anesthetic and as a Class IB antiarrhythmic agent. As an anesthetic, this agent demonstrates rapid onset of action (acts quickly) and a longer duration of action (lasts longer) than most amino ester-type local anesthetics. The most frequently observed side effects
are changes in the central nervous system (CNS) (e.g. dizziness, lightheadedness, tinnitus). Lidocaine is extensively
metabolized by the CYP1A2 isozymes to a variety of metabolites.
1. Conduct a complete structural evaluation of ow.
1. Conduct a complete structural evaluation of lidocaine, place your answers in the grid provided, and then
use the evaluation information in the grid to inform your answers to some of the questions that follow.
C H3
N
C H3
CH3
C H3
Lidocaine
Lidocaine
Function
Character
Acidic,
Unless place next to the relevant arrow.
Basic,
Character
Function
or Neutral
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Provide
pKa When
Relevant
Solubility
and/or
Absorption
Function
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
Amino Acids That

Can Interact with
the Functional Group
via H-Bonding
Interactions at
pH=7.4
None Is Acceptable
2. Based on the information in the structure evaluation grid, determine whether or not lidocaine is likely
soluble in the blood (pH=7.4).

65
66
3. Local anesthetics that have a rapid onset of action are rapidly distributed in the body and can be
absorbed easily across lipophilic membranes. Based on the information in the structure evaluation
grid, provide a rationale for why lidocaine is rapidly distributed and can easily be absorbed across
lipophilic membranes.
4. Unless excreted unchanged, drug molecules undergo one or more metabolic transformations to
deactivate the drug and/or make the drug sufficiently water soluble to permit elimination. There are
a variety of transformations that are possible for most drugs, but only the minimum number of transformations actually occurs. The following diagram captures the metabolic pathways for lidocaine
that are
clinically.
eachappear
transformation,
identify
which
Onobserved
page 66 some
of theFor
atoms
to be different
colors.
A phase I metabolic transformation
has taken place next to the relevant arrow.
Lidocaine
Monoethylglycinexylidide
3-Hydroxy-monoethylglycinexylidide
Glycinexylidide

1.19 Lidocaine
67
5. Now that you have identified the metabolic transformations that generate products that have been
identified, put your detective hat on and list any additional phase I transformations that could have
occurred.
6. Lidocaine suffers from CNS-based toxicities largely due to production of the N-dealkylated metabolic
product monoethylglycinexylidide once the parent drug has crossed the bloodbrain barrier.
a. Provide a structural rationale for why lidocaine is able to cross the bloodbrain barrier.
b. Interestingly,
neither
1.19 and
2.19 tolycaine
remove nor
boldtocainide
from labeldemonstrates similar CNS-based toxicities. Provide a
structural rationale for why these two local anesthetics are devoid of CNS-based side effects.
Tolcainide
Tolycaine
A
B
C
D
Sitagliptin
Sitagliptin phosphate


1.20 Montelukast and Zafirlukast
Shown below are the structures of montelukast and zafirlukast. These drug molecules are administered orally for the
treatment of asthma and allergic rhinitis.
Montelukast
Zafirlukast
1. The structure of montelukast contains one acidic functional group (pKa=4.4) and one basic functional
group (pKa=3.1), whereas the structure of zafirlukast only contains one acidic functional group (pKa=4.3).
1. The
structure
of basic functional groups and predict whether they will be primarily ionized or
Identify
these
acidic and
primarily
a stomach
a urine
a cellular
pH=6.1,
a plasma
pH=7.2,
and a solu2. In unionized
the use theatRule
of NinespH=1.9,
to calculate
the pH=5.4,
percent of
the functional
group
that would
be ionized.
tion pH=8.3.
3. The an explanation for this difference.
Primarily
Unionized occur at a physiological pH of 7.4.
4. Montelukast and zafirlukast.
Assume
that allIonized
bindingorinteractions
Acidic or
Functional
Group log P these hepatic
Basic
1.9
5.4primarily excreted
6.1
7.2
5. Calculated
metabolism
or be
unchanged?
8.3
6. Shown below is to perform with zafirlukast.

2. In the previous question, we examined three pKa values in five different environments for a total of 15
different scenarios. Which of these 15 scenarios allow you to use the Rule of Nines to calculate the percent
of ionization of the functional group in the specific environment? Identify the specific scenarios and use
the Rule of Nines to calculate the percent of the functional group that would be ionized.

69
70
3. The sodium salt of montelukast is required for its oral administration, whereas zafirlukast can be
administered orally as its unionized free acid form. Conduct a structural analysis of these two drug
molecules and provide an explanation for this difference.
4. Montelukast and zafirlukast exert their mechanism of action by interacting with cysteinyl leukotriene
Montelukast
receptors and blocking the normal actions of endogenous leukotrienes (LTC4, LTD4, and LTE4). It has
been proposed that this interaction requires five key elements: an ionic interaction, a hydrogen bond
interaction where the antagonist acts as the H-bonding acceptor, as well as the interaction of the
antagonist with three separate hydrophobic pockets within the receptor. Using this information and
the structures of montelukast and zafirlukast, propose potential binding interactions between these
drug molecules and cysteinyl leukotriene receptors. Assume that all binding interactions occur at a
Zafirlukast
physiological pH=7.4.
5. Calculated log P values of montelukast and zafirlukast lie in the range of 5.5 to 6.4 depending on the
computer program used to predict these values. Given this information, would these drug molecules
be
to be
1. predicted
The structure
ofhighly plasma protein bound or minimally plasma protein bound? Additionally,
would you expect these drug molecules to undergo extensive hepatic metabolism or be primarily
2. In theunchanged?
use the Rule of Nines to calculate the percent of the functional group that would be ionized.
excreted
3. The an explanation for this difference.
6. Shown
below is the
ofAssume
zafirlukast
a list of
five metabolic
4. Montelukast
and structure
zafirlukast.
that and
all binding
interactions
occurtransformations.
at a physiologicalFor
pH each
of 7.4.
metabolic transformation, indicate if it is a phase I or a phase II transformation and if zafirlukast has
5. Calculated log P these hepatic metabolism or be primarily excreted unchanged?
6. appropriate
Shown belowmetabolite;
is to performifwith
the
youzafirlukast.
answer NO, then provide a brief explanation as to why this metabolic transformation is not possible to perform with zafirlukast.
Metabolic Pathways
A. Methylation
B. Aromatic Oxidation
C. Hydrolysis
D. Oxidative O-Dealkylation

1.21 Phenobarbital and

Other Barbiturates
Shown
below are the structures of butabarbital, secobarbital, and phenobarbital. These drug molecules are used as
1.21PhenobarbitalandOtherBarbiturates
sedative-hypnotic agents in the treatment of insomnia and inducing sedation prior to surgical procedures. Phenobar
bital can be used in the treatment of a number of different seizure disorders. Their sedative properties are due to their
Shown
belowwith
are the
of butabarbital,
seconervous system (CNS).
in the central
ability
to interact
the structures
GABAA receptor
HN
NH
HN
Butabarbital
NH
HN
NH
Secobarbital
Phenobarbital
1. Conduct a structural analysis of these drug molecules and provide an explanation as to why they can be
1. Conduct
a structural
analysis. previously listed.
administered
orally
for the indications
2. Butabarbital and as to why these two drug molecules need to be administered as their sodium salts.
2. Butabarbital and secobarbital are marketed as their sodium salts and phenobarbital is marketed in its free
acid form (i.e., non-salt form). Draw the sodium salt of either butabarbital or secobarbital and provide an
explanation as to why these two drug molecules need to be administered as their sodium salts.
3. Using the phenobarbital is a long-acting agent (= 3060 minutes; duration = 1016 hours).
3. Using
information
in questions
1 andor2unionized
and your answers
to those questions,
provide
anand
explanation
4. the
Secobarbital
contains
an ionized
at pH environments
of 1.5, 5.9,
6.3, 7.4,
8.9.
as to why secobarbital is a short-acting agent (onset of action = 1015 minutes; duration = 34 hours),
butabarbital is an intermediate-acting agent (onset of action = 4560 minutes; duration = 6-8 hours), and
phenobarbital
is aoflong-acting
agent
(onset of action = 3060 minutes; duration = 1016 hours).
5. As stated
the amino acids
indicated.
4. Secobarbital
contains
an ionizable
with a pKactivity?
=7.9. Using
table
shown below, identify
a
6. Shown
below. Would
you to functional
retain their group
pharmacological
Whythe
or why
not?
the functional group, provide the normal pKa range for the functional group, and identify if the functional group would be primarily ionized or unionized at pH environments=1.5, 5.9, 6.3, 7.4, and 8.9.
Functional Group
Acidic or
Basic

pKa Range

Metabolite of
1.5
5.9
6.3
7.4
8.9
71
Metabolite of
Metabolite of
72
5. As stated above, barbiturates exert their mechanism of action by interacting with the GABAA receptors. Assume that the following amino acids are involved in this binding: Val, Phe, Ser, Asn, and Lys.
Using the functional groups present within the structure of secobarbital, identify five specific binding
interactions between secobarbital and the side chains of the amino acids indicated.
Chapters1.21and2.21
6. Shown below are known metabolites of butabarbital, secobarbital, and phenobarbital. Identify the
PleasereplacetheindicatedstructureinQuestion6inboth1.21and2.21(theonethatispartofthequestion)
metabolic transformations that are required to produce each metabolite and indicate if they are
phase I or phase II transformations. Would you expect any of these metabolites to retain their
withtheonebelow.Bothstructureshadanidenticalerror.
pharmacological activity? Why or why not?
Metabolite of
butabarbital
Metabolite of
secobarbital
Metabolite of
phenobarbital

Chapter2.22
PleasereplacethestructurefortheanswertoQuestion3inChapter2.22withtheonebelow.

Intramolecular
Hydrogen Bond
Intramolecular
Hydrogen Bond
Pravastatin

Fluvastatin
1.22 Pravastatin and Fluvastatin

ShownShown
below are
theare
structures
of pravastatin
andhave
fluvastatin.
These drug molecules are used in the treatment of
below
the structures
of groups
been boxed.
various types of hyperlipidemia/dyslipidemias. A total of six functional groups have been boxed.
F
E
Pravastatin
Fluvastatin
1. Using the table below, identify the six boxed functional groups. For each of the functional groups you
1. indicate
Using the
table
below, or hydrophobic
in explanation
for Also
your provide
response.
identify,
if it
is hydrophilic
or hydrophobic
in character.
a brief explanation for your
response.
2. The log P drug a structural explanation for the difference in these log P values.
3. The normal pKa range for normal range.

Answer
4.Functional
Pravastatin,
as to how pravastatin
andorfluvastain
inhibit HMG CoA reductase.
Groupand
Name
Hydrophilic
Hydrophobic
A
B
C
HMG CoA
Reductase
D
E
F
HMG CoA
Mevalonic Acid
2. The log P values of pravastatin and fluvastatin are 1.44 and 3.62, respectively. Conduct a structural analysis
of these drug molecules and provide a structural explanation for the difference in these log P values.
5. Shown below are the postulate a reason why this structural change results in a loss in activity.
3. The normal pKa range for carboxylic acids is 2.5 to 5. The pKa values for the carboxylic acids present within
the structures of pravastatin and fluvastatin are 4.21 and 4.56. Conduct a structural analysis and provide a
reason why these pKa values are at the high end of the normal range.

73
E
74
Pravastatin
Medicinal Chemistry
Self Assessment
Fluvastatin
Fluvastatin
Pravastatin
1. Pravastatin
Using the table
or hydrophobic
in explanation for
your response.
4.
and below,
fluvastatin
exert their hyperlipidemic
effects
by inhibiting the enzyme HMG CoA
reductase.
As
shown
below,
HMG
CoA
reductase
converts
3-hydroxy-3-methylglutaryl
CoA (HMG
1. PUsing
table below,
or hydrophobic
in explanation
forlog
your
2. The log
drug the
a structural
explanation
for the difference
in these
P response.
values.
CoA) to mevalonic acid. This conversion is required for the synthesis of cholesterol and acts as a
2. ThepK
logrange
P drugfor
a normal
structural
explanation for the difference in these log P values.
range.
3. primary
The normal
controla site
for production
of this endogenous steroid. Using the structures of HMG CoA,
range
for
normal
3.
The
normal
pK
mevalonic
acid,
pravastatin,
and
fluvastatin,
provide aninhibit
explanation
as to
how pravastatin and fluvastatin
a
4. Pravastatin, and as to how
pravastatin andrange.
fluvastain
HMG CoA
reductase.
inhibit
HMG
CoA
reductase.
4. Pravastatin, and as to how pravastatin and fluvastain inhibit HMG CoA reductase.
HMG CoA
Reductase
HMG CoA
Reductase
HMG CoA
Mevalonic Acid
HMG CoA
Mevalonic Acid
5. Shown below are the structures of fluvastatin and a conformationally restricted analog. The addition
5. of
Shown
below
are the
postulate
a reason
why this structural
change
resultsabolish
in a loss
activity.
another
carbon
atom
and the
conformational
restriction
essentially
theintherapeutic
activity
5. Shown
below
are the
postulatepostulate
a reasonawhy
this structural
change results
in aresults
loss inin
activity.
of fluvastatin.
Using
these
structures,
reason
why this structural
change
a loss in
activity.
Fluvastatin
Fluvastatin
Conformationally
RestrictedConformationally
Analog
of Fluvastatin
Restricted Analog
of Fluvastatin
6. Pravastatin
is primarily
metabolized to its 3 epimer. This metabolite is completely inactive as an
6. Pravastatin
is is inactive.
HMG CoA reductase inhibitor. Identify the metabolic transformations required to produce this
metabolite and provide an explanation as to why this metabolite is inactive.
3D epimer

1.23 Quinapril
1.23 Quinapril
Shown below is the structure of quinapril. It is an angiotensin converting enzyme (ACE) inhibitor that is used in the
Shown below is are identified.
treatment of hypertension and heart failure. Five functional groups are identified.
B
H3C
O
D
O
H
N
C H3
OH
E
tableidentify
if it is hydrophilic
or hydrophobic
in brief explanation
response.
1. Using 1.
the Using
table the
below,
the five boxed
functional groups.
For each of for
theyour
functional
groups you
identified,
indicate
if
it
is
hydrophilic
or
hydrophobic
in
character.
Also
provide
a
brief
explanation
for
2. Using the ionized or unionized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
your response.
3.
Answer
CH3
O
O
H
N
D
E
C H3
O
4. Quinapril is a is administered orally instead of quinaprilat.

75
OH
B
H3C
76
Chapter1.23
D
O
N the following table, identify all of the acidic and

PleasereplacethestructureforQuestion2inChapter1.23withtheoneshownbelow.(NOTE:Theanalogous
2. Using the unmodified structure of quinapril and
N
basic
functional
groups
present
in
the
structure,
structureinChapter2.23isfine.)
C provide the normal pKa range for each functional
C H 3be primarily ionized or unionized at pH environgroup, and identify if each functional group would
O
ments=1.5, 4.8, 6.3, 7.4, and 8.1.
OH
E
1. Using the table if it is hydrophilic or hydrophobic in brief explanation for your response.
2. Using the ionized or unionized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
3.
CH3
O
O
H
N

Functional Group
Chapters1.23and2.23
Acidic or
Basic
Primarily Ionized
N or Unionized
pKa Range
1.5
C H3
4.8
O
6.3
7.4
8.1
OH

PleasereplacethestructuresforAngiotensinIandQuinaprilatinQuestion4forboth1.23and2.23withtheone

providedbelow.
3. Quinapril is a prodrug. It is administered as an oral tablet and converted in vivo to its active metabolite,
the metabolic
pathway
that converts quinapril to quinaprilat, and offer a
4.quinaprilat.
Quinapril is Identify
a is administered
orally instead
of quinaprilat.
reason why quinapril is administered orally instead of quinaprilat.
Leu
Phe
His
Quinapril
Angiotensin I
R = Asp-Arg-Val-Tyr-Ile-His-Pro
Quinaprilat
Quinaprilat
4. Quinapril inhibits ACE. This enzyme is a relatively nonspecific dipeptidyl carboxypeptidase. It is a zinc

protease that converts angiotensin
I, a decapeptide, to angiotensin II, an octapeptide. The peptide
cleavage is catalyzed by the zinc atom and is shown below. Quinapril, along with other ACE inhibitors, is a tripeptide mimic that can interact with the enzyme resulting in enzyme inhibition rather
than hydrolysis. Using this information and the structures provided below, identify how quinapril can
interact with ACE. Assume that all drug binding interactions are occurring at a pH=7.4.

providedbelow.
1.23 Quinapril
77
5. Quinapril inhibits ACE. This at a pH of 7.4.
LeuLeu
HisHis
PhePhe
Quinaprilat
Quinaprilat
AngiotensinI I
Angiotensin
R
=
Asp-Arg-Val-Tyr-Ile-His
6. Shown below are in these pathways.

5. Shown below are four possible metabolic pathways for quinapril. Identify the metabolic transformations involved in these pathways.
Quinapril
C

78
6. Although it is possible for quinapril to undergo all of the above metabolic transformations, pathway
B is the major pathway. Other metabolites have been identified, but only at very low levels. Provide
an explanation for this finding.

1.24 Rivastigmine
1.24Rivastigmine
ShownShown
belowbelow
is the structure
of rivastigmine.
Four of
its functional
groups
have been
is the structure
of rivastigmine.
Four
of its functional
groups
have identified.
been identified.
C H3
H3C
C
O
CH3 D
C H3
N
C H3
Rivastigmine
1. Using the table

1. Using the table below, identify the four boxed functional groups. For each of the functional groups you
2. Based
on their
identified,
indicate
if it induction.
is hydrophilic or hydrophobic in character. Also provide a brief explanation for
your response.
3. Rivastigmine is an e. Glutamic acid, with acetylcholine.
Answer
Labile
ester
bond
Functional
Group
Name
A
B
C
D
2. Based on their electronic properties AND their relative positions in the molecule, identify if functional
groups A and B are electron withdrawing or electron donating. Additionally, identify if this effect is due
Rivastigmine
to resonance or induction.
3. Rivastigmine is an acetylcholinesterase inhibitor. Inhibition of this enzyme prolongs the half-life of acetylAcetylcholine
to active site
choline, allowing
for higherbound
concentrations
of acetylcholine at muscarinic and nicotinic receptors. This
of acetylcholinesterase
action is useful in the
treatment of Alzheimers disease, myasthenia gravis, and glaucoma. Shown below is
the structure of acetylcholine interacting with the active site of acetylcholinesterase. Glutamic acid, histidine, and serineA.are involved
inrivastigmine
the mechanism
of esterhow
hydrolysis
can form
specific interactions with
Conduct a
and indicate
it couldand
interact
with acetylcholinestase.
acetylcholine.
B.
The serine explanation as to how rivastigmine inhibits acetylcholinesterase.

79
1. Using the table

80 2.
C H3
Medicinal
Chemistry
Self Assessment Rivastigmine
Based
on their
induction.

1. Using the table
2. Based on
theirester
induction.
Labile
bond
Labile ester bond
Rivastigmine
Acetylcholine bound to active site

Rivastigmine
A. a Conduct
a rivastigmine
and indicate and
how indicate
it could interact
acetylcholinestase.
a. Conduct
structural
analysis of rivastigmine
how it with
could
interact with acetylcholinAcetylcholine
bound
to
active
site
esterase.
B.
The serine explanation as to how rivastigmine inhibits acetylcholinesterase.
b. The serine residue of acetylcholinesterase attacks the ester bond of acetylcholine causing hydrolysis and acetylation of the serine. A similar reaction occurs between the carbamate group of
A.
Conduct
rivastigmine
and indicate
howwhile
it could
interact with isacetylcholinestase.
rivastigmine
andathe
serine residue;
however,
acetylcholine
a substrate of acetylcholinesterase,
rivastigmine
is an inhibitor.
Compare
the functional
groups involved and provide an
B.
The
serine explanation
as to how
rivastigmine
inhibits acetylcholinesterase.
explanation as to how rivastigmine inhibits acetylcholinesterase.
Intermediate in the hydrolysis of

acetylcholine

acetylcholine

Analogous intermediate formed with

rivastigmine

rivastigmine
1.24 Rivastigmine
81
4. Neostigmine is a structural analog of rivastigmine. Similar to rivastigmine, neostigmine is able to

interact with acetylcholinesterase and cause inhibition due to the presence of a carbamate functional
group. The primary differences between rivastigmine and neostigmine are their routes of administration and their therapeutic indications. Rivastigmine is administered orally in the treatment of
Alzheimers disease, whereas neostigmine is administered intramuscularly (IM) or subcutaneously
(SC) in the treatment of myasthenia gravis. Conduct structural analyses of these drug molecules and
4.
Neostigmine
is a structural
analog
of es in routes
of administration.
provide
an explanation
for these
differences
in routes
of administration and therapeutic indications.
4. Neostigmine is a structural analog of es in routes of administration.
4. Neostigmine is a structural analog of es in routes of administration.
+
Neostigmine Bromide
+
Bromide
Rivastigmine
a longer
durationofofaction
aNeostigmine
longer
duration
of action.A comparison of the structures of
5. 5.
Rivastigmine
hashas
a longer
duration
than
neostigmine.
rivastigmine and neostigmine reveals that the carbamate
+ group present in rivastigmine is slightly
larger
than that has
present
in neostigmine.
Using
the
mechanism
of action given in question 3, provide
5.
Rivastigmine
a
longer
duration
of
a
longer
duration
of action.
Methyl
Neostigmine
Bromide
a reason why this structural difference results
in a longer
duration
of action.
Methyl
Methyl
Methyl
5. Rivastigmine has a longer duration of a longer duration of action.
Methyl
Methyl
Methyl
Neostigmine
Ethyl
+
Ethyl
Methyl
Rivastigmine
+
Rivastigmine
6. EvaluationNeostigmine
of the structure of rivastigmine ability to inhibit acetylcholinesterase.
Methyl
Ethyl
6. Evaluation of the structure+of rivastigmine ability to inhibit acetylcholinesterase.
para
orientation
meta orientation
6. Evaluation ofNeostigmine
the structure
of rivastigmine reveals that the aliphatic
chain
containing the tertiary
Rivastigmine
amine is located meta to the carbamate group. Similar orientations can be seen with neostigmine.
Using the information from the previous questions, provide an explanation
as to why a para orientapara orientation
orientation
6.
of the meta
structure
of rivastigmine
to inhibit acetylcholinesterase.
tionEvaluation
of these functional
groups
would leadability
to a significant
decrease in the ability to inhibit acetylcholinesterase.
meta orientation
Rivastigmine
para orientation
para Analog of
Rivastigmine
Rivastigmine
para Analog of
Rivastigmine
Rivastigmine
para Analog of
Rivastigmine


1.25 Sitagliptin
Sitagliptin is an inhibitor of dipeptidyl peptidase IV (DPP-IV), a serine protease that catalyzes the deactivation/degra1.25 Sitagliptin
dation of GLP-1. GLP-1 is a 36-amino acid peptide that is responsible for promoting insulin secretion in response to
an increase
in blood
Currently there are four DPP-IV inhibitors on the market, all of which contain an
Sitagliptin
is anglucose
inhibitorlevels.
of dipeptidyl
essential basic amino functional group that represents the penultimate amino-terminal alanine residue found within
GLP-1.
N H2 O
N
F
N
CF3
Sitagliptin
Sitagliptin
1. Conduct a structural evaluation of sitagliptin, focusing on the boxed functional groups, and use the information
the gridato
your answers
to the questions that follow.
1. inConduct
toinform
the questions
that follow.
2. Sitagliptin is salt form.
Function
Function
Character
Character
Name of
Functional
Group
Acidic, Basic,
F
or Neutral
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
Function
Hydrophilic
Solubility
F Provide pK
and/or
a
N and/or
H2 O
Hydrophobic
C
D
Sitagliptin
3. Sitagliptin is designation.
4. At 38%, the bound (e.g., warfarin).
5. Approximately.
6. Assess each of ransformation has occurred.

83
N
CF3
Amino Acids That Can

Interact with the Functional Group via Ion
Dipole Interactions at
pH=7.4
None Is Acceptable
84
Chemistry
Assessment
1.Medicinal
Conduct
a to theSelf
questions
that follow.
2. Sitagliptin is salt form.

2. Sitagliptin is formulated as a phosphate salt. Identify the most basic functional group and modify the
structure to show the phosphate salt form.
F
F
N H2 O
N
N
F
Sitagliptin
Sitagliptin
N
CF3
3. Sitagliptin is marketed as the R-enantiomer. Evaluate the structure of sitagliptin and provide a struc3. rationale
Sitagliptin
is the
designation.
tural
for
R-enantiomer designation.
4. At 38%, the bound (e.g., warfarin).

4. At 38%, the fraction of sitagliptin reversibly bound to plasma proteins is relatively low. By way of
5. Approximately.
reminder, only the unbound fraction of drug is able to exert its biological activity and undergo
metabolism. Describe the relative risk of a plasma protein binding interaction between sitagliptin
6. Assess each of ransformation has occurred.
and another drug that is highly protein bound (e.g., warfarin).
5. Approximately 79% of sitagliptin is excreted unchanged in the urine. Provide a structural rationale
that supports this observation.

1.25 Sitagliptin
6. Assess each of the possible metabolic products generated from sitagliptin and determine which
phase I metabolic transformation has occurred.
A
B

85

1.26 Sorafenib
Because protein tyrosine kinases regulate cellular proliferation, differentiation, and survival, it is no surprise that
several neoplastic disorders can be tied to altered activity of protein tyrosine kinases. Clinically relevant antineoplastic
tyrosine kinase inhibitors interact with the active site of the enzyme via several types of binding interactions. The
adenosine triphosphate (ATP) binding domain of the tyrosine kinases contains a hydrophobic domain that includes
a significant number of isoleucine, leucine, alanine, and valine residues. There are at least five binding pockets that
flank this region in which van der Waals, hydrophobic, hydrogen bonding, and electrostatic interactions occur.
Sorafenib
a tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma, a highly vascularized
1.26isSorafenib
tumor. The drug specifically targets vascular endothelin growth factor 2 (VEGF2) that is instrumental in the generaprotein
tyrosine kinases regulate
tion ofBecause
new blood
vessels.
C
E
A
B
D
Sorafenib
Sorafenib
1. Conduct a structural evaluation of sorafenib, focusing on the boxed functional groups, and use the infor1. Conduct a structural to the questions that follow.
mation in the grid to inform your answers to the questions that follow.
2. Sorafenib interacts in the local environment

Character of the enzyme.
Character298
3. Nilotinib, another and Leu

Name of
Functional Group
299Acidic,
359Basic,
/Val
Hydrophilic
and/or
A
Hydrophobic
Function
in each of the respective five Interaction(s)

binding pockets.
or Neutral
Provide pKa
When Relevant
/Phe
Function
Solubility
and/or
Absorption

pH=7.4
C
D
E
F
Nilotinib
A. Consider the side chains of the the five binding pockets. Assume pH=7.4.

87
B. Determine acid side chains are both at pH=7.4.
88
2. Sorafenib interacts with Cys919, Phe1047, and Asp1046 via hydrogen bonding and hydrophobic interactions.
1.26
Sorafenib
Identify
which functional groups could interact with the side chains of these amino acids. Assume
that Asp1046 is unionized in the local environment of the enzyme.
Because protein tyrosine kinases regulate
Functional
Group
Interacts with Cysteine919

Interaction
Yes or No
Interacts with Aspartic Acid1046

F
Interaction
Interacts with Phenylalanine1047

via a Hydrophobic Interaction
Yes or No
Yes or No
B
C
Sorafenib
1. Conduct a structural to the questions that follow.

3. Nilotinib, another tyrosine kinase inhibitor (via Bcr-Abl) indicated for the treatment of Philadel2. Chromosome
Sorafenib interacts
in the local
environment
of the enzyme.
phia
(Ph+) positive
chronic
myelogenous
leukemia, also interacts with each of the five
binding pockets found within this
biological
target.
This
drug interacts with Leu285/Val289, Asp391/Glu286,
298
299
359
315 Nilotinib,
318
298
299
359
3.
another
and
Leu
/Val
/Phe
in
each
of
the
respective
five binding
Thr , Met , and Leu /Val /Phe in each of the respective
five binding
pockets.pockets.
A
B
Nilotinib
Nilotinib
a. Consider the side chains of the amino acids indicated and determine which type(s) of binding
A. Consider
the side
chains
thefive
the binding
five binding
pockets.
Assume
pH=7.4.
interactions
are possible
in each
ofofthe
pockets.
Assume
pH=7.4.
Leu285/Val289
Asp391/Glu286
Thr315
Met318
Leu298/Val299/Phe359
C. It has been participate in this interaction.

b. Determine which of the boxed functional groups (AE) can interact with the side chains of the
amino acids found in each of the five binding pockets. Indicate the type of interaction(s) possible
in the appropriate box. None is an acceptable answer. Assume that the drug and the amino acid
side chains are both at pH=7.4.
Leu285/Val289
Asp391/Glu286
Thr315
A
B
C
D
E

Methionine
Met318
Nilotinib
A. Consider the side chains of the the five binding pockets. Assume pH=7.4.
1.26 Sorafenib
89

c. It hasC.
been
documented
that the
pyridyl
nitrogen atom (functional group E) of nilotinib particiIt has
been participate
in this
interaction.
pates in a hydrogen bonding interaction with methionine. Draw a diagram that clearly shows
which atom(s) within the structure of methionine participate in this interaction.
Methionine
Methionine
4. Sorafenib enters cells via passive diffusion. Using the information in the structure evaluation grid as a
starting point, identify which functional groups contribute to the ability of this drug to enter cells via
passive diffusion.
5. Nilotinib is considered significantly more hydrophobic than sorafenib (distribution coefficient log D is
2.4 and 0.8, respectively). Provide a structural rationale for this property difference.
6. Sorafenib is marketed as a tosylate salt, a lipid-soluble organic salt. Nilotinib is marketed as a hydrochloride monohydrate salt, an inorganic salt. In general, what is the value of each of these types of
salts?


1.27 Zanamivir and Oseltamivir

1.27ZanamivirandOseltamivir
Shown
below is the structure of zanamivir. This drug molecule is administered via oral inhalation for the treatment of
Shown below is the d B infections.
influenza A and B infections.
Zanamivir
1. Identify
all of
the H
of 7.2.
1. Identify
all of the
acidic
and
basic functional groups, provide the normal pKa range for each functional
group,
and
identify
if
each
functional
group would
bethat
primarily
ionized
or unionized
at of
a pulmonary
2. Identify all other water soluble functional
groups
are present
within
the structure
zanamivir.
pH=7.2.
3. Based on your or capsule.
4. Zanamivir exerts its n. Using neuraminidase.
2. Identify all other water soluble functional groups that are present within the structure of zanamivir.
3. Based on your answers to questions 1 and 2, explain why zanamivir is administered as an oral inhaler
instead of an oral tablet or capsule.
4. Zanamivir exerts its antiviral action by inhibiting neuraminidase, a viral enzyme that is required for the
spread of the viral infection. A key component of neuraminidases action is the hydrolysis of N-acetylsialic
acid from surface viral glycoproteins. Shown below is the structure of N-acetylsialic acid bound to a glycoprotein. Using this structure Glycosidic
and the structure
bond of zanamivir, provide an explanation of how zanamivir
inhibits neuraminidase.
N-Acetylsialic acid bound to glycoprotein
Zanamivir
5. Shown below is a, or similar to that of zanamivir?

91
1. Identify all of the H of 7.2.

3. Based on your or capsule.
92
Medicinal
Chemistry
Self Assessment
3. Based
on your
or capsule.
4. Zanamivir
exerts
its n. Using neuraminidase.
Zanamivir
4. Zanamivir exerts
its n. Using neuraminidase.
of the H of 7.2.
other water soluble functional groups that are present within the structure of zanamivir.
our or capsule.
xerts its n. Using neuraminidase.
Glycosidic bond
Glycosidic bond
Zanamivir
Zanamivir
5. Shown
below
is a, or similar
to that ofIdentify
zanamivir?
5. Shown
below is
a stereoisomer
of zanamivir.
if the stereoisomer is an enantiomer, a diastereomer,
5. aShown
below
is a, oran
similar
to that
of zanamivir?
geometric
isomer,
epimer,
and/or
a conformational isomer. Predict whether this stereoisomers
pharmacological activity is likely to be more active, less active, or similar to that of zanamivir.
Glycosidic bond
alic acid bound to glycoprotein
Zanamivir
w is a, or similar to that of zanamivir?
6. Shown below is the oseltamivir .

6. Shown below is the oseltamivir .
6. Shown below is the structure of oseltamivir and a list of five metabolic transformations. For each
metabolic transformation, indicate if it is a phase I or a phase II transformation and if oseltamivir has
a functional group present that can undergo the indicated transformation. When evaluating these
metabolic transformations, consider functional groups that are initially present within the structure
of oseltamivir as well as those that can be added/revealed through phase I metabolism. If you answer
YES, .then draw the appropriate metabolite; if you answer NO, then provide a brief explanation as to
w is the oseltamivir
why this metabolic transformation is not possible for oseltamivir.
Metabolic Pathways
A. Hydrolysis
B. Allylic Oxidation
C. Glucuronide Conjugation
D. -Oxidation
E. Oxidative O-Dealkylation

Part 2 ANSWERS

2.1
2.2
2.3
2.4
2.5
2.6
2.7

Functional Group Characteristics and Roles................... 95

Identifying Acidic and Basic Functional Groups.............. 99
Solving pH/pKa Problems.............................................. 105
Salts and Solubility....................................................... 109
Drug Binding Interactions............................................ 113
Stereochemistry and Drug Action................................. 117
Drug Metabolism......................................................... 123

Section 3 General Self Assessment Answers

The bold has been removed.
2.1 Functional Group Characteristics

and Roles
The exact same structures are in both of these chapters, but I have provided two
copies in the event you wanted that.

1. Shown below are the structures of warfarin, phenytoin, bromfenac, and salmeterol.
a. Identify each of the boxed functional groups.
A
F
C
E
D
Warfarin
Bromfenac
Phenytoin
H
I
Salmeterol
Answer
Box
-Dicarbonyl (enol form)
Ketone
C
D
E
F
G
H
I
J
K
L
B
A Phenyl ring; aromatic ring; aromatic hydrocarbon
C
O
Imide
H 2N
Halogen (bromo)
OH
Primary aromatic amine; aniline
Carboxylic acid
PrimaryIbuprofen
hydroxyl group; primary alcohol
Phenol; phenolic hydroxyl group
Secondary amine
Alkyl chain; aliphatic alkane
Ether

D
O
S
O
C H3
N
H
Sulfamethoxazole
95
96
b. For each of the functional groups you identified, indicate if it is hydrophilic or hydrophobic in
Structures
for 1.1 and
character.
Also2.1
provide a brief explanation for your response.
Answer
The bold
has been removed. The exact same structures are in both of these chapters, but I have provided two
Box
copies in the event youAcidic

wanted
that.
functional group; hydrophilic due to its ability to ionize and ability to participate in hydrogen bonding in its
A
unionized form.
Hydrophilic due to its ability to act as a hydrogen bond acceptor.
Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional groups enhance lipid
solubility.
Acidic functional group; hydrophilic due to its ability to ionize and ability to participate in hydrogen bonding in its
unionized form.
F
Hydrophobic due to its inability to ionize or form hydrogen bonds.
Weakly basic functional group; hydrophilic primarily due to its ability to form hydrogen bonds, although it is
possible for this functional group to be ionized. If unionized, primary aromatic amines can act as hydrogen bond
E
donors and acceptors.
Acidic functional group; hydrophilic due to its ability to ionize and ability to participate in hydrogen bonding in its
unionized form.
D
Warfarin
H
Hydrophilic
due to its ability to form hydrogen bonds; can act as both a hydrogen bond
donor and acceptor.
Bromfenac
B
Phenytoinprimarily due to its ability to form hydrogen bonds. If unionized,

Weakly acidic functional group; hydrophilic
phenolic hydroxyl groups can act as hydrogen bond donors and acceptors.
Basic functional group; hydrophilic due to its ability to ionize and ability to participate in hydrogen bonding in its
unionized form.
Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional groups enhance lipid
solubility.
The ether oxygen atom is hydrophilic

due to its ability to act as a hydrogen bond acceptor; however, due to
J
K
L chain attached to the secondary amine could be
I hydrocarbon surrounding this ether on both sides, the entire side
classified as primarily hydrophobic.
Salmeterol
2. Shown below are the structures of ibuprofen and sulfamethoxazole. Four functional groups have
been highlighted. Based on their electronic properties AND their relative positions in the molecule,
identify if they are electron withdrawing or electron donating. Additionally, identify if this effect is
D
O
OH
Ibuprofen
H 2N
S
O
C H3
N
H
Sulfamethoxazole
Answer
Functional group A: This is an alkyl group (aliphatic chain). Because it is directly attached to an
aromatic ring, it can act as an electron donating group through induction.
Functional group B: This is a carboxylic acid that will most likely be ionized at physiological pH and
carry a negative charge. Therefore, it can be electron donating through induction.
Functional group C: This is an aniline (or primary aromatic amine). Because the nitrogen atom is
directly attached to the aromatic ring, it acts as an electron donating group through resonance.
This electron donating property is responsible for the low basicity of aromatic amines (discussed in
Chapter 3*).
2.1 Functional Group Characteristics and Roles
97
Functional group D: This is a heterocyclic aromatic ring. It is electron withdrawing due to induction.
This electron withdrawing property is responsible for the increased acidity of the adjacent sulfonamide (discussed in Chapter 3*).
3. Shown below is the structure of imipramine as well as three analogs. Evaluate each analog and
provide an overall evaluation of how each change will affect the chemical properties of imipramine.
Imipramine
Analog A
Analog B
Analog C
Answer
Analog A: In this analog, a chlorine atom has replaced a hydrogen atom. A hydrogen atom generally
does not contribute to electronic and solubility properties. Additionally, it is the smallest atom and
thus sterically occupies the least amount of space. In contrast, the chlorine atom is electron withdrawing in character, enhances the overall lipid solubility of imipramine, and sterically is larger than
the original hydrogen atom.
Analog B: Similar to Analog A, this analog occurs via the replacement of a hydrogen atom with
another functional group. The alkyl chain (propyl chain) is electron donating, enhances the overall
lipid solubility of imipramine, and is sterically much larger than the original hydrogen atom.
Analog C: In this analog, a methyl group has been replaced by an acetyl group that converts the
tertiary amine to an amide. The methyl group is electron donating and contributes to the basicity
of the tertiary amine. In contrast, the carbonyl group is electron withdrawing. This significantly
decreases the availability of the lone pair of electrons on the nitrogen atom such that it is no longer
basic. In terms of solubility, the substitution of the acetyl group for the methyl group decreases water
solubility. This is because the nitrogen atom is no longer basic and thus cannot undergo ionization.
The resulting amide is water soluble due to its ability to act as a hydrogen bond acceptor; however,
the change from a functional group that can ionize to one that can only participate in hydrogen
bonding results in an overall decrease in water solubility. Finally, the acetyl group is sterically larger
than the original methyl group.

98
4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side chains of the
four amino acids have been boxed.
4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side
chains of the four amino acids have been boxed.
a. Identify the four amino acids that comprise this tetrapeptide sequence.
Answer

Tyrosine (Tyr)Aspartic Acid (Asp)Valine (Val)Glutamine (Gln)
b. For each amino acid, identify the key chemical properties of its highlighted side chain.
Answer
Tyrosine: This side chain is one of the largest seen in amino acids and is involved in dictating
Page2of2
the overall conformation of the peptide. Although the phenyl ring is hydrophobic, the phenolic
hydroxyl group can act as both a hydrogen bond donor and acceptor and contributes to the
overall water solubility.
Aspartic Acid: This side chain is acidic and will most likely be ionized at physiological pH. This will
enhance the overall water solubility of the peptide. It will most likely reside in a water soluble
pocket of the overall peptide.
Valine: This is an aliphatic, lipid soluble, hydrocarbon side chain. It contributes to the overall lipid
solubility of the peptide and can contribute to lipid soluble pockets within the peptide. Additionally, the isopropyl side chain can impart some steric bulk that may influence the overall conformation of the molecule.
Glutamine: Overall, this side chain is normally classified as a polar, water soluble side chain due to
its ability to act as both a hydrogen bond donor and acceptor. The two methylene carbon atoms
allow the amide to be oriented in different locations and may contribute a little to the overall
lipid solubility of the peptide.
Go to Section 1.1

2.2 Identifying Acidic and Basic

Functional Groups
2.2
groups.
groups.
Answer
2
4
4. Page 99: The box around
the
phenol
needs
to
include the aromati
Bromfenac
7
7
8
8
6
6
Sorbinil
Answer:

Page 101: The box around the phenolate needs to include the aromatic rin
Drug Name
Acidic Functional Groups
Sulfonamide (2)
Amidine (1)
Bromfenac
Carboxylic acid (4)
Aromatic amine or aniline (3)
As discussed in Chapter 3*, there are two key structural features of an acidic functional group. The first is the
presence of a proton (H+) that can leave (i.e., dissociate), and the second is the presence of adjacent atoms that
acid and an imide are acidic, while

functional groups such as secondaryNone
hydroxyl groups (i.e., secondary
Sorbinil
Imide (5)
Experimental
(6)
alcohols)Antidiabetic
and thiolsAgent
are neutralPhenol
functional
groups.
Sulfonamide (7)
Secondary amine (8)
Resonance stabilization
of resulting negative charge
No resonance available
if proton would leave
99
Sorbinil
100
2. Using any one of the acidic functional groups that you identified in question 1, provide an explanaAnswer:
tion as to why the functional group is acidic. Also provide a similar type of analysis for any one of the
basic functional groups that you identified in question 1.
As discussed in Chapter 3*, there are two key structural features of an acidic functional group. The first is the
Answer
presence
of a proton
(H+) that 3*,
canthere
leave are
(i.e.,two
dissociate),
and the
secondof
is an
the acidic
presence
of adjacent
atoms
As discussed
in Chapter
key structural
features
functional
group.
Thethat
+
first is the presence of a proton (H ) that can leave (i.e., dissociate), and the second is the presence
acid and
an imideatoms
are acidic,
functional
groups
such as secondary
hydroxyl
groups resonance.
(i.e., secondary
of adjacent
that while
are able
to share
the resulting
negative charge
through
Hence,
functional groups such as a carboxylic acid and an imide are acidic, while functional groups such as
alcohols)
and thiols
are neutral
functional
groups. alcohols) and thiols are neutral functional groups.
secondary
hydroxyl
groups
(i.e., secondary
Resonance stabilization
of resulting negative charge
Carboxylic
Acid
No resonance available
if proton would leave
Secondary
Hydroxyl
Imide
Sulfhydryl
For basic functional groups, the key structural feature is a nitrogen atom that has a lone pairPage1of5
of
+
nonbonding
electrons
that
can
accept
a
proton
(H
).
The
relative
ability
of
the
electrons
on
different

nitrogen-containing functional groups determines their relative basicity. Thus, amidines and
secondary amines are basic, while amides are not.
For basic functional groups, the key structural feature is a nitrogen atom that has a lone pair of nonbonding
amides are not.

Resonance with
adjacent carbonyl greatly
decreases availablity of electrons
Amidine
Secondary
amine
Amide
3. Using the structures from question 1, modify all of the acidic functional groups to show their ionized forms and
in the table below identify the normal pKa range for the specific functional group.
Answer:

amine
Amide
4. Page 99: The box around the phenol needs to include the aromati
2.2 Identifying Acidic and Basic Functional Groups
101
3. Using the structures from question 1, modify all of the acidic functional groups to show their ionized forms and
in3.
theUsing
table the
below
identify the
normal
pKa range
for the
functional
group. groups to show their ionized
structures
from
question
1, modify
all specific
of the acidic
functional
forms and in the table below identify the normal pKa range for the specific functional
group.
7
Answer:
Answer
8
6
Page 101: The box around the phenolate needs to include the aromatic rin
Bromfenac
7
8
6
_
Sorbinil

Drug Name
Acidic Functional Group
Normal pKa Range
Sulfonamide
pKa=5 to 10
Bromfenac
Carboxylic acid
pKa=2.5 to 5
Sorbinil
Imide
pKa=4.5 to 8.5 (generally on the higher end,

7.0 to 8.5)
Phenol
pKa=9 to 10
Sulfonamide
pKa=5 to 10

Page2of5
4.
UsingMedicinal
the structures
from Self
question
1, modify all basic functional groups to show their ionized forms and in the
102
Chemistry
Assessment
table below identify the normal pKa range for the specific functional group.
4. Using the structures from question 1, modify all basic functional groups to show their ionized forms
Answer:
and in the table below identify the normal pKa range for the specific functional group.
Answer
OCH3
O
+
H2 N
H 2N
O
NH2
OH
N
H
Br
Bromfenac
H
N
HN
+
NH3
H
N
O
HO
N
Sorbinil
N
H
N
H2

Drug Name
Basic Functional Group
Normal pKa Range
Amidine
pKa=10 to 11
Bromfenac
Aromatic amine (aniline)
pK =2 to 5
Sorbinil
None
Not applicable
Secondary amine
pKa=9 to 11
5. Shown below is the structure of clonidine, an D adrenergic agonist that can abe used to treat hypertension.
functional groups, such as that seen with arginine are much more basic with a pKa of 12.5. Provide a chemical
5. Shown below is the structure of clonidine, an 2 adrenergic agonist that can be used to treat hyperexplanation
for this
difference.
tension.
Clonidine
contains a guanidine functional group (highlighted in bold) that has a pKa=8.3.
Other guanidine functional groups, such as that seen with arginine, are much more basic with a
pKa=12.5. Provide a chemical explanation for this difference.
pKa = 12.5
pKa = 8.3
Clonidine
Arginine
Answer
Unlike the side chain of the amino acid arginine, the guanidine group of clonidine is directly
Answer:
attached to an aromatic ring. As such, the nitrogen atom directly attached to the aromatic ring
(highlighted
can donate
electrons
the aromatic
thus making
it attached
less available
Unlike the
side chainbelow)
of the amino
acid arginine,
theinto
guanidine
group ofring,
clonidine
is directly
to an for
resonance stabilization of a positive charge. In addition, the aromatic ring of clonidine is attached to
two
ortho
chloro
Each
ofdirectly
these halogens
is electron
withdrawing
and further
the
aromatic
ring.
As such,
thegroups.
nitrogen
atom
attached to
the aromatic
ring (highlighted
below)decreases
can donate
basicity of the guanidine group. The combination of these two effects decreases the basicity of the
Page3of5
guanidine
group byring,
greater
four
orders
of magnitude.
electrons
into the aromatic
thus than
making
it less
available
for resonance stabilization of a positive charge. In

From: addition,
ASHP eBooks
the(digital.ashp.org)
aromatic ring of clonidine is attached to two ortho chloro groups. Each of these halogens is electron
withdrawing and further decreases the basicity of the guanidine group. The combination of these two effects
2.2than
Identifying
Acidic
decreases the basicity of the guanidine group by greater
four orders
of and
magnitude.
Cl
H
N
103
Involved in resonance
with aromatic ring
H
N
N
Cl
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug molecule,
Clonidine
an amphoteric drug molecule, or a nonelectrolyte.
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug
Answer:
molecule, an amphoteric drug molecule, or a nonelectrolyte.
Answer
Basic
O
N
H
Acidic
H 2N
Basic
N
H
N
O
NH
Acidic
N
H
Lomitapide
COOH
NH
CF3
CF3
C H3
Argatroban
Page4of5
Acidic
COOH
HO
CH3
H
N Basic
OCH3
OH
H3C
O
C H3
Cl
C H3
H 2N
N
N
N
H
NH2
HO
Pravastatin
NH
Amiloride
N H2
Basic
S
O
N
CH3
O
CH2 N(CH3 )2 Basic
Diltiazem
Drug Molecule
Acid/Base Character of Drug Molecule
Lomitapide
Basic: Contains only a basic tertiary amine
Argatroban
Amphoteric: Contains two acidic functional groups (a carboxylic acid and a sulfonamide) and two basic functional groups (a guanidine group and an aromatic amine)
Pravastatin
Acidic: Contains only an acidic carboxylic acid
Amiloride
Basic: Contains a basic guanidine group as well as a basic aromatic heterocyclic ring (pyrazine)
Diltiazem
Basic: Contains only a basic tertiary amine
Go to Section 1.2


Chapter 3
molecules
contains
one ionizable functional group. The pKa values have been provided.
Solving
pH/pK
a Problems
a. Match the pKa values provided with the appropriate functional groups. For each functional group,
1. Shown
below the
are name
the structures
of cefotaxime,
nitrofurantoin,
atenolol,
and ezetimibe. Each of these drug
identify
of the group
and whether
it is acidic
or basic.
molecules
one ionizable
functional
TheitpK
been provided.
b. For contains
each functional
group
indicategroup.
whether
would
behave
primarily
ionized or primarily unionized at a
a values
stomach pH=1.8, a urinary pH=6.1, or a plasma pH=7.4. Provide an explanation for your responses for
Answer:
cefotaxime at a plasma pH=7.4, nitrofurantoin at a urinary pH=6.1, and atenolol at a stomach pH=1.8.
Answer
Imide
Acidic
Cefotaxime
pKa = 3.4
Nitrofurantion
Nitrofurantoin
pKa = 7.1
Carboxylic acid
Acidic
Aromatic
hydroxyl
(phenol)
Acidic
Secondary amine
Basic
Atenolol
pKa = 9.6
Ezetimibe
pKa = 10.2
Cefotaxime contains an acidic carboxylic acid. At a plasma pH=7.4, the environment (i.e., the pH) is more
basic than the functional group (i.e., the pH > pKa). An acidic functional group will be primarily ionized in
a
basicbelow
environment.
3. Shown
is the structure of natamycin. It contains two functional groups that could be potentially ionized.
Nitrofurantoin contains an acidic imide group. At a urinary pH=6.1, the environment (i.e., the pH) is more
acidic than the functional group (i.e., the pH < pKa). An acidic functional group will be primarily unionized
in an acidic environment.
Atenolol contains a basic secondary amine. At a stomach pH=1.8, the environment (i.e., the pH) is more
H
acidic than the functional group (i.e., the pH <OpKa). A basicOfunctional
group will be primarily ionized in
O
OH
an acidic environment.
H3C
OH
105
COOH
Answer:
106
Drug (pKa Value)
Stomach (pH=1.8)
Urine (pH=6.1)
Imide
Acidic
Plasma (pH=7.4)
Cefotaxime (3.4)
Primarily unionized
Primarily ionized
Primarily ionized
Nitrofurantoin (7.1)
Primarily unionized
Primarily unionized
Primarily ionized
Cefotaxime
Atenolol (9.6)
pKa = 3.4
Ezetimibe (10.2)
Primarily ionized
Primarily ionized
Carboxylic acid
Primarily unionized
Primarily unionized
Acidic
Primarily ionized
Nitrofurantion
= 7.1unionized
pKPrimarily
a
2. In the previous question, we examined four pKa values in three different environments for a total
Aromatic
of 12 different scenarios. Which of these 12 scenarios allow you to use the Rule of Nines to calculate
hydroxyl
scenarios and use the Rule
of Nines
to calculate the percent of the functional group that would(phenol)
be
Secondary
amine
Acidic
ionized.
Basic
Answer
Atenolol
To use the Rule of Nines, pK
the =
difference
between the pH and the pK
must be an integer (i.e., 1,
9.6
a
Ezetimibe
a
2, 3). In evaluating the above 12 scenarios, there are only two scenarios
10.2 meet this criterion,
pK = that
cefotaxime (pKa=3.4) in a plasma pH=7.4 and nitrofurantoin (pKa=7.1)a in a urinary pH=6.1. For cefotaxime, |pH pKa| is equal to 4; thus, there is a 99.99:0.01 ratio. Because the carboxylic acid (pKa=3.4)
would be primarily ionized in a basic environment (pH=7.4), we can use this ratio to determine that
it would be 99.99% ionized. For nitrofurantoin, |pH pKa| is equal to 1; thus, there is a 90:10 ratio.
The imide (pKa=7.1) functional group is acidic, so it would be primarily unionized in an acidic environment
(pH=6.1).
We can use
this information
to predict
that it would
ionized.
3. Shown
below
is the structure
of natamycin.
It contains
two functional
groups be
that10%
could
be potentially ionized.

3. Shown below is the structure of natamycin. It contains two functional groups that could be potentially ionized. The pKa values for natamycin are 4.6 and 8.4.
H3C
OH
O
O
OH
OH
COOH
C H3
Natamycin
HO
OH
N H2
a. Match the pKa values provided to the appropriate functional groups and identify if the functional
group is acidic or basic.
Page1of2
b. Using the Henderson-Hasselbalch equation, calculate the percent ionization that occurs for each
of these functional groups at an intestinal pH=6.2.

each of these functional groups at an intestinal pH of 6.2.

107
Answer:
Answer
a.
H3C
OH
O
O
OH
OH
COOH
Carboxylic acid
(pKa = 4.6)
Acidic
C H3
Natamycin
HO
OH
N H 2 Primary amine
(pKa = 8.4)
Basic
b. For the carboxylic acid, the pKa=4.6 and the pH=6.2. Using the Henderson-Hasselbalch equation
gives the group
following:
4. The most basic functional
present within the structure of ranitidine has a pK value of 8.2. Identify this
a
Form]
functional group
and calculate the [Base

6.2 = 4.6 +log pH that is necessary for this functional group to be 70% ionized.
[Acid Form]
Answer:
Solving the equation provides a ratio of [Base Form]/[Acid Form].
1.6 = log
[Base Form]
[Acid Form]
The electron withdrawing property of the nitro

group greatly decreases the pKa value for the
[BaseForm]
39.8 [BaseForm] adjacent nitrogen containing group.
39.8 =
or
=
[AcidForm]
1
[AcidForm]
amine
Tertiary
pKa = 8.2
Ranitidine
For every molecule that contains this functional group in the acid form, there are 39.8 molecules that
contain this functional group in the base form. Because the functional group is acidic, the base form
is equal to the ionized form, and the acid form is equal to the unionized form.

39.8 Molecules in Base Form + 1.0 Molecule in Acid Form = 40.8 Total Molecules
Base Form = Ionized Form and Acid Form = Unionized Form for This Functional Group
39.8MoleculesinIonizedForm
PercentinIonizedForm =
x100%
40.8TotalMolecules
Percent in Ionized Form= 97.5%
For the primary amine, the pKa=8.4 and the pH=6.2. Using the Henderson-Hasselbalch equation gives
the following:
[BaseForm]
6.2 = 8.4 +log
[AcidForm]

Page2of2
Answer:
108
Solving the equation provides a ratio of [Base Form]/[Acid Form].

OH
O
O
OH
[Base Form]
2.2 = log
[Acid Form]H 3 C
O
OH O
Carboxylic acid
COOH
(pKa = 4.6)
[Base Form]
0.0063 [Base Form]
0.0063 =
or
=
Acidic
[Acid Form]
1
[Acid Form]
O
O
C H3
For every molecule that contains this functional group in the acid form, there are 0.0063 molecules
that contain this functional group in the
base form. Because the functional group is basic, the base
Natamycin
form is equal to the unionized form, and the acid formHisOequal to theOionized
form.
H
0.0063 Molecules in Base Form + 1.0 Molecule in Acid Form = 1.0063

Molecules
N H 2 Total
Primary
amine
(pKa = 8.4)
Base Form = Unionized Form and Acid Form = Ionized Form for This Functional
BasicGroup
1MoleculeinIonizedForm
x100%
1.0063TotalMolecules
4. PercentinIonizedForm
The most basic functional =99.4%
group present within the structure of ranitidine has a pKa value of 8.2. Identify this
4. Answer:
The most basic functional group present within the structure of ranitidine has a pKa=8.2. Identify this
Answer
group greatly decreases the pKa value for the
adjacent
nitrogen
containing
group.
group
greatly
decreases
the pKa value
for the
adjacent nitrogen-containing group.
Tertiary amine
pKa = 8.2
Ranitidine
We can use the Henderson-Hasselbalch equation to solve this problem. Because the ionized form of
a basic functional group can also be designated as its protonated form or its conjugate acid form,
either of the following equations can be used.
pH =pK a +log
[BaseForm]
[AcidForm]
orpH =pK a +log
[UnprotonatedForm]
[ProtonatedForm]
Therefore, if 70% of this functional group is ionized:
pH = 8.2 + log
[30]
[70]
pH = 8.2 + log
[30]
= 8.2 + ( 0.37) = 7.83
[70]
Because a pH=7.83 does not exist physiologically, this percent ionization could only occur in an
exogenously prepared solution.

Page2of2
1. Some drug molecules can be formulated as either a potassium salt or hydrochloride salt. Evaluate all of
the acidic and basic functional groups in each of the drug molecules drawn below and fill in the grid with
the appropriate information.
Answer
Name of Drug
Molecule
Name of Functional
Group That Can Form
a Potassium Salt
Is the Potassium Salt

Acidic, Basic, or Neutral?
Name of Functional
Group That Can Form a
Hydrochloride Salt
Is the Hydrochloride
Salt Acidic, Basic, or
Neutral?
Arformoterol
Phenol
Basic
Secondary amine
Acidic
Baclofen
Carboxylic acid
Basic
Primary amine
Acidic
Irbesartan
Tetrazole
Basic
Amidine
Acidic
Ciprofloxacin
Carboxylic acid
Basic
Secondary amine (NH)

component of piperazine
Acidic
Aniline component (N) of

piperazine
Acidic
Tertiary amine
Acidic
Tetracycline
Phenol
Basic
2. Each of these drug molecules will treat a particular ailment by either managing a symptom or
-dicarbonyl
Basic
modulating
biochemical
pathway.
In either
case,
the drugthe
hasconjugate
to get to its
biological
Using your
Note: The
ionized aform
of an acidic
functional
group
is termed
base
of that target.
functional
group. The ionized form of a basic functional group is termed the conjugate acid of that functional group.
knowledge about functional group character, describe how both of the drugs get to their respective
biological targets. Consider the concepts of solubility, absorption, distribution, and route of administration
2. Each of these drug molecules will treat a particular ailment by either managing a symptom or modulating
a biochemical pathway. In either case, the drug has to get to its biological target. Using your knowlin your answer. [pH (stomach) = 1; pH (intestine) = 8; pH (plasma) = 7.4]
edge about functional group character, describe how both of the drugs get to their respective biological
targets. Consider the concepts of solubility, absorption, distribution, and route of administration in your
answer. [pH (stomach)=1; pH (intestine)=8; pH (plasma)=7.4]
NCH3
Cl
OH
N
CONH2
Loperamide
O
O
CH2OH
Scopolamine
3.atlantic
Based
on your
structural evaluation, provide a rationale for why each of these drugs cannot be
Purchased by palm beach
university,
Ed Nordine
109
delivered via an oral route of administration, or why there is limited absorption of the drug when it is
110
Biological Targets and Routes of Administration

Loperamide: opioid receptors located in the large intestine; oral administration
Scopolamine: muscarinic acetylcholine receptors (M1) located in the peripheral nervous system;
transdermal administration
Answer
Loperamide:
Oral tablet is swallowed.
Tablet dissolves in aqueous contents of the stomach (requires drug to be water soluble).
The amide, piperidine (tertiary amine), and tertiary alcohol have hydrophilic character and
contribute to the water solubility of the drug.
Do not want absorption into systemic circulation via stomach lining.
The piperidine (tertiary amine pKa=911) will be predominantly ionized in the stomach
pH=1 (pH < pKa).
Distribution into intestinesmaller fraction in ionized form; retain water solubility.
The piperidine (tertiary amine pKa=911) will be somewhat less (but still predominantly) ionized
in the intestine pH=8 (pH < pKa).
Interaction with receptor located in intestinethere is no need for absorption out of the gastrointestinal (GI) system and into systemic distribution.
Scopolamine:
Patch is placed on skin.
Absorption of drug occurs from patch into skin lipophilic bilayer (requires hydrophobic
character).
The aromatic ring and bicyclic heterocycle contribute to hydrophobic character of the drug and
allow for absorption and transport through skin.
Drug transports through skin and dissolves into circulation (requires drug to be water soluble).
The bicyclic heterocycle (tertiary amine pKa=911) will be primarily ionized in the plasma pH=7.4
(pH < pKa). The ester, ether, and primary alcohol are hydrophilic in character and contribute to
the water solubility of the drug.
Distribution to peripheral receptors (requires drug to be water soluble).
The bicyclic heterocycle (tertiary amine pKa=911) will be primarily ionized in the plasma pH=7.4
(pH < pKa). The ester, ether, and primary alcohol are hydrophilic in character and contribute to
the water solubility of the drug.
Interaction occurs with receptors located in periphery.

OH
CH2OH
CONH2
111
3. Based on your structural evaluation, provide a rationale for why each of these drugs cannot be delivScopolamine
ered
via an oral route of administration, or why there is limited absorption of the drug when it is
Loperamide
Insulin Structure
ased on your structural evaluation, provide aS rationale for why Seach of these drugs cannot be
A Chain
Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn COOH
H2NofGly
ered via an oral route
administration,
or why there is limited absorption of the drug when it is
nistered orally.
H2 N Phe Val Asn Gln His
Leu Cys Gly Ser His
Leu Val Glu Ala Leu Tyr
Leu Val Cys
B chain
Gly Glu Arg
Gly
HOOC
Thr30
Lys29 Pro28
Thr27
Tyr
Phe Phe
PO3Na2
PO3Na2
H2N
OH
Alendronate
Insulin
Answer
Insulin is a molecule composed of two peptide subunits connected to one another via two disulfide
linkages. Peptide bonds do not survive the hydrolytic environment found in the stomach. Insulin can
undergo acid catalyzed hydrolysis in the aqueous environment of the stomach, as well as enzymatically catalyzed hydrolysis in the same physiological compartment. Because of this rapid degradation,
peptide-based drugs like insulin cannot be delivered via the oral route.
Alendronate contains two ionizable phosphonates, an ionizable primary amine, and a tertiary
alcohol. These functional groups impart significant hydrophilic character and make alendronate very
water soluble. There is very, very, little hydrophobic character to contribute to absorption across the
GI mucosal membranes. Although alendronate can be administered orally, less than 6% of a given
dose is absorbed and distributed systemically.

Embeconazole

112
Answer
Can this be formulated as
a. a topical ointment or cream? YES NO
b. an aqueous solution?
YES NO
c. Which structural features and corresponding characteristics did you consider when answering
each of these questions?
Although there are hydrophilic functional groups that can participate in hydrogen bonding
interactions with water and impart a reasonable amount of water solubility (fluorine atoms on
the aromatic hydrocarbons, tertiary alcohol, a weakly basic nitrogen containing heterocycle [1,2,4
triazole], and oxygen containing heterocycle [1,3 dioxane]), their effect is overwhelmed by the
functional groups that are hydrophobic in character (two aromatic hydrocarbons, alkene, thioether). This hydrophobic character allows for good drug penetration into and across the skin if
applied as a topical cream or ointment; however, this character is likely to significantly limit the
drugs water solubility as an aqueous solution.
Go to Section 1.4

2.5
Drug Binding Interactions
1. Both delapril and lisinopril are inhibitors of angiotensin converting enzyme (biological target) a
2.5
other interacts with a Zn+2 atom. Both of these interactions are critical for drug action. Do the followin
Drug Binding Interactions
a. Modify the molecules below to show the form of the active drug at physiological pH.
1. Both delapril and lisinopril are inhibitors of angiotensin converting enzyme (biological target) a
b. Identify the type of interaction possible between the carboxylic acids and the residues pr
other interacts with a Zn+2 atom. Both of these interactions are critical for drug action. Do the followin
the biological
target. converting enzyme (biological target) and as such
1. Both delapril and lisinoprila.arewithin
inhibitors
of angiotensin
Modify
the molecules
below to show the form of the active drug at physiological pH.
are valuable drugs used in the management of hypertension. The active form of these drugs requires the
Answer:
presence of two carboxylic
acids
or twothe
functional
groups thatpossible
can participate
similar
types of
interactions
b.
Identify
type of interaction
betweeninthe
carboxylic
acids
and the residues pr
at physiological pH. One of the carboxylic acids interacts with an active site arginine residue, and the other
interacts with a Zn+2 atom. Both
of these
interactions
are critical for drug action. Do the following:
within
the biological
target.
a. Modify the molecules below to show the form of the active drug at physiological pH (pH=7.4).
Answer:
b. Identify the type of interaction possible between the carboxylic
acids and the residues present within
H 2N
2+
the biological target.
CH2 R
Zn
O
Answer
O
Zn
O
2+
C H3
+
N
H H O
O C H3
+
Delapril N
N
H H O
H 2N
O
O
+
NH2
+
NH2
CH2 R
H
Ionic interactions areDelapril

possible between the carboxylic acids and the zinc ion and the ionized arginine
residue.
Ionic interactions are possible between the carboxylic acids and the zinc ion and the ionized arginine
residue.
Ionic interactions are possible between the carboxylic acids and the zinc ion and the ionized arginine
residue.

Lisinopril
Lisinopril

113
114
in the treatment
of overactive
bladder.
Based
on the structure
process described
2.used
Tolterodine
(Detrol), fesoterodine
(Toviaz
), and
oxybutynin
(Ditropanevaluation
) are anticholinergic
agents in
Chapter 6* and previous chapters,* read each of these drug molecules and determine how each
of these drug molecules interact via hydrogen bonding with the muscarinic receptor. Fill in the grid
provided with your answers.
Tolterodine
Fesoterodine
Oxybutynin
Answer
Function
Function
Name of ALL Anticholinergics That

Contain Functional Group
H-bond donor,
H-bond
acceptor, both
or neither
One amino acid that interacts (via side

chain) with the functional group via a
complementary H-bonding interaction;
NONE is a possible answer
Alkane (i.e.,
alkyl chain)
Tolterodine, fesoterodine, oxybutynin
Neither
None
Cycloalkane
Oxybutynin
Neither
None
Aromatic hydrocarbon
Tolterodine, fesoterodine, oxybutynin
Neither
None
Alkyne
Oxybutynin
Neither
None
Tertiary alcohol
Oxybutynin
Both
Serine, threonine, cysteine, tyrosine, glutamic

acid, aspartic acid, lysine, arginine, asparagine,
glutamine, histidine, tryptophan
Primary alcohol
Fesoterodine
Both

Name of
Functional
Group

115
Continued from previous page

Phenol
Tolterodine
Both

Tertiary amine
Oxybutynin, fesoterodine, tolterodine
Acceptor

Ester
Fesoterodine, oxybutynin
Acceptor

Note: Please remember that if a functional group is ionized, then it can no longer participate in
hydrogen bonding interactions.
3. Each of the three odorant molecules drawn below produces a unique scent on interaction with the
olfactory receptors. Unlike most biological targets for drug action, olfactory receptors typically have
anEach
affinity
wideodorant
variety molecules
of odorantdrawn
molecules
can adopt
uniquescent
conformations
to enhance
3.
of for
the athree
belowand
produces
a unique
on interaction
with the
the affinity of a given odorant for the receptor. Based on the structural features found in each molecule, what
type of Unlike
interactions
are possible
withforthe
olfactory
receptorsreceptors
at physiological
olfactory
receptors.
most biological
targets
drug
action, olfactory
typically pH?
haveIndicate
an
which functional group(s) can participate in each of the interactions identified.
Sclareol
(herbal scent)
Nerolidol
(green
(greenwoody
woodyscent)
scent)
Vanillin
Sclareol
Vanillin
Interaction Type
Functional Group
Interaction Type
Nerolidol
Functional Group
Interaction Type
Functional Group
Cycloalkane,
aliphatic
van der
Waals,
Phenol
der Waals,
Aliphatic
4.Hydrophobic
There are five basic
flavors
that our
taste
receptors
detect: salty, van
sour,
sweet, bitter,
andalkanes
umami
alkane, alkene
Hydrophobic
Hydrophobic
and alkenes
(savory).
The taste Tertiary
receptors
are located
on taste
areether,
on our tongue,
soft
palate, Tertiary
epiglottis,
and
Hydrogen bond
alcohol
Hydrogen
bondbuds that
Phenol,
Hydrogen
bond
alcohol
Iondipole
(as the dipole)
H 2N
Tertiary alcohol
CO2 H
(acceptor)
aldehyde
(acceptor and
donor)
Hydrogen bond
(donor)
Phenol
Iondipole
(as the dipole)
Phenol, ether,
aldehyde
CO2 H
Glutamic Acid

Cucumber flavor

O
Green Pepper Flavor
116
Sclareol
(herbal
Assessment Vanillin
Medicinal scent)
Chemistry Self
Nerolidol
(green woody scent)
4. There are five basic flavors that our taste receptors detect: salty, sour, sweet, bitter, and umami
(savory). The taste receptors are located on taste buds that are on our tongue, soft palate, epiglottis,
and
upper
esophagus.
andthat
saltyour
flavors
mediated
by ion
channels,
whereas
sweet,
bitter,
4.
There
are
five basicSour
flavors
tasteare
receptors
detect:
salty,
sour, sweet,
bitter,
and
umami
and umami flavors are derived from activation of the respective G-protein coupled receptor. The
umami receptor
is receptors
activatedare
by L-amino
acids,
glutamate.
Determine
what interactions
(savory).
The taste
located on
tastespecifically
buds that are
on our tongue,
soft palate,
epiglottis, and
are possible with the side chain of glutamate (at physiological pH) and then determine if any of the
following flavor molecules can interact with and activate this receptor.
CO2 H
H 2N
CO2 H
Glutamic Acid
Cucumber flavor
Green Pepper Flavor
O
N
O
HO
HO
P
O
HO
OH
Shitaki Mushrooms
Inosinic Acid
Answer
The side chain of glutamic acid (glutamate) contains a carboxylic acid that will be ionized at physiological
pH. In its ionized form glutamic acid can participate in an ionic interaction or in an iondipole interaction (as the ion). The functional groups in both cucumber and green pepper flavor cannot participate in ionic interactions with glutamate as none of the functional groups are ionized (cationic) at
physiological pH. Iondipole interactions (as the dipole) are possible between glutamate and the
aldehyde found in cucumber flavor and the methyl ether found in green pepper flavor. Inosinic acid is
a component found with shitaki mushrooms that is thought to contribute to their unique flavor. Structural evaluation of this molecule reveals a phosphate that is ionized at physiological pH. This functional
group can participate in iondipole interactions with the umami receptor to elicit a savory flavor.
Go to Section 1.5
2.6
Stereochemistry and Drug Action
compounds,
identify
allcenters.
chiral centers.
compounds,
identify
all chiral
OH
OH
HO
HN
Estradiol
Acebutolol
H3C
OH
N
H
O
C H3
N
N
CO2 H
H3 CO2 C
NO2
Nifedipine
117
C H3
CO2 CH3
Cefamandole

H
N
118
Answer:
Answer
OH
OH
HO
HN
Estradiol
5 chiral centers
Acebutolol
1 chiral center
H3C
H
N
C H3
*
OH
N
H
O
C H3
N
N
CO2 H
Cefamandole
3 chiral centers
H3 CO2 C
CO2 CH3
NO2
Nifedipine
0 chiral centers
The highlighted carbon atom
is symmetrical
3. Shown below is the structure of fluvastatin, an HMG-CoA reductase inhibitor used to lower plasma LDL levels.
2. For each of the four drug molecules shown in question 1:
Fluvastatin contains two chiral centers, designated as A and B. Using the structure of fluvastatin and the Cahna. Identify if it can have an enantiomer. Provide an explanation for your response.
Ingold-Prelog
(CIP) if
system,
the R/S configurations
each of its for
chiral
centers.
b. Identify
it can determine
have a diastereomer.
Provide anfor
explanation
your
response.
c. Identify if it can have a geometric isomer. Provide an explanation for your response.
Answer
HO A
CO2 H
a. Acebutolol, estradiol, and cefamandole can have enantiomers,
while nifedipine cannot. For a
drug molecule to have an enantiomer, its structure
must
contain
at least one chiral center. AcebuB OH
tolol, estradiol, and cefamandole all meet this criterion. Because the structure of nifedipine does
H
not contain a chiral center, it cannot have enantiomers.
b. Estradiol and cefamandole can have diastereomers, but acebutolol and nifedipine cannot. For
F
a drug molecule to have a diastereomer, its structure must contain at least two chiral centers.
N have five and three chiral centers, respecBecause the structures of estradiol and cefamandole
tively, these two drug molecules meet this criterion and can have diastereomers. Acebutolol (one
chiral center) and nifedipine (0 chiral centers) do not meet this criterion and thus cannot have
diastereomers.
c. Estradiol and cefamandole can have geometric isomers, while acebutolol and nifedipine cannot.
Fluvastatin
Geometric isomers are a specialized type of
diastereomer and result from restricted rotation
about a carboncarbon bond. Geometric isomers can occur in the presence of either a double
bond or an alicyclic ring. Both estradiol and cefamandole contain alicyclic rings and thus can
have geometric isomers. Acebutolol and nifedipine do not meet the above criterion and cannot
Page2of3

2.6 StereochemistryBand Drug Action
119
have geometric isomers. Please note that the double bonds seen in the 1,4-dihydropyridine ring
of nifedipine reside in a six-membered ring and thus cannot participate in the formation of
2. Thesamestructurefonterroralsoappearsinquestion3withfluvastatinonpages32and129.Compare
geometric isomers.
3. Shown
below is the structure of fluvastatin, an HMG-CoA reductase inhibitor used to lower plasma
LDL levels. Fluvastatin contains two chiral centers, designated as 1 and 2. Using the structure of
fluvastatin and the Cahn-Ingold-Prelog (CIP) system, determine the R/S configurations for each of its
chiral centers.
HO 1
CO2 H
2 OH
H
F
N
Fluvastatin
Answer:
Answer
Chiral center 1
D
C
Chiral center 2
A
D
C
Fluvastatin
Fluvastatin
Using the CIP sequence rules for chiral center 1, the hydroxyl group (A) has the first priority because
oxygen always has priority over carbon. Carbon atoms B and C are identical because each is attached
4. Shown below is the enantiomer of fluvastatin. Which of the following properties/actions would be expected to
to one carbon atom and two hydrogen atoms. It is therefore necessary to examine the two adjacent
carbon for
atoms.
The carbon
adjacent
carbon
C (O,O,O)
has priority
over the carbon atom adjabe identical
fluvastatin
and itsatom
enantiomer
andtowhich
would
be expected
to be different?
cent to carbon B (O,C,H); thus, the final priority is hydroxyl group (A) > carbon atom C > carbon atom
B > a.
hydrogen
(D). The
Percentatom
ionization
at ahydrogen
pH of 7.4 atom is projected into the paper and located away from the
reader. Applying the above priorities reveals a clockwise orientation. Thus, the correct designation
for chiral center 1 is R.
Using the CIP sequence rules for chiral center 2, the hydroxyl group (A) once again has the first
H Opriority. Carbon atom C (C,C,H) has priority over
priority, and the hydrogen atom (D) has the least
CO2 H
carbon atom B (C,H,H); thus, the final priority is hydroxyl group
(A) > carbon atom C > carbon atom
OH

120
B > hydrogen atom (D). Unlike chiral center 1, the hydrogen atom of chiral center 2 is projected out
of the paper and located directly toward the reader. In situations like this, there are three options:
Answer:
(1) redraw the chiral center with the hydrogen projected into the paper while maintaining the
correct stereochemical orientation of all other groups;
(2) imagine that you are viewing the object from the other side of the paper; or
D
A
(3) use the given projection
and make an alteration in your final answer.
C
Options 1 and 2 are often difficult for students to accomplish without producing errors; therefore,
optionChiral
3 is suggested.
atom
(or2the atom ofA lowest priority) IS
center 1 Initially pretend that the hydrogen
Chiral
center
projected into the plane ofBthe paper and apply the sequence rules. In this Bcase, there is a clockwise
D stereochemorientation that is consistent with the R isomer. Because it was necessary to invert the
istry of the chiral center to do this, the correct designation is the exact opposite. CIn this case, chiral
center 1 has the S configuration.
4. Shown below is the enantiomer of fluvastatin. Which of the following properties/actions would
be expected to be identical for fluvastatin and its enantiomer and which would be expected to be
different?
Fluvastatin
Fluvastatin
a. Hepatic metabolism
b. Water solubility
4. Shown
is the
enantiomer
c. below
Adverse
effect
profile of fluvastatin. Which of the following properties/actions would be expected to
d. Active
renal reabsorption
by transport
proteins
be identical
for fluvastatin
and its enantiomer
and which
would be expected to be different?
e. Potency (dosage given)
a. Percent ionization at a pH of 7.4
f. Percent ionization at a pH=7.4
HO
CO2 H
OH
H
F
N
Enantiomer of
Fluvastatin
Answer
Enantiomers have identical physical and chemical properties, with the exception of the direction
in which they rotate plane polarized light. Thus, water solubility and the percent ionization of the
carboxylic acid at a pH of 7.4 would be expected to be identical. The major difference and most
important aspect of enantiomers are their relative abilities to interact with three-dimensional
biological targets. Hepatic metabolism and active renal reabsorption depend on binding to metabolizing enzymes and transport proteins, respectively, and would be expected to be different. Adverse
effects can be due to the interaction of these drug molecules with other biological targets and/or the
121
formation of a specific metabolite. Differences in potency can result in differential metabolism (i.e.,
one enantiomer may be inactivated quicker than the other) or differential binding to the biological
target.
Go to Section 1.6
Note: References to chapters are related to Chapter 7 in Harrold MW and Zavod RM, Basic Concepts in Medicinal Chemistry, American Society of Health-System Pharmacists, 2013.


2.7 Drug Metabolism

2.7
Drug is
Metabolism
1. Heroin
a synthetic derivative of the naturally occurring opioid analgesic morphine. Given its illicit
nature, heroin is not subject to Food and Drug Administration (FDA) regulation; therefore, the actual
1. Heroin isofaasynthetic
derivative
the naturally
occurring
opioidmolecules
analgesicdrawn
morphine.
Given
its illicit
composition
given heroin
batchof
varies
significantly.
The three
below
represent
the
three major components found within a batch of heroin. The users intense rush has been attributed to
morphine. Which phase I transformation is responsible for the conversion of heroin to morphine?
the conversion of heroin into morphine. Which phase I transformation is responsible for the conversion of
heroin to morphine?
Heroin
Morphine
2. Estradiol, the estrogen component of many oral contraceptives, undergoes a phase II conjugation then
Answer
Heroin is the diacetyl ester of morphine. Two successive phase I ester hydrolysis reactions are responsible
(at least
in part).to
Consider
the structure of estradiol drawn below and do the following:
forreabsorbed
the conversion
of heroin
morphine.
transformation).
2. Estradiol, the estrogen component of many oral contraceptives, undergoes a phase II conjugation reaction
to produce
metabolite
that
is eliminated
viathis
a fecal
route
(at least in part). The conjugated hormone
b.aWhich
enzyme
is required
to make
sulfate
conjugate?
undergoes a process called enterohepatic recycling. In this process the sulfate conjugate is cleaved by gut
bacteria toAnswer:
regenerate
the active drug,
which is then reabsorbed (at least in part). Consider the structure
Sulfotransferase
(SULT)
of estradiol drawn below and do the following:
transformation).
b. Which enzyme is required to make this sulfate conjugate?
Answer: Sulfatase
Answer
Sulfotransferase (SULT)

123
transformation).
124
b. Which enzyme is required to make this sulfate conjugate?
Answer: Sulfotransferase (SULT)

c. Which deconjugating enzyme catalyzes removal of the sulfate group thus allowing for enterohepatic
recycling?
c. Which
deconjugating enzyme catalyzes removal of the sulfate group thus allowing for
Answer
Sulfatase
Answer: Sulfatase
3. Metabolites do not necessarily have the same mechanism of action as the parent drug. In the case of
chlorimipramine (a tricyclic antidepressant that inhibits serotonin uptake), a phase I transformation
produces a metabolite that is also a tricyclic antidepressant, but whose mechanism of action is via
inhibition of norepinephrine reuptake. Which phase I transformation has occurred? What additional
phase I transformations
are possible?
3. Metabolites
do not. In the case
of I transformations are possible?
Chlorimipramine
Answer
4. Evaluate each of the which phase I metabolic transformation has occurred.
Phase I transformation that has occurred: oxidative N-dealkylation
Other phase I transformationsHpossible: ortho/para aromatic hydroxylation; benzylic oxidation;
N-oxidation; oxidative N-dealkylation
is still a methyl group); oxidative deamination (of the
N
C H(there
N H2
3
doubly-demethylated product). One of the products from the oxidative deamination
is an aldehyde,
which can undergo further oxidation (aldehyde oxidation) to the carboxylic acid.
C H3
CF3
Dexfenfluramine

C H3
CF3
2.7 Drug Metabolism
125
Chlorimipramine
4. Evaluate each of the following metabolic transformations and determine which phase I metabolic
transformation has occurred.
4. Evaluate each of the which phase I metabolic transformation has occurred.
H
N
C H3
N H2
C H3
C H3
CF3
CF3
Dexfenfluramine
Fluvoxamine

H2N
CO2 H O
OH
OH
Cl
Cl
Baclofen
Answers
Oxidative N-dealkylation
Oxidative O-dealkylation
Oxidative deamination followed by oxidation of the resulting aldehyde to a carboxylic acid
Go to Section 1.7
Note: References to chapters are related to Chapter 8 in Harrold MW and Zavod RM, Basic Concepts in Medicinal Chemistry, American Society of Health-System Pharmacists, 2013.

Part 2 ANSWERS
Section 4 Whole Molecule Drug

Evaluation

2.8
2.9
2.10
2.11
2.12
2.13
2.14
2.15
2.16
2.17
2.18
2.19
2.20
Aliskiren..................................................................... 129
Aripiprazole................................................................ 137
Cefprozil..................................................................... 143
Cetirizine.................................................................... 149
Chlorpropamide and Other Sulfonylureas.................. 153
Dabigatran Etexilate.................................................. 159
Fenofibrate and Gemfibrozil....................................... 165
Fluvoxamine............................................................... 169
Haloperidol................................................................ 173
Hydrocortisone........................................................... 177
Levothyroxine (T4)...................................................... 183
Lidocaine.................................................................... 189
Montelukast and Zafirlukast...................................... 193
2.21
2.22
2.23
2.24
2.25
2.26
2.27
Phenobarbital and Other Barbiturates....................... 199

Pravastatin and Fluvastatin........................................ 205
Quinapril.................................................................... 211
Rivastigmine.............................................................. 217
Sitagliptin................................................................... 223
Sorafenib.................................................................... 227
Zanamivir and Oseltamivir......................................... 233


Answers
2.8 Aliskiren
Aliskiren is an orally active agent used in the treatment of hypertension. This non-peptide drug acts as an inhibitor
of renin, the enzyme that converts angiotensinogen (its endogenous substrate) to angiotensin I. Biologically inactive,
angiotensin I is rapidly converted to angiotensin II by angiotensin converting enzyme. Angiotensin II is a potent
agonist when bound to its receptor and produces significant vasoconstriction, as well as an increase in blood pressure.
In the presence of aliskiren, angiotensinogen is not converted to angiotensin I so less angiotensin II is produced to
activate the angiotensin II receptor. Consequently, less vasoconstriction occurs, and a drop in blood pressure results.
Chapters 1.8 and 2.8
1. Conduct a structural evaluation of aliskiren, focusing on the boxed functional groups and use the informaChapter 1.8/2.8 (remove bold from drug name x2)
tion in the grid to inform your answers to the questions that follow.
Aliskiren
Aliskiren

129
130
Answer
Function
Function
Character
Character
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Ether
Hydrophilic (O)
Provide pKa
When Relevant
Solubility
and/or
Absorption
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
Neutral
Solubility (O)
H-bonding (A)
Absorption (R)
Dipoledipole
Function
Acidic, Basic, or
Neutral
Hydrophobic (R)
Amino Acids That

Can Interact with
the Functional
Group via Ion
Dipole Interactions
at pH=7.4
None Is Acceptable
Asp, Glu, Lys, Arg
Iondipole (as the

dipole)
B
Hydrophobic
Neutral
Absorption
Hydrophobic
None
van der Waals

- stacking
Aliphatic alkane
Hydrophobic
Neutral
Absorption
Hydrophobic
None
van der Waals
Primary amine
Secondary alcohol

Solubility (NH2)
Iondipole (as the ion) Ser, Thr, Cys, Tyr, Asn,
Chapters
1.8 and 2.8
Hydrophilic (NH2)
Basic
Hydrophobic (R)
pKa ~911
Absorption (R)
Neutral
Solubility (OH)
H-bonding (A + D)
Absorption (R)
Dipoledipole
Chapter 1.8/2.8 (remove bold from drug name x2)
Hydrophilic (OH)
Hydrophobic (R)
Amide
Glu, His, Trp
Ionic
Hydrophilic
(CONH2)
Hydrophobic (R)
D
Neutral
Asp, Glu, Lys, Arg
Iondipole (as the

dipole)
Solubility
(CONH2)
H-bonding (A)
Absorption (R)
Iondipole (as the

dipole)
Asp, Glu, Lys, Arg
Dipoledipole
Aliskiren
2. Aliskiren is marketed as the pure 2S, 4S, 5S, 7S
C enantiomer. Circle all of the chiral carbon atoms and
determine if diastereomeric or geometric isomers are possible.
Aliskiren

2.8 Aliskiren
Answer
131
Aliskiren
If there are two or more chiral carbon atoms, then it is possible for the drug to have diastereomeric
forms. In the case of
aliskiren,
chiral
carbon
atoms; therefore, there are a lot of poten(remove
boldthere
from are
drugfour
name)
Chapter
1.8/2.8
tial diastereomeric forms. A quick reminder on how to determine if a pair of isomers is diastereomericif one chiral carbon is held constant (e.g., R-isomer) and you vary at least one additional chiral
carbon, then the pair of isomers will be diastereomeric to one another. In the example shown below,
there
areheldisconstant
and theand
(*) chiral
center
varied.isThe
pair of
isomers
are diastereom
the chiral center Ifthat
is circled
held constant
the (*)
chiraliscenter
varied.
The
pair ofdrawn
isomers
drawn are diastereomers.
*
Amlodipine
For geometric isomers to be possible there must be restricted rotation around a carboncarbon
of the ring).
absorbed
dose ofofaliskiren
excreted
the urineofunchanged.
bond (e.g., presence 4.
of aApproximately
double bond 25%
or alicyclic
Evaluation
aliskirenis reveals
theinabsence
double bonds and alicyclic rings; therefore, geometric isomers cannot exist.
transformation has occurred and whether or not it represents an oxidative transformation.

132
3. Although aliskiren is administered orally, its oral bioavailability

is ~2.5% and is very poorly absorbed.
*
Using the information in the structure evaluation grid, provide a structural rationale for this unfortunate property.
Answer
Oral bioavailability is dependent on the drugs ability to dissolve in the aqueous contents of the
gastrointestinal (GI) tract and its ability to cross the lipid bilayer membrane. The hydrophilic character of the drug promotes aqueous solubility. Evaluation of the entire molecule (not just the boxed
functional groups) for hydrophilic character reveals two ethers, two amides, a primary amine (in its
ionized form), and a secondary alcohol that will contribute meaningfully to the hydrophilic character
of the drug. (NOTE: the drug is sold as a hemifumarate salt that further increases the overall water
solubility of the drug.) The hydrophobic character* of the drug promotes absorption across the lipid
bilayer. Evaluation of the entire molecule (not just the boxed functional groups) for hydrophobic
character reveals an aromatic hydrocarbon, a lipophilic ether, and several aliphatic alkanes. The drug
is formulated as a water soluble salt and had ample hydrophilic character. Unfortunately it does not
have sufficient hydrophobic character to allow for meaningful absorption.
4. Approximately 25% of the absorbed dose of aliskiren is excreted in the urine unchanged. It is
Approximately
25%
of the absorbed
dose
of aliskiren
is excreted
in the urine unchanged. It is
unknown how much 4.
of an
absorbed dose
is metabolized,
and
several
metabolites
from CYP3A4
mediated transformations have been identified. Several possible metabolic products are illustrated.
transformation has occurred and whether or not it represents an oxidative transformation.
Identify which metabolic transformation has occurred and whether or not it represents an oxidative
transformation.

2.8 Aliskiren
133
Answer
5. Renin catalyzes the cleavage of a specific Leu-Val peptide bond within the structure o
Oxidative or Non-Oxidative
Oxidative
Oxidative O-dealkylationchains of these two amino acids
and box the non-hydrolyzable hydroxyethylene group.
Alcohol oxidation
Oxidative
Oxidative deamination
Oxidative
Oxidative O-dealkylation*
Oxidative
Amide hydrolysis*
Non-oxidative
* This metabolite has been identified as one of the two primary metabolites produced.

134
5. Renin catalyzes the cleavage of a specific Leu-Val peptide bond within the structure of angiotensin5. The
Renin
catalyzes
the cleavage
of afunctional
specific Leu-Val
bondthe
within
structure
of side
ogen.
structure
of aliskiren
contains
groupspeptide
that mimic
side the
chains
for these
two
amino acids. The hydrolyzable peptide bond (found between Leu-Val) has been replaced by a nonchains of
these two aminogroup
acids in
and
box the non-hydrolyzable
hydroxyethylene
hydrolyzable
hydroxyethylene
aliskiren.
Circle the functional
groups that group.
mimic the amino
acid side chains of these two amino acids and box the non-hydrolyzable hydroxyethylene group.
Answer:
Answer
H3 C
H3C
C H3
H H3C
N
HO
H2 N
C H3

O
H3 CO
O
H3C
N H2
C H3
6. Aliskiren can be co-administered with other anti-hypertensive agents to provide better likely is it
6. Aliskiren can be co-administered with other anti-hypertensive agents to
provide better hypertension
Aliskiren
that a plasma
protein is
binding
interaction will occur
if these drugscalcium
are co-administered?
management.
Amlodipine
a second-generation
dihydropyridine
channel blocker used in
the treatment of hypertension. Aliskiren and amlodipine are both plasma protein bound (4751%
and 9397%, respectively). How likely is it that a plasma protein binding interaction will occur if
these drugs are co-administered?(remove bold from drug name) Chapter 1.8/2.8
Amlodipine
Amlodipine

2.8 Aliskiren
135
Answer
It is important to first determine whether these drugs are basic, acidic, or amphoteric in nature.
Based on a structural evaluation of the entire aliskiren molecule (not just the boxed functional
groups), there is one basic functional group (primary amine) and no acidic functional groups present.
The same evaluation for amlodipine yields identification of two basic functional groups (primary
amine and dihydropyridine ring) and no acidic functional groups. Based on this evaluation, both
drugs are basic and both would be bound to 1-acid glycoprotein (plasma protein). It is important to
remember that plasma protein binding interactions are likely to happen when a drug is >90% plasma
protein bound. Given the extent to which amlodipine is plasma protein bound, it is highly likely that
a plasma protein binding interaction will occur when aliskiren displaces amlodipine from the glycoprotein binding site. When this type of interaction occurs, there will be a greater fraction of amlodipine present in its unbound form. This leads to an increase in pharmacological activity resulting in
hypotension (excessively low blood pressure).
Go to Section 1.8


Answers
2.9 Aripiprazole
2.9
2.9Aripiprazole
Aripiprazole
Shown below is the structure of aripiprazole, a serotonin receptor modulator used for the treatment of depression,
Shown
of depression,
depression,schizophrenia,
schizophrenia,autism,
autism,
mania,
and
bipolar
disorder.
Shownbelow
belowisisthe
theor
orused
usedfor
for the
the treatment of
mania,
and
bipolar
disorder.
schizophrenia, autism, mania, and bipolar disorder.
Aripiprazole
Aripiprazole
1. Identify
all ofall
the
functional
provide at
the
pKofa range
1. Identify
ofacidic
wouldand
be basic
primarily
ionizedgroups,
or unionized
a normal
urine pH
5.6. for each of the identi1.
all groups,
of wouldand
beidentify
primarily
ionized
or unionized
at a urine
pH of 5.6.
fiedIdentify
functional
if each
functional
group would
be primarily
ionized or unionized at a
urineAnswer
pH=5.6.
Answer
Answer
Tertiary amine (Basic functional group)

Tertiary
amine
(Basic
group)
Normal pH
range
= 9 tofunctional
11
Normal
pHprimarily
range =ionized
9 to 11at a pH = 5.6
Would be
Would be primarily ionized at a pH = 5.6
Cl
Cl
H
NH
N
O
O
Cl
Cl
N
Aripiprazole
Aripiprazole
Aromatic amine (Aniline, Basic functional group)
Normal pH
range(Aniline,
= 2 to 5 Basic functional group)
Aromatic
amine
Would be primarily unionized at a pH = 5.6
Normal pH range = 2 to 5
Would be primarily unionized at a pH
= 5.6
2. Identify all of the of aripiprazole.

Answer
2. Identify
all of the of aripiprazole.
3. Answer
3.

(Lipid soluble)
137
Alkyl (aliphatic)
chain
Ether oxygen
(Lipid
soluble)
Halogens
(Water soluble)
Amide
(Water soluble)
138
2. Replacementstructurefortheanswertoquestion2inChapter2.9(Aripiprazole)
Identify all of the remaining functional groups, and indicate how each group contributes to the
overall water solubility or the overall lipid solubility of aripiprazole.
Answer
(Lipid soluble)
Ether oxygen
(Water
soluble)
Halogens
Amide
(Water soluble)
(Lipid soluble)
Hydrocarbon portion
of bicyclic ring
(Lipid soluble)
Aromatic (phenyl) ring

(Lipid soluble)
Aripiprazole
(Lipid soluble)
3. Using your answers from the previous two questions, provide an explanation as to why aripiprazole
can be administered orally for the indications previously listed.
Sulfonylureas)
Answer
The tertiary amine, aromatic amine, amide, and ether oxygen atom provide adequate water solubility that allows aripiprazole to dissolve in the aqueous contents of the gastrointestinal (GI) tract.
Once dissolved, aripiprazole must pass through the GI mucosal membrane to enter the blood stream.
The dichloro phenyl ring, the alkyl chain, and the hydrocarbon portion of the bicyclic ring will
Cl solubility to allow for absorption across
provide adequate lipid
O the mucosal membrane. The tertiary
O
amine will be primarily ionized within
the GI tract, whereas
the aromatic amine will be primarily
O
unionized once it leaves the stomach. Remember thatSionization
N
N is an equilibrium process with some
H
H Le Chateliers principle, as soon as
fraction of unionized molecules present at all times. According
to
N
O
one unionized molecule passes through
the
GI
membrane,
the
equilibrium
will reset to provide addiH
tional unionized molecules. O
This same principle also allows ionizable functional groups to penetrate
the bloodbrain barrier Hand
nervous system (CNS). The same functional groups that
Glyburide
3 C enter the central
allowed aripiprazole to pass through the GI mucosal membrane will also provide sufficient lipid solubility to allow it to cross the bloodbrain barrier and reach its target receptors within the CNS.
O
S
H3C
N
H
N
H

OH
O
N
H
2.9 Aripiprazole
139
4. Using your answers from the previous

4. Drug molecules that are highly plasma protein bound may undergo a drug interaction due to the
5. Drug molecules
or losartan?
displacement
of one drug
molecule from a plasma protein by another drug molecule. Shown below
are the structures of tolbutamide and losartan. Both of these drugs are highly plasma protein bound.
Aripiprazole is also highly plasma protein bound (>99%). Would you expect there to be a drug interaction between aripiprazole and either tolbutamide or losartan?
4. Using your answers from the previous

Tolbutamide
5. Drug molecules or losartan?
Losartan
Answer
The6.answer
herethat
is no.
andinteraction
losartan are
acidic
moleculespH
due
Assume
thisTolbutamide
that this binding
occurs
at adrug
physiological
of to
7.4.the presence of an
acidic sulfonylurea and a tetrazole functional group, respectively. Aripiprazole is a basic drug molecule due to the presence of a tertiary amine and an aromatic amine. Acidic drug molecules primarily
bind to albumin, whereas basic drug molecules primarily bind to 1-acid glycoprotein. Plasma protein
D
binding interactions (also known as plasma protein displacement interactions)
occur due to the
nonspecific nature of the plasma proteins that bind and transport drug molecules. These types of
A
interactions are only therapeutically important when the drug molecules are highly plasma protein
C drugs, the difference in their acid/base
bound (i.e., over 90%). Although this is true of all three
nature significantly decreases the probability ofBa drug interaction due to plasma protein displacement.
Tolbutamide
Aripiprazole
Losartan
5. Assume that the boxed functional groups of aripiprazole form four key binding interactions with
a serotonin receptor. Further assume that these binding interactions occur with the side chains of
Tyr, Asp, Ile, and Gln. Using this information, identify four possible binding interactions between
aripiprazole and the given amino acids. Assume that this binding interaction occurs at a physiological
6. Assume that this that this binding interaction occurs at a physiological pH of 7.4.
pH=7.4.
D
A
C
B
Aripiprazole

140
Answer
Answer
H
N
R4
Gln
R3
H
N
R1
Cl
Hydrogen Bond
R2
R8
OH
R7
O
H
N
O
van der Waals;

Hydrophobic Interaction
N
H
Cl
N
Asp
Ionic Bond
van der Waals;

H
N
R6
R5
O
Ile
Tyr
Other binding interactions are possible among these four functional groups and four amino acids.
Isoleucine could form van der Waals and hydrophobic interactions with the halogenated aromatic
ring, whereas tyrosine could form the same types of interactions with the alkyl chain. Aspartic acid
could form an iondipole interaction (as the ion) with the amide, whereas glutamine could form an
iondipole interaction (as the dipole) with the ionized tertiary amine. Please note that it is possible
for tyrosine to form hydrogen bonds with the amide and an iondipole interaction (as the dipole)
with the ionized tertiary amine. However, in the scenario given in this question, if tyrosine was used
to form an interaction with either the amide or the ionized tertiary amine, neither aspartic acid or
glutamine could be used to form van der Waals and hydrophobic interactions with the halogenated
aromatic ring.

2.9 Aripiprazole
141
6. Shown below are three known metabolites of aripiprazole. Identify the metabolic transformations
that would be7.required
formare
each
the metabolites.
For each metabolic transformation, indicate
Showntobelow
or of
a phase
II transformation.
if it is a phase I transformation or a phase II transformation.
Metabolite A
Metabolite B
Metabolite C
Answer
Answer
Metabolite A: Aromatic
oxidation,
phase oxidation,
I
Metabolite
A: Aromatic
phase I
Note: This is somewhat
of an B:
unexpected
metabolite
because
the presence of halogen substitutents
Metabolite
Benzylic oxidation,
phase
I
on the aromatic ring generally deactivates these rings from oxidation. The difference in this particto the ability
form a conjugated
system,
thisaromatic
secondary
hydroxyl
group readily
ular drug moleculeNote:
is theDue
presence
of an to
adjacent
aromatic amine.
This
amine
can donate
electrons into the undergoes
ring via resonance
andtoeither
override
or neutralize
dehydration
form the
following
metabolite.the electronic effects of the
chloro groups, thus allowing for aromatic oxidation.
Metabolite B: Benzylic oxidation, phase I
Dehydration
allows
Note: Due to the ability to form a conjugated system, this secondary hydroxyl
group
readily underconjugation
between
goes dehydration to form the following metabolite.
the amide and the
aromatic ring.

Metabolite A: Aromatic oxidation, phase I

Metabolite B: Benzylic oxidation, phase I
142
Note: Medicinal
Due to theChemistry
ability to Self
formAssessment
a conjugated system, this secondary hydroxyl group readily
undergoes dehydration to form the following metabolite.
Dehydration allows
conjugation between
the amide and the
aromatic ring.
Metabolite C: Oxidative N-dealkylation followed by oxidation of the resulting aldehyde to a carboxylic acid by aldehyde dehydrogenase, phase I
Go to Section 1.9
1. Page 30 Question 5: font size.

Section
Answers
2.10 Cefprozil
Cefprozil is a second-generation cephalosporin that exhibits good Gram (+) activity with improved Gram () activity
as compared to the first-generation cephalosporins. Effective against the majority of bacteria that cause upper and
lower respiratory infections, as well as skin infections, cefprozil was a first-line anti-infective agent until an increase in
the incidence of resistance and the development of newer agents decreased its favored status.
N H2
N
O
HO
C H3
CO2 H
Cefprozil
1. Conduct a complete structural evaluation of cefprozil and use the information in the grid to inform your
answers to the questions that follow.
Answer
O
O
H3 C
O
Character
H3 C
Character
Acidic, Basic,
or Neutral N
O
N
Function
Solubility
and/or
Provide pKa
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Phenol
Hydrophilic (OH)
Acidic
Hydrophobic (Ar)
(pKa 910)
Solubility (OH)
Absorption (Ar)
Function
H
N
Function
Interaction(s)
Possible with
N Biological Target
CH
3
at
Physiological
pH=7.4
OH:
H-bonding (A+D)
Dipoledipole
mesylate
Iondipole (as the
dipole)
Ar:
van der Waals
Hydrophobic
- Stacking

143
Amino Acids
That Can
Interact
N H 2 with
Functional
O
Group via
N
H-Bonding
(at
pH=7.4) O(CH2 )5 CH3
None Is
Acceptable
Ser, Tyr, Trp, His,
Thr, Cys, Asn, Gln
144

Function
Function
Character
Acidic, Basic,
or Neutral
Character
Function
Solubility
and/or
Provide pKa
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Primary amine
Hydrophilic (NH2)
Basic
Solubility (NH2)
Iondipole (as the ion)
Hydrophobic (R)
(pKa 911)
Absorption (R)
Ionic
Hydrophilic (CONH)
Neutral
Solubility (CONH)
H-bonding (A + D)
Absorption (R)
Dipoledipole
Amide
Hydrophobic (R)
Amino Acids
That Can
Interact with
Functional
Group via
H-Bonding (at
pH=7.4)
None Is
Acceptable
None
Ser, Tyr, Thr, Cys,

Asn, Gln, Trp, His
Iondipole (as the

dipole)
D
Lactam
Hydrophilic (CON)
(cyclic amide)
Hydrophobic (R)
Neutral
Solubility (CON)
H-bonding (A)
Absorption (R)
Dipoledipole
Ser, Tyr, Thr, Cys,

Asn, Gln, Trp, His
Iondipole (as the

dipole)
E
Thioether
Hydrophobic
Neutral
Absorption
Hydrophobic
None
van der Waals

F
Carboxylic
acid
Hydrophilic (COOH)
Acidic
Solubility (COOH)
Hydrophobic (R)
(pKa 2.55)
Absorption (R)
Ionic
Alkene
Hydrophobic
Neutral
Absorption
Hydrophobic
Chapter 2.10 (remove bold from drug name)
None
None
van der Waals
D (four membered ring)

E
C
F
Cefprozil
2. Based on the information in the structure evaluation grid, determine if cefprozil is an acidic, basic, or
amphoteric drug. Provide a brief explanation for your answer.
Answer
Cefprozil contains two acidic functional groups (phenol and carboxylic acid) and one basic functional
group (primary amine). Because this drug contains both acidic and basic functional groups, it is
considered amphoteric in nature.

2.10 Cefprozil
145
3. Cefprozil is administered orally as a tablet or liquid suspension. Consider each of the acidic and basic
functional groups and determine whether each group will be predominantly ionized or unionized
as it moves through the gastrointestinal (GI) tract, into systemic circulation, and then into the urine.
[The relevant pKa values=10, 1.7, and 7.2.] Complete the grid below.
Answer
Name of
Functional
Group
Acidic or
Basic
(pKa)
Ionized or
Unionized at
pH=5 (saliva)
Ionized or
Unionized
at pH=1
(stomach)
Ionized or
Unionized
at pH=7.4
(plasma)
Ionized or
Unionized at
pH=8
(intestine)
Ionized or
Unionized at
pH=6 (urine)
Phenol
Acidic
Unionized
Unionized
Unionized
Unionized
Unionized
Ionized
Unionized
Ionized
Ionized
Ionized
Ionized
Ionized
Likely 50%/50%
ionized/unionized
Unionized
Ionized
pKa~10
Carboxylic acid
Acidic
pKa ~1.7
Primary amine
Basic
pKa~7.2
4. Given the predominant ionization state of these acidic and basic functional groups as they
traverse the GI tract and the information in the structure evaluation grid, determine in which GI
compartment(s) drug absorption could occur.
Answer
Drug absorption is enhanced as hydrophobic character is increased and as the percent unionized
increases. Cefprozil contains several hydrophobic functional groups including the aromatic ring
portion of the phenol, the thioether, and the alkenes. In the stomach (pH=1), the carboxylic acid
and the phenol will be predominantly unionized; however, the primary amine will be predominantly ionized. In the intestine (pH=8), the phenol and the primary amine will be unionized, and the
carboxylic acid will be primarily ionized. This means that cefprozil will always be predominantly in
an ionized form regardless of the GI location. A quick reminderan equilibrium exists between the
ionized form and the unionized form of a drug molecule. In the case of cefprozil, there is only a very
small fraction of the drug that is completely unionized at any point in time regardless of its location
within the GI tract. When cefprozil is in its unionized form, there is sufficient hydrophobic character
to permit the drug to cross the lipid bilayer membranes of the GI tract and enter systemic circulation.
Based on this evaluation, it is possible that drug absorption can occur in both GI compartments.

146
5. Approximately 60% of a cefprozil dose is recovered in the urine unchanged. Because impairment in
Cefprozil
(Cefzil)the half-life of the drug by several hours, it is likely that cefprozil underhepatic function
increases
goes a variety of metabolic transformations catalyzed by liver enzymes. For each of the metabolic
transformations AF, identify which metabolic transformation has occurred and whether the product
Chpater
Corrected
structure
E transformation)
formed 1.10/2.10
was the result
of a phase
I or(product
phase IIofmetabolic
transformation.
N
O
HO
N
O
HO
H H
H H
CH 3
CO2 H
N H2
NH 2
HO
OH
C H3
CO2 H
HO
H 2N
H
N
H H
N
O
HO
CH 3
CO2 H
C
N H2
C H3
CO2H
NH 2
H
N
HO
H H
N
O
CH 3
N H2
N H
O
-O
OH
NH 2
H
N
HO
H H
S
O
OH
CO2 H
Answer
Name of Transformation
Phase I or Phase II
Phase I
Aromatic hydroxylation
Phase I
Amide hydrolysis
Phase I
Sulfate conjugation
Phase II
Allylic oxidation
Phase I
Amino acid conjugation (with glycine)
Phase II

C H3
CO2 H
H
N
2.10 Cefprozil
147
6. Like the penicillins, the cephalosporins suffer from chemical instability of the -lactam bond. Chemical hydrolysis of this bond renders the drugs in the class of anti-infective agents inactive. This bond
is also subject to cleavage by -lactamases (due to the presence of a nucleophilic serine side chain
[CH2OH] within the active site of the enzyme). Show how the -lactam bond can be hydrolyzed by
chemical and enzymatic (-lactamase) mechanisms.
Answer
Chemical Hydrolysis
OH-
Enzymatic Hydrolysis
Go to Section 1.10


Answers
2.11 Cetirizine
Cetirizine is a popular second-generation antihistamine used in the management of allergy symptoms. It is the
metabolic byproduct produced from the prescription
antihistamine
hydroxyzine.
Although cetirizine is labeled as
Chapters
1.11 and
2.11
non-sedating and is one of the preferred allergy medications for long-haul drivers, hydroxyzine causes significant
drowsiness that limits its utility in the management of typical allergy symptoms. Hydroxyzine is commonly used in
Chapter
1.11 (remove
drug names)
the treatment
of pruritus
(severebolded
itching).
Cetirizine
Hydroxyzine
1. Conduct a complete structural evaluation of hydroxyzine and use the information in the grid to inform
Hydroxyzine

149
150
Answer
Function
Character
Character
Acidic,
Basic, or
Neutral
Function
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Provide
pKa When
Relevant
Solubility
and/or
Absorption
Amino Acids That

Can Interact with
Functional Group
Interaction(s)
via H-Bonding (at
Possible with
Biological Target pH=7.4)
None Is
at Physiological
Acceptable
pH=7.4
Halogenated
aromatic
hydrocarbon
Hydrophobic
Neutral
Absorption
Cl:
Function
None
Dipoledipole
Iondipole (as the
Medicinal Chemistry Self-Assessment
Book: Batch Two
dipole)1.11 and 2.11
Chapters
Ar:
van der Waals
Hydrophobic
- Stacking
Aromatic
hydrocarbon
Hydrophobic
Neutral
Absorption
Piperazine (two
tertiary amines)
Hydrophobic (R)
Basic
Absorption (R)
Hydrophilic (N)
(pKa 911)
Solubility (N)
Neutral
Absorption (R)
van der Waals
None
Hydrophobic
- Stacking
Ether
Hydrophobic (R)
Hydrophilic (O)
Primary alcohol
Hydroxyzine
Hydrophobic (R)
Neutral
Hydrophilic (OH)
Iondipole (as the

ion)
None (ionized at
pH=7.4)
Ionic
Solubility (O)
H-bonding (A);
Dipoledipole;
Iondipole (as the
dipole)
Ser, Thr, Cys, Tyr, Gln,

Cetirizine
Asn, His, Trp
Absorption (R)
H-bonding (A+D);
Solubility (OH)
Dipoledipole;
Ser, Thr, Cys, Tyr, Gln,

Asn, His, Trp
Chapter 2.11 (remove bolded drug names) Iondipole (as the

dipole)
Hydroxyzine
2. Name the phase I metabolic transformation(s) that hydroxyzine undergoes to produce cetirizine.
Answer
Alcohol oxidation followed by aldehyde oxidation to the carboxylic acid.

2.11 Cetirizine
151
3. Based on your structural evaluation of both hydroxyzine and cetirizine, name ALL of the phase I
metabolic transformations possible.
Answer

Alcohol oxidation
Aromatic hydroxylation (less likely on halogenated aromatic hydrocarbon)
NOTE: Although there is a benzylic carbon with a hydrogen atom attached to it, benzylic oxidation
does not occur because the benzylic carbon is already directly attached to another heteroatom (N).
4. A metabolic product from a phase II metabolic transformation has been identified. Which phase II
transformations can cetirizine undergo?
Answer
The carboxylic acid can undergo phase II transformations including glucuronidation and amino acid
conjugation (with glutamic acid and glycine [major], and aspartic acid, serine, and taurine [minor]).
(NOTE: the glucuronide conjugate is the metabolite that has been identified.)
5. Review the structure of cetirizine (pKa=2.9 and 8.3) and identify all of the acidic and basic functional
groups present. Determine the predominant ionization state of each functional group as it travels
through several compartments of the body after oral administration. Complete the table below.
Answer
Name of
Functional
Group
Acidic or
Basic
(pKa)
Ionized or
Unionized at
pH=5 (saliva)
Ionized or
Unionized
at pH=1
(stomach)
Ionized or
Unionized
at pH=7.4
(plasma)
Ionized or
Unionized at
pH=8
(intestine)
Ionized or
Unionized at
pH=6 (urine)
Tertiary amine
(piperazine)
Basic
pKa 8.3
Ionized
Ionized
Ionized
Ionized
Ionized
Carboxylic acid
Acidic
pKa 2.9
Ionized
Unionized
Ionized
Ionized
Ionized
6. Provide a structural rationale for why hydroxyzine is classified as a sedating antihistamine and cetirizine is categorized as a non-sedating antihistamine.
Answer
Hydroxyzine contains functional groups that contribute to the overall hydrophobic character of the
molecule (e.g., aromatic hydrocarbon, halogenated aromatic hydrocarbon, aliphatic alkane), as well
as functional groups that contribute to the hydrophilic character of the molecule (e.g., ether, primary
alcohol, and tertiary amines/piperazine). The hydrophilic character of the molecule enhances its
water solubility, whereas the hydrophobic character enhances its ability to be absorbed across lipid
bilayer membranes. At pH=7.4, the tertiary amine will be predominantly in its ionized form which
will further increase the water solubility of the molecule.
The hydrophilic character contributes to the ability of the drug to be distributed in the body in the
aqueous plasma. The hydrophobic character contributes to the ability of the drug to be absorbed
across the membranes of the gastrointestinal tract and eventually across the bloodbrain barrier. It
is important to remember that the tertiary amine (one of the two) will be predominantly ionized at
physiological pH. Because an equilibrium exists between the ionized and unionized form of the drug,
some fraction of the drug will be unionized at any point in time and, therefore, can cross the blood
brain barrier and have an effect on the histamine receptors.
152
NOTE: When activated, the histamine receptor in the brain is responsible for wakefulness. When
hydroxyzine interacts with this receptor, it prevents histamine from binding to and activating its
receptor. As a result, the feeling of wakefulness is very limited, and the patient feels sleepy.
Cetirizine contains a carboxylic acid instead of the primary alcohol found in hydroxyzine. The carboxylic acid significantly increases the water solubility of cetirizine as compared to hydroxyzine. The
carboxylic acid is also predominantly ionized at physiological pH. Although there is an equilibrium
between the ionized and unionized forms of the tertiary amine and of the carboxylic acid, the overall
percent of cetirizine in which both functional groups are unionized is especially small. As a result,
very, very little of a cetirizine dose can cross the bloodbrain barrier and interact with the histamine
receptors. Because the central histamine receptors can still be activated, the feeling of wakefulness
remains, and the patient does not feel sleepy.


Answers
2.12 Chlorpropamide and
Other Sulfonylureas
Shown below are the structures of tolbutamide and chlorpropamide. These drug molecules are used in the treatment of type 2 diabetes mellitus. They stimulate the release of insulin from the pancreatic -cells by interacting with
Shown below are the structures of tolbutamide potassium channels.
adenosine triphosphate (ATP)-sensitive potassium channels.
Shown below are the structures of tolbutamide potassium channels.
Tolbutamide
Chlorpropamide
1. uncommon
It is not uncommon
for patients
with2type
2 diabetes
that diagnosed
a drug interaction
could occur?and
1. It is not
for patients
with type
diabetes
to beate
dually
with hypertension
require additional pharmacotherapy. In this scenario, it is possible for drug interactions to occur if the
prescribed combination therapy is not appropriately evaluated. Angiotensin II receptor antagonists,
Tolbutamide
Chlorpropamide
commonly known as
angiotensin II receptor blockers (ARBs), are often
used to treat hypertension.
Losartan (shown below) is an ARB, and similar to tolbutamide and chlorpropamide, is highly plasma
protein bound. If losartan was selected for use in a patient who is already taking tolbutamide or chlor1. It is not uncommon for patients with type 2 diabetes ate that a drug interaction could occur?
propamide, would you anticipate that a drug interaction could occur?
Losartan
Losartan
Answer
Plasma protein binding interactions (also known as that a drug interaction could occur.
Sulfonylurea
Answer
Sulfonylurea
Answer
Plasma protein binding interactions (also known as plasma protein displacement interactions) occur due
to the
nonspecific
nature interactions
of the plasma
proteins
bind
and interaction
transport drug
There are two
Plasma
protein binding
(also
known that
as that
a drug
couldmolecules.
occur.
key concepts to consider when evaluating the probability of a plasma protein binding interaction. First,
these types of interactions are therapeutically important only when the drug molecules are highly plasma
protein bound Sulfonylurea
(i.e., over 90%). Second, acidic drugs primarily bind Sulfonylurea
to albumin, whereas basic drugs
primarily bind to 1-acid glycoprotein. The information provided in the question indicates that all of these
Tolbutamide
Chlorpropamide
compounds are highly
plasma protein bound; therefore, we need to evaluate
the acid/base nature of
153
Losartan
154
these drug molecules. The structures of tolbutamide and chlorpropamide contain an acidic sulfonylurea,
Answer
whereas
the structure of losartan contains an acidic tetrazole. Because both of these drug molecules
are acidic
and are
highly
plasma
protein bound
to albumin,
a high probability
that a drug
Plasma
protein
binding
interactions
(also known
as that athere
drugisinteraction
could occur.
interaction could occur.
Sulfonylurea
Sulfonylurea
Chlorpropamide
Tolbutamide
Acidic protons
are circled
Tetrazole
Losartan
2. The normal pKa range for sulfonylureas is 5 to 6. When comparing the pKa values of chlorpropamide
and tolbutamide, it is found that the sulfonylurea of one of these drug molecules has a pKa=5.4 and
the other has a pKa=4.9. Evaluate the structures of these two drug molecules, assign the pKa values to
the correct molecules, and provide an explanation for the difference in pKa values.
2. The normal pKa range forrect molecules, and provide an explanation for the difference in pKa values.
Answer
Answer evaluation of chlorpropamide and tolbutamide reveals two chemical differences.
A structural
Three carbon
aliphatic chain
Halogen
Chlorpropamide
Four carbon
aliphatic chain
Methyl group
Tolbutamide
The differences in the length of the aliphatic hydrocarbon chains would not be expected to have a
major effect on the acidity of the sulfonylurea because they would both donate electrons through
Thus,
the difference
in the
pKawill
values
can beatattributed
to the
electronic
differences
3.induction.
Using your
answer
from question
2, that
be ionized
an intestinal
pH of
6.1.
between the halogen and the methyl group. Halogens act as electron withdrawing groups through
Answer
induction, whereas the methyl group acts as an electron donating group through induction. Because
acidic functional groups (i.e., sulfonylureas) form anions once the proton leaves, adjacent functional
groups that are electron withdrawing will increase acidity. Adjacent functional groups that are
[Base~Form]
electron
donating
will decrease acidity. Thus, the sulfonylurea group present within the structure
pH =~pK
a +log ~
[Acid~Form]

[Base~Form]
2.12 Chlorpropamide and Other Sulfonylureas
155
of chlorpropamide would be expected to be more acidic (pKa=4.9) than the one present within the
structure of tolbutamide (pKa=5.4) due to the electron withdrawing character of the halogenated
aromatic ring.
3. Using your answer from question 2, calculate the percent of tolbutamide that will be ionized at an
intestinal pH=6.1.
Answer
As determined in question 2, the pKa of the sulfonylurea groups of tolbutamide is 5.4. To solve this
problem, we need to use the Henderson-Hasselbalch equation. Because the functional group is acidic,
the ionized form (R-SO2NCO-R) is the base form and the unionized form (R-SO2NHCO-R) is the acid
form.
[BaseForm]
pH =pK a +log
[AcidForm]
[BaseForm]
6.1=5.4 +log
[AcidForm]
[BaseForm]
0.7 =log
[AcidForm]
5.01=
[BaseForm] or5.01 =[BaseForm]

1
[ AcidForm]
[ AcidForm]
This ratio indicates that for every one molecule that contains the functional group in the acid (or
unionized) form, there are 5.01 molecules that contain the functional group in the base (or ionized)
form. The following equations can then be used to correctly calculate the percent of the molecules
that are ionized and the percent that are unionized.
5.01 Molecules in Base Form + 1.0 Molecule in Acid Form = 6.01 Total Molecules
Base Form = Ionized Form and Acid Form = Unionized Form
5.01MoleculesinIonizedForm
100% = 83.4%
6.01TotalMolecules
PercentinUnionizedForm =
1MoleculeinUnionizedForm
100% = 16.6%
6.01TotalMolecules
The question asks for the percent that will be ionized, so the correct answer is 83.4%.
4. The mechanism of action of this class of drugs involves the ability to interact with the ATP-sensitive
potassium channels in the pancreas. Using the structure of tolbutamide, identify the types of binding
interactions that would be possible between its functional groups and a protein ion channel. Also
identify amino acids present within this ion channel whose side chains could participate in the interactions identified. Assume a plasma pH=7.4 for all ionizable functional groups.

156
4. The mechanism of action of this class of to interact with the ATP-sensitive potassium groups.
Answer
Answer
B
C
Tolbutamide
Aminothan
Acids
Capable of Forming
5. Tolbutamide has a half-life of 4.5 to 6.5 hourssignificantly longer half-life
tolbutamide.
A
B
Functional Group
Types of Binding Interactions
Specific Bond
Phenyl ring; aromatic ring;

aromatic hydrocarbon
van der Waals; Hydrophobic
Tyr, Phe, Trp (better bond*); Val, Leu, Ile, Met, Ala
Sulfonylurea
(1) Ionic
(1) Lys, Arg, His**
(2) IonDipole (as the Ion)
(2) Ser, Thr, Tyr, Cys, Asn, Gln, His**
(1) IonDipole (as the Dipole)
(1) Asp, Glu (with the hydrogen); Arg, Lys, His**

(with the nitrogen)
(2) DipoleDipole
(2) Ser, Thr, Tyr, Cys, Asn, Gln, His**
(3) Hydrogen Bond (Donor and/or Acceptor)
(3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His**
Val, Leu, Ile, Met, Ala (better bond*); Tyr, Phe, Trp
Answer
Metabolism of Tolbutamide
C
Nitrogen atom of sulfonylurea

not involved in resonance
Alkyl group; alkyl chain;

aliphatic chain
Z oxidation
Z-1 oxidation
*Due to steric fit, stronger van der Waals interactions occur when aromatic rings interact with aromatic
rings
and when aliphatic chains interact with aliphatic chains; however, all of the listed amino acids could
Benzylic
possibly
interact with the boxed functional group.
oxidation
**Histidine is primarily unionized at a pH=7.4. The small fraction that is ionized could participate in
an iondipole interaction with a partially negative atom, while the unionized fraction can serve as a
hydrogen bond donor or acceptor. It can also serve as the dipole in an iondipole bond.
1. Alcohol
dehydrogenase
5. Tolbutamide has a half-life of 4.5 to 6.5 hours, whereas chlorpropamide has a half-life of 36 hours.
Propose a chemical/structural reason
why chlorpropamide has a significantly longer half-life than
2. Aldehyde
tolbutamide.
dehydrogenase
Answer
As discussed in question 2, there are two structural differences between tolbutamide and chlorpropamide: the length of the aliphatic chain and the para substituent on the phenyl ring. Both drug
Metabolism of Chlorpropamide
molecules can undergo and -1 oxidation of their respective aliphatic chains. Metabolism at these
sites would be expected to be similar; however, the additional carbon atom present in tolbutamide
may cause the butyl side chainZto
be less sterically hindered and more susceptible to oxidation than
oxidation
the propyl chain present in chlorpropamide. The more significant difference is metabolism of the
para substituent. The para methyl group present within the structure of tolbutamide can undergo
benzylic oxidation followed by two additional oxidative transformations to convert the benzylic
hydroxyl group into a para carboxylic acid. The para chloro group present within the structure of
chlorpropamide deactivates oxidation of the aromatic ring due to its electron withdrawing effects.
As a result, tolbutamide hasZ-1
a much
shorter half-life than chlorpropamide.
oxidation
Electron withdrawing
halogen prevents
aromatic oxidation

Tolbutamide
5. Tolbutamide has a half-life of 4.5 to 6.5 hourssignificantly
longer half-life and
thanOther
tolbutamide.
2.12 Chlorpropamide
Sulfonylureas
Answer
Metabolism of Tolbutamide
Z oxidation
Z-1 oxidation
Benzylic
oxidation
1. Alcohol
dehydrogenase
2. Aldehyde
dehydrogenase
Metabolism of Chlorpropamide
Z oxidation
Z-1 oxidation
Electron withdrawing
halogen prevents
aromatic oxidation

157
(Lipid soluble)
158
Sulfonylureas)
6. Glyburide is a second-generation sulfonylurea that is structurally similar to chlorpropamide and

tolbutamide. Shown below are the structures of glyburide and one of its known metabolites. Identify
the metabolic pathways that are required to produce this metabolite.
Cl
S
N
H
O
H3C
N
H
N
H
Glyburide
H3C
N
H
OH
O
N
H
N
H
Answer
This metabolite is formed as the final product of three metabolic transformations. Oxidation of
the alicylic ring produces the secondary alcohol. Hydrolysis of the initial amide bond of glyburide
produces a primary amine that can undergo phase II acetylation. In most cases, further metabolism of
a primary amine involves oxidative deamination; however, there are some cases where the primary
amine is acetylated. Please note that the oxidation of the alicyclic ring is independent of the coupled
hydrolysis and acetylation transformations.
Go to Section 1.12

Answers
Thrombin is the enzyme responsible for catalyzing the conversion of fibrinogen to fibrin. The production of fibrin is
important in the formation of sturdy blood clots. As you might expect, inhibition of thrombin prevents the formation of fibrin. As shown in the diagram below, a catalytic triad of amino acids (Asp, His, Ser) found in the active site
of thrombin is responsible for hydrolyzing a key peptide bond found within fibrinogen. Orientation of fibrinogen in
the active site ofChapters
thrombin1.13/2.13
relies on the
interaction
a key
tri-peptide
sequence
(D-Phe-Pro-Arg)
found within the
Concern
about of
His
(revised
diagram
+ removed
bolded names)
structure fibrinogen with key amino acids in the enzyme active site.
Chapters
1.13/2.13
Concern about
His (revised
diagram
+ removed
bolded
names)is an orally active direct
Dabigatran
etexilate
is administered
as a prodrug.
In its
active form,
dabigatran
etexilate
thrombin inhibitor used in the prevention of stroke and blood clots in patients diagnosed with atrial fibrillation.

Thrombin catalyzed
amide hydrolysis
Thrombin catalyzed
amide hydrolysis
Fibrin
Fibrin

159
160
1. Conduct a complete structural evaluation of dabigatran etexilate (prodrug) and use the information
in the grid to inform your answers to the questions that follow.
Answer
Function
Character
Function
Character
Acidic, Basic,
or Neutral
Function
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Provide pKa
When
Relevant
Solubility
and/or
Absorption
Interaction(s)
Possible with
Biological Target at
Physiological
pH=7.4
Ester
Hydrophilic (COO)
Neutral
Solubility (COO)
H-bonding (A)
Absorption (R)
Dipoledipole
Hydrophobic (R)
Amino Acids That

Can Interact with
Functional Group
via H-Bonding (at
pH=7.4)
None Is Acceptable
Ser, Thr, Cys, Tyr, His,
Asn, Gln, Trp
Iondipole (as the dipole)
Amide
Hydrophilic (CON)
Neutral
Hydrophobic (R)
Solubility (CON)
H-bonding (A)
Absorption (R)
Dipoledipole

Asn, Gln, Trp
Pyridine
Hydrophilic (N)
Basic
Solubility (N)
(Azine)
Hydrophobic (R)
pKa=15
Absorption (R)
Pyridine N:
H-bonding (A)

Asn, Gln, Trp
Dipoledipole
Iondipole (as the
dipole)
(R):
Hydrophobic
van der Waals
- Stacking
Benzimidazole
Hydrophilic (imidazole N atoms)

Hydrophobic (R)
Basic
pKa=15
Solubility (imidazole Ns)

Absorption (R)
Imidazole (N atoms):
H-bonding (A)
Dipoledipole
Iondipole (as the
dipole)

Asn, Gln, Trp
Ar:
Hydrophobic
van der Waals
- Stacking
E
Aromatic amine Hydrophilic (NH2)
Basic
Solubility (NH2)
(aniline)
pKa=25
Absorption (Ar)
Hydrophobic (Ar)
NH2:
H-bonding (A+D)
Dipole-dipole
Iondipole (as the
dipole)

Asn, Gln, Trp
Ar:
Hydrophobic
van der Waals
- Stacking
F
Carbamate
Hydrophilic (OCON)
Neutral
Hydrophobic (R)
Solubility (OCON)
H-bonding (A)
Absorption (R)
Dipoledipole


Asn, Gln, Trp
Chapters 1.13/2.13 (removed bolded text)
E
D
161
2. Dabigatran etexilate is a non-peptidomimetic prodrug. Provide a brief rationale for the value of
converting an active
drug into
a prodrug.
Chapters
1.13/2.13
(removed bold drug name)
Answer
There are situations (e.g., the need to enhance water or lipid solubility) when it is therapeutically
beneficial to administer drug molecules that have been covalently modified to produce inactive (or
very weakly active) analogs (i.e., prodrugs) (see Chapter 5 in Basic Concepts in Medicinal Chemistry).
Bioactivation of these prodrugs via rapid metabolic transformation (e.g., ester hydrolysis) can occur
via chemical or enzymatic mechanisms. Typically metabolic activation (via hydrolysis) occurs within
the gastrointestinal (GI) tract. Given that esterases are ubiquitous, release of the active drug can
occur in the plasma or even at the target tissue.
In the case of dabigatran etexilate, a carboxylic acid is converted to an ester and an amidine is
converted to a carbamate. In both cases, the modified functional group is significantly more lipid
soluble than the parent functional group. Dabigatran is not absorbed orally, so it is necessary to
develop a prodrug analog to allow for sufficient absorption from the GI tract.
3. Dabigatran etexilate rapidly undergoes two esterase-catalyzed hydrolytic reactions to the active drug
dabigatran. Show the products from each
of the esterase-catalyzed
Dabigatran
etexilate mesylatehydrolytic reactions that occur in
the plasma.

162
Chapter 2.13 (removed bolded drug names)

Answer
O
H 3C
H
N
NH 2
N
O(CH2)5CH3
C H3
Dabigatran Prodrug
HO
H
N
N H2
N
O(CH2 )5 CH3
C H3
O
H 3C
N
N
HO
N
N
H
N
N
N
CH 3
N
N
N H2
NH

N H2
NH
C H3
163
4. In its active form, dabigatran mimics the D-Phe-Pro-Arg tripeptide sequence, but does not contain a
peptide backbone (non-peptidomimetic). Review the tripeptide sequence drawn below noting that
there are numbers 13 that indicate where each amino acid is located in the sequence. Determine the
4. ofIninteractions
its active form,
dabigatran
tripeptide
types
possible
with mimics
each ofthe
theD-Phe-Pro-Arg
amino acid side
chains. chains.
NH
H 2N
H
H 2N
N
O
N
2
R
H

Answer
Types of Interactions Possible
5. Review side chain indicated.
D-Phe (1)
Hydrophobic
van der Waals

- Stacking
Pro (2)
A
Hydrophobic
van der WaalsO

Arg (3)

Ionic
HO
E
D
H
N
N
N
N H2
NH
C H3
5. Review the structure of dabigatran and determine which of the boxed groups will likely mimic the
interactions found within the D-Phe-Pro-Arg tripeptide sequence. Given the three-dimensional
nature of both peptides and small molecules, it is important to remember that the functional groups
within dabigatran do not need to lineActive
up in the
same
order. Using the table provided to guide your
form
ofname)
Dabigatran
Chapter 2.13 (remove bolded
drug
analysis, place a Yes or No in each box to indicate whether the functional group could mimic the
amino acid side chain indicated.
6. Dabigatran salt. Provide a brief rationale for the value of administering the salt form of a drug.

164

Answer
D-Phe mimic
N H2
Pro mimicH
Arg mimic
No
No
No
No
HO
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Cefprozil
No
Yes
No
No
C H3
No
CONo
2H
6. Dabigatran etexilate
a mesylate
3. Page is45formulated
Question 6 as
and
page 164:salt. Provide a brief rationale for the value of
administering the salt form of a drug.
O
O
H3 C
O
H3 C
N
N
N H2
N
O
N
C H3
O(CH2 )5 CH3

Answer
Mesylate salts are considered water soluble organic salts. The use of water soluble organic salts is
one method to enhance the overall water solubility of your drug. This is accomplished by increased
solvation and dissolution of the drug. The use of a water soluble organic salt also helps to ensure an
adequate water/lipid balance necessary for oral absorption. As we have already determined in the
structure evaluation grid, there is some hydrophobic character present, but there is also substantial
hydrophilic character.
Go to Section 1.13

Answers
Fenofibrate is a member of the fibrate class of anti-hyperlipidemic agents. It is used as adjunct therapy to diet in the
management of dyslipidemias, including in the treatment of severe hypertriglyceridemia. The specific mechanism(s)
by which fenofibrate decreases triglyceride and total cholesterol levels, as well as increases the levels of high density
lipoproteins (HDL), is unknown. What
know
is that
thedecrease
very low density lipoproteins (VLDLs)
1.14 we
anddo2.14
(drug
name
remove in
bold)
results from fenofibrate stimulation of lipoprotein lipase.
Fenofibrate
Gemfibrozil
1. Conduct a complete structuralLetter

evaluation
of fenofibrate
and use the information in the grid to inform
C add
bold
Answer
Function
Function
Character
Character
Name of
Functional
Group
A
Halogenated
aromatic
hydrocarbon
Hydrophilic
and/or
Hydrophobic
Acidic, Basic,
or Neutral
Provide pKa
When Relevant
Ketone
C
Solubility
and/or
Absorption
remove bold from

label
Hydrophobic 2.14Neutral
Absorption
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
Hydrophobic
None Is Acceptable
None
van der Waals

- Stacking
B
A
Function
Amino Acids That

Functional Group
via H-Bonding
Interactions at
pH=7.4
Hydrophilic (CO)
Hydrophobic (R)
Neutral
F
C
Dipoledipole
Iondipole (as the

dipole)
Solubility (CO)
H-bonding (A)
Absorption (R)
Dipoledipole
Fenofibrate
Ser, Thr, Tyr, Cys, Asn, Gln,

His, Trp
Iondipole (as the

dipole)

165
166

C
Aromatic
hydrocarbon
Fenofibrate
Hydrophobic
Neutral
Fenofibrate
Absorption
Hydrophobic
Gemfibrozil
Gemfibrozil
van der Waals
Letter C add bold
Letter
D C
Ether add boldHydrophilic (O)
None
- Stacking
Neutral
Hydrophobic (R)
Solubility (O)
H-bonding (A)
Absorption (R)
Dipoledipole

His, Trp
Iondipole (as the

dipole)
E
Aliphatic
alkane
Hydrophobic
Ester
Hydrophilic
(COO)
Neutral
Absorption
Hydrophobic
None
van der Waals

Neutral
Solubility (COO)
H-bonding (A)
Absorption (R)
Dipoledipole
HydrophobicC(R)

His, Trp
Iondipole (as the

dipole)
.
B
B
A
AF
F
C
E
E
Fenofibrate
Fenofibrate
2.14
remove bold
label hydrolysis to the active drug. Draw the
2. Fenofibrate is administered
as a prodrug
and from
undergoes
active
drug.
Provide
a
brief
rationale
for
the
value
of administering fenofibrate as a prodrug.
Answer
O
C H3
O
Ester
O
OHydrolysis
O
O
C H3
O
O
C H3
Ester
O
O
H3 C C H3
Hydrolysis
OH
O
CH
Cl
H3C
Cl
C H3
H3C
Cl
Cl
H3C
Active
Active
There are situations (e.g., the need to enhance water or lipid solubility) when it is therapeutically
beneficial to administer drug molecules that have been covalently modified to produce inactive (or
very weakly active) analogs (i.e., prodrugs) (see Chapter 5 in Basic Concepts in Medicinal Chemistry).
Bioactivation of these prodrugs via rapid metabolic transformation (e.g., ester hydrolysis catalyzed
by esterases) can occur via chemical or enzymatic mechanisms. Typically metabolic activation occurs
within the gastrointestinal (GI) tract, but given that esterases are ubiquitous, release of the active
drug can occur in the plasma or even at the target tissue.
In the case of fenofibrate, a carboxylic acid is converted to an ester to form a prodrug. The resulting
modified functional group (now an ester) is significantly more lipid soluble than the parent functional group (originally a carboxylic acid). The calculated log P for fenofibrate is 5.24, which suggests
that the prodrug is lipophilic.
C H3
Inactive
Inactive
167
3. The calculated
P for
fenofibrate
is 5.24,
whereas the calculated log P for gemfibrozil is 3.9.
1.14 andlog
2.14
(drug
name remove
bold)
Provide a structural rationale for the difference in this pharmacokinetic property.
Fenofibrate
Gemfibrozil
3. The calculated for difference in this pharmacokinetic property.
Answer
Letter C add bold
A larger calculated log P value reflects the presence of additional hydrophobic character. Lets see
if that statement pans out as we evaluate each of these molecules. The structure evaluation grid
for fenofibrate reveals that there are several functional groups that contribute to its hydrophobic
character including the halogenated aromatic hydrocarbon, the aromatic hydrocarbon, and both
aliphatic alkanes. Evaluation of gemfibrozil reveals hydrophobic character from a dimethyl substituted aromatic hydrocarbon and an aliphatic alkane. The larger calculated log P value for fenofibrate
is justified by the presence of significantly more functional groups with hydrophobic character.
Fenofibrate
4. From an elimination perspective,
60% of a fenofibrate dose is foundGemfibrozil
in the urine and 25% is found
C(drug name remove bold)
and
in the feces. The active1.14
form
of 2.14
fenofibrate
undergoes both phase I and phase II metabolic transformations. The phase II conjugate is eliminated in the urine. Oxidative metabolism does not occur.
Evaluate each of the metabolic products and determine if it is the conjugate that is eliminated in the
4. From
anremove
elimination
2.14
bold NOT
from occur).
label
urine (that does occur), the product of a non-oxidative phase I transformation (that does occur), or
the product of an oxidative phase I transformation (that does NOT occur).
B
HO
OH
Fenofibrate
C H3
H3 C
Cl
Gemfibrozil
A C add bold
Letter
Fenofibrate
O
O
Answer
H3C
Cl
C H3
O
C H3
Ester
Hydrolysis
C H3
C
C
Cl

Nameaofstructural
Metabolicrationale
Transformation
Type of Productdoes not occur.
Inactive
5. Provide
for why oxidative O-dealkylation
Ketone reduction
Glucuronide conjugation
Answer:

Active
Product of oxidative transformation (does not occur)
B
A
ProductF
of non-oxidative transformation (does occur)
D Product of conjugation transformation (does occur)

1
H3C
OH
C H3
C
168
Answer:
Answer
Oxidative O-dealkylation transformations occur with ethers that have at least one -carbon (adjacent carbon atom) with at least one hydrogen atom attached. Evaluation of the ether found within
the structure of fenofibrate reveals that one of the carbons (#1) attached to the ether oxygen atom
is part of an aromatic ring. It does not have a hydrogen atom attached to it. Carbon #2, attached
to two aliphatic alkanes (methyl groups) and a carboxylic acid, also does not have a hydrogen atom
attached to it. Because neither of the -carbons has at least one hydrogen atom attached to it, this
ether is not subject to oxidative O-dealkylation.
6. Fenofibrate and gemfibrozil have dramatically different elimination half-lives (2022 hours and 1.5
4 and 2.14 (drug name remove bold)
hours, respectively). Identify the possible metabolic transformations for gemfibrozil and provide a
justification for the significant difference in this pharmacokinetic parameter.
Fenofibrate
Gemfibrozil
Answer
er C add bold
Possible phase I metabolic transformations:

Benzylic oxidation (two different locations)*
Aromatic hydroxylation (multiple)
*Note: Each benzylic hydroxyl group can be further oxidized to carboxylic acids.
Possible phase II conjugation transformations:
C
Glucuronide conjugation
Amino acid conjugation (with glutamine, glycine, arginine or taurine)

4 remove bold from label
The difference in aromatic substituents between the two drugs has a large impact on the number of
B potential phase IFtransformations that produce more water soluble metabolites. Oxidative OA
dealkylation not only generates more water soluble products, but also splits gemfibrozil in half,
D deactivation. Based on this assessment, it is no surprise that there is a difference in the
causing
drug
C
elimination half-lives of these two drugs and that gemfibrozil is eliminated much more rapidly.
E
Fenofibrate
From: ASHP eBooks
(digital.ashp.org)

Section
Answers
O
O
O
OH
H3C
Cl
C H3
2.15 Fluvoxamine
Fenofibric Acid
Fluvoxamine is an inhibitor of the serotonin reuptake transporter (SSRI) and prevents the reuptake of serotonin at the
presynaptic membrane in the central nervous
is indicated
for use
in the treatment of depression. Fluvox1.15 andsystem.
2.15 It
remove
bold from
label
amine is structurally unique relative to the rest of the serotonin selective reuptake inhibitor class of drugs.
A
B
D
Fluvoxamine
1. Conduct a structural evaluation of fluvoxamine, focusing on the boxed functional groups, and use the
information in the grid to inform your answers to the questions that follow.
Answer
F3 C
Character
C H3
Function
NH3
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Interaction(s)
Possible with
Provide
Solubility
Fluvoxamine maleateBiological Target
pKa When
at Physiological
and/or
pH=7.4
Absorption
Relevant
Halogenated
aliphatic alkane
Hydrophilic (F)
Neutral
Character
Acidic, Basic, N
O
or Neutral
Function
Function
Hydrophobic (R)
Solubility (F)
Dipoledipole
Absorption (R)
H-bonding (A)
Amino Acids That

O Interact with
Can
O
the Functional
Group
via H-Bonding
Interactions
O H at
pH=7.4
None Is Acceptable
Trp, His
Iondipole (as the

dipole)
B
Hydrophobic
Aliphatic alkane
Hydrophobic (R)
Neutral
Absorption
Hydrophobic
None
van der Waals

- Stacking
Neutral
Absorption
Hydrophobic
van der Waals

169
None
170
Corrections/AnswerstoQuestions

PleasenotethatthepagenumbersrefertothePDFpagenumbers,notthepagenumbersofthechapters.
D Ether
Hydrophilic (O)
Neutral
Solubility (O)
H-bonding (A)
His, Trp

Hydrophobic (R)
Absorption (R)
Dipoledipole
1. IndoingaquicklookthroughtheChapters,Inoticedwhatappearstobeafonterrorontwoofthe
Iondipole (as the
structures.Onpages62and180,theatomfontonfluvoxamineinquestion2seemstobetoobig.The
dipole)
structureoffluvoxamineappearsinquestions2and3.Thestructuresarethesamesize,butthefonts
Solubility (NH2)
Basic
Iondipole (as the ion) Ser, Thr, Cys, Tyr, Asn, Glu,
E Primary amine
Hydrophilic (NH2)
His, Trp
aredifferent.Thefontforthestructureinquestion3iscorrect,whilethefontforthestructurein
Hydrophobic (R)
pKa 911
Absorption (R)
Ionic
question2appearstobelarger.Ihaveprovidedareplacementstructurebelowforquestion2onpages
62and180.

2.
Fluvoxamine
is
marketed
as a single isomer. Is the product sold as a single enantiomer, diastereomer,

or geometric isomer? Provide a brief rationale for your answer.

O
1'
O
O
2'
H3C
Cl
OH

2'
1'
C H3
Fenofibric Acid
Answer
There are no chiral carbon atoms present; therefore, there are no enantiomeric or diastereomeric
2. Thesamestructurefonterroralsoappearsinquestion3withfluvastatinonpages32and129.Compare
isomers possible.
A not mirror images of one another and are not superimposable (see Chapter
Geometric isomers are
B Chemistry). These isomers typically occur in the presence of a
7 in Basic Concepts in Medicinal
carboncarbon double bond, where the double bond causes conformational restriction and forces
C in one of twoDorientations. In the case of fluvoxamine, there
the bond substituents to be positioned
is a carbonnitrogen double bond present. When evaluating isomer A, the 1' and 1 substituents
are located on opposite sides of the carbonnitrogen double bond. This represents the trans- or
E-geometric isomer. When evaluating isomer B, the 1' and 1 substituents are located on the same side
E
of the carbonnitrogen double bond. This represents
the cis- or Z-geometric isomer. The marketed
HO 1
CO2 H
product is the E-geometric isomer.
2 OH
Fluvoxamine
3. Fluvoxamine is formulated as a maleate salt. What type of salt is a maleate salt, and what type of
properties does it confer
to2.15
the overall
properties
the drug?
1.15 and
remove
bold fromof
label
F
F3 C
O
N
NH3
Fluvastatin
Fluvoxamine maleate

C H3
O
O
OH
2.15 Fluvoxamine
171
Answer
Maleate salts are water soluble organic salts. Water soluble organic salts generally enhance overall
drug water solubility (see Chapter 5 in Basic Concepts in Medicinal Chemistry). Maleate salts typically
demonstrate enhanced solvation and dissolution as compared to their free base forms. This is exceptionally beneficial in the preparation of parenteral, nasal, and ophthalmic dosage forms where the
delivery of small volumes of highly concentrated solutions is necessary.
4. Fluvoxamine is well absorbed and has an oral bioavailability of ~50%. Using the information found in
the structure evaluation grid, provide a rationale for these pharmacokinetic properties.
Answer
Orally administered drugs must strike a balance between having enough hydrophilic character to
promote dissolution and solubility in the aqueous contents of the gastrointestinal (GI) tract, and
sufficient hydrophobic character to allow for absorption across the lipid bilayer membrane. Fluvoxamine has a fluorinated aliphatic alkane, an ether, and an ionized primary amine that contribute
to the overall hydrophilic character of the drug. An aromatic hydrocarbon and aliphatic alkane
contribute to the overall hydrophobic character of the drug. Based on this evaluation, it is no surprise
that the drug undergoes rapid dissolution and solvation in the aqueous contents of the GI tract.
Although it appears that there is only a moderate amount of hydrophobic character, this appears to
be sufficient to allow for absorption across the lipid bilayer membrane.
5. A number
fluvoxamine
metabolites
have
been
identified,
all of whichhas
demonstrate
5. A of
number
of Evaluate
each of the
which
metabolic
transformation
occurred. little or no
pharmacological activity. Evaluate each of the metabolic products drawn below and identify which
metabolic transformation has occurred.

172
Answer
A
Oxidative O-dealkylation followed by alcohol oxidation
Allylic oxidation*
Acetylation
*Note: This carbonnitrogen double bond acts similarly to a carboncarbon double bond. If a carbon
substituent attached to this carbonnitrogen double bond bears a hydrogen atom, then it can
undergo oxidation. In this case, there is only one carbon substituent that fulfills that criterion, and
there is only one location possible for an allylic oxidation to occur.
6. Fluvoxamine is a strong inhibitor of CYP1A2, CYP3A4, and CYP2C19. These enzyme isoforms catalyze
a number of the phase I oxidative metabolic transformations. Several of the benzodiazepines (used
in the treatment of anxiety), including the very popular alprazolam, rely heavily on hepatic oxidation
for metabolic inactivation and elimination. Other benzodiazepines, including the equally popular
lorazepam, rely on glucuronide conjugation for metabolic inactivation and elimination. Which
combination of drugs, fluvoxamine + alprazolam or fluvoxamine + lorazepam, is the most likely to
generate an enhanced anxiolytic effect?
Answer
Fluvoxamine inhibits several of the metabolism isoforms that catalyze oxidative metabolic transformations. Alprazolam relies on hepatic oxidation for metabolic inactivation and elimination. If fluvoxamine inhibits the same enzymes that alprazolam relies on for hepatic oxidation, then the levels of
active alprazolam will exist for a longer period of time than expected. With more alprazolam available to produce an anxiolytic effect for a longer period of time, it is likely that an enhanced anxiolytic effect will be observed.
Because lorazepam relies on a different set of enzymatic isoforms for glucuronide conjugation, the
co-administration of fluvoxamine will have little or no effect on the metabolic inactivation and elimination of lorazepam, and an enhanced anxiolytic effect will not be observed.


Answers
2.16 Haloperidol
Shown below is the structure of haloperidol. Six of its functional groups have been identified.
E
D
C
A
1. Using 1.
the Using
table below,
the se. identify the six boxed functional groups. For each of the functional groups you
identified, indicate if it is hydrophilic or hydrophobic in character. Also provide a brief explanation for
2. Based on their electronic induction.
your response.
3. Using the in pH environments of 1.7, 5.5, 6.0, 7.4, and 8.5.
Answer
Answer
A
The
structure
only
functional
and
noacceptor;
acidic functional
groups.
Halogen;
fluorineof haloperidol contains
Effects
canone
vary;basic
fluorine
can act as agroup
hydrogen
bond
however, studies
have
shown that the substitution of a hydrogen atom with a fluorine atom tends to slightly
enhance lipid solubility.
Tertiary Hydrophilic
amine
due to its ability to act as a hydrogen bond acceptor.
Ketone
Alkyl group; alkyl chain; aliphatic chain
Tertiary amine
Tertiary hydroxyl group; tertiary alcohol
Cl
Hydrophilic
O due to its ability to form hydrogen bonds as either a donor or an acceptor.
Phenyl ring; aromatic ring; aromatic

hydrocarbon
Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional
groups enhance lipid solubility.
OH
groups enhance lipid N
solubility.
Hydrophilic due to its ability to ionize (form an iondipole interaction with water) and to
participate in hydrogen bonding (acceptor) in its unionized form.
4. Shown below is a structural analog can enhance the duration of haloperidol.

2. Based on their electronic properties AND their relative positions in the molecule, identify if functional
groups A, C, and E are electron withdrawing or electron donating. Additionally, identify if this effect is
Answer
Functional Group A is a halogen. Because all halogens are more electronegative than an adjacent
aromatic ring, the fluorine atom acts as an electron withdrawing group through induction.

Functional Group C is an alkyl group and has a lower electronegativity than the oxygen atom of the
ketone or the nitrogen atom of the tertiary amine; therefore, it acts as an electron donating group
through induction.

173
E
174
D
C
Functional Group E is a tertiary hydroxyl group. Based on its position in the molecule and the
fact that it is notAdirectly attached to an aromatic ring, it acts as an electron withdrawing group
F
through induction.
B
F
B
3. Using
unmodified
1. the
Using
the se. structure of haloperidol and the table below, identify all of the acidic and
basic functional groups present in the structure, provide the normal pKa range for each functional
2. Based on their electronic induction.
group, and identify if each functional group would be primarily ionized or unionized in pH environ1. Using
se.the in pH environments of 1.7, 5.5, 6.0, 7.4, and 8.5.
3. the
Using
ments=1.7,
5.5, 6.0, 7.4, and 8.5.
2. Based
on
their
electronic induction.
Answer
Answer
3. The
Using
the
in pH
of
1.7, 5.5,
6.0,
7.4,
and functional
8.5.
The
structure
of haloperidolcontains
contains
only
one
basic
functional group
groups.
structure
of environments
haloperidol
only
one
basic
groupand
andno
noacidic
acidicfunctional
functional
groups.
Answer
The structure of haloperidol contains only one basic functional group and no acidic functional groups.
Tertiary amine
OH
Tertiary amine
OH
Cl
O
F
Functional Group
Acidic or
Basic
Tertiary amine
Basic
Cl
pKa Range

1.7
5.5
6.0
7.4
8.5
911
Ionized
Ionized
Ionized
4. Shown below is a structural analog can enhance the duration of haloperidol.

Ionized
Ionized
4. Shown
Shownbelow
below is
is aa structural
structural analog
enhance the Evaluate
duration ofthe
haloperidol.
4.
analogcan
of haloperidol.
structural change and propose an
explanation as to how this structural modification can enhance the duration of haloperidol.
5. Using the table below ionizable functional groups.

Answer
Structural evaluation of this analog reveals that the tertiary hydroxyl group has been converted to a
soluble
ester.
Lipid
solublefunctional
esters cangroups.
be administered as either an intramuscular (IM) or subcu5. lipid
Using
the table
below
ionizable
C
taneous (SC) injection. After injection, the lipid soluble ester dissolves
slowly from its initial injection
site into the plasma in a consistent manner over an B
extended period of time. Once in the plasma, the
ester is hydrolyzed to release haloperidol. Remember that
C esterases are ubiquitous within the body
and that lipid and water soluble esters are frequently used as prodrugs D
to provide a variety of theraB
A
peutic advantages.

2.16 Haloperidol
175
5. Using the table below, identify the types of binding interactions that could be possible between the
boxed functional groups and a protein or enzyme receptor. Also identify amino acids present within
5. Usingorthe
table below
ionizable
functional
a receptor
enzyme
whose
side chains
could groups.
participate in the interactions that you identified.
Assume a plasma pH=7.4 for all ionizable functional groups.
C
B
A
Answer
B
C
Amino Acids Capable of Forming

Specific Binding Interaction
Functional Group
Types of Binding Interactions
Ketone
(1) Asp, Glu (with carbon of ketone); Arg, Lys,

His* (with oxygen of ketone)
(2) DipoleDipole
(2) Ser, Thr, Tyr, Cys, Asn, Gln, His*
(3) Hydrogen Bond (Acceptor)
(3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His*
(1) Ionic
(1) Asp, Gln
(2) IonDipole (as the Ion)
(2) Ser, Thr, Tyr, Cys, Asn, Gln
(1) Asp, Glu (with hydrogen of hydroxyl); Arg, Lys,

His* (with oxygen of hydroxyl)
(2) DipoleDipole
(2) Ser, Thr, Tyr, Cys, Asn, Gln, His*
(3) Hydrogen Bond (Donor and/or Acceptor)
(3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His*
Tyr, Phe, Trp (better interaction**); Val, Leu, Ile,

Met, Ala
Tertiary amine
Tertiary hydroxyl
Phenyl ring; aromatic ring;

*The side chain of histidine is primarily unionized at a pH=7.4. The small fraction that is ionized could
form an iondipole interaction with a partially negatively charged atom, while the unionized fraction
can serve as a hydrogen bond donor or acceptor. Additionally, it can serve as the dipole in an ion
dipole interaction.
**Stronger van der Waals interactions occur when aromatic rings interact with aromatic rings;
however, all of the listed amino acids could possibly interact with the indicated functional group.
6. Shown below is the structure of haloperidol and a list of five metabolic transformations. For each
metabolic transformation, indicate if it is a phase I or a phase II transformation and if haloperidol has
the appropriate metabolite; if you answer NO, then provide a brief explanation as to why this meta6. Shown below is the to perform with haloperidol.
bolic transformation is not possible to perform with haloperidol.
Metabolic Pathways
A. Reduction
B. Sulfate Conjugation
C. Hydrolysis
D. Oxidative N-Dealkylation
Answer
A. Reduction: Phase I, Yes

176
Answer
A. Reduction:
Answer Phase I, Yes
Answer
B. Sulfate conjugation is a phase II transformation. It is possible; however, due to steric hindrance,

B. Sulfate conjugation is a phase II ation is low.
the probability of this metabolic transformation is low.
B. Sulfate conjugation is a phase II ation is low.
C. Hydrolysis is a phase I transformation. It is not possible for haloperidol because its structure does
not contain
a functional
group that undergoes this type of transformation.
C. Hydrolysis
is aN-Dealkylation:
phase
I biotransformation.
D. Oxidative
Phase I, Yes
D. Oxidative N-Dealkylation: Phase I, Yes
C. Hydrolysis is a phase I biotransformation.
E. Benzylic oxidation is a phase I transformation. It is not possible for haloperidol because one
benzylic position is occupied by a ketone (and therefore is not capable of being oxidized) and the
other is directly attached to a heteroatom and lacks a hydrogen atom.


Answers
2.17 Hydrocortisone
Hydrocortisone is a glucocorticoid used in the management of inflammation. Derivatives of hydrocortisone are used
in the management of asthma and chronic obstructive pulmonary disease.
1.17 and 2.17
remove boldand
fromuse
label
1. Conduct a complete structural evaluation
of hydrocortisone
the information in the grid to inform
E
C
F
B
D
Hydrocortisone
Answer

Function
Function
Character
Character
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Ketone
Hydrophilic (CO)
Interaction(s)
Acidic, Basic,
or Neutral
Provide
pKa When
Relevant
A
Function
21 Possible with
and/or
Absorption
Biological
Target
at Physiological
pH=7.4
Solubility (CO)
H-bonding (A)
Absorption (R)
Dipoledipole
17
11 Solubility
Neutral
Hydrophobic (R)
Amino Acids That

Can Interact with
the Functional
Group via Ion
Dipole Interactions
at pH=7.4
None Is Acceptable
Lys, Arg, Glu, Asp
Iondipole (as the

dipole)
B
Cycloalkene
Hydrophobic
1.18Neutral
and 2.18 remove
bold fromHydrophobic
label
Absorption
None
van der Waals

C
Secondary
alcohol
Hydrophilic (OH)
Neutral
Hydrophobic (R)
HO

Solubility (OH)
Absorption (R)
I
I
O
B177 I
H-bonding (A+D)
Dipoledipole
O
D Iondipole
(as the
dipole)
N H2
OH
Lys, Arg, Glu, Asp
178

D
Cycloalkane
Hydrophobic
Neutral
Absorption
Primary alcohol
Hydrophilic (OH)
Neutral
Solubility (OH)
H-bonding (A+D)
Absorption (R)
Dipoledipole
Hydrophobic
None
van der Waals

Hydrophobic (R)
Lys, Arg, Glu, Asp
Iondipole (as the

dipole)
F
Tertiary alcohol
Hydrophilic (OH)
Neutral
Hydrophobic (R)
Solubility (OH)
H-bonding (A+D)
Absorption (R)
Dipoledipole
Lys, Arg, Glu, Asp
Iondipole (as the

dipole)
2. The glucocorticoids interact with residues within the glucocorticoid receptor (Arg611, Asn564, Thr739,
Gln642, and Gln570) via hydrogen bonding and iondipole interactions at physiological pH (7.4). Identify which functional groups could interact with the side chains of these amino acids.
Answer
Functional
Group
A
Can Interact with Arginine611

via an IonDipole Interaction
Can Interact with

Asparagine564 and
Threonine739 via a
Hydrogen Bonding
Interaction
Can Interact with

Glutamine642 and
Glutamine570 via a
Hydrogen Bonding
Interaction
Yes or No
Yes or No
Yes or No
Yes
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
C
Yes
Yes
Yes
Yes
No
Yes
No
3. Several of the functional groups identified in the structure evaluation grid are essential for biological
D render the glucocorticoids inactive. These
activity. There are several metabolic
A transformations that
transformations include the following:
1. Ring A ketone reduction
Hydrocortisone
2. Ring A double bond reduction

3. C-17 oxidation
4. C-11 oxidation
21
11
17

2.17 Hydrocortisone
179
Based on this information, consider the array of products drawn in the scheme that follows. Identify each type of reaction or transformation that has occurred and evaluate each of the products to
determine if each product is active or inactive.
F
11
17
21
E
D
Answer
Pathway
Type of Reaction or Transformation
Active or Inactive
Allylic oxidation followed by dehydration
Active
C-11 oxidation
Inactive
C-17 oxidation
Inactive
C-21 esterification (acetylation)
Active
A ring double bond reduction
Inactive
A ring ketone reduction
Inactive

180
4. The synthetic glucocorticoids are often esterified at C-21 to produce prodrugs. Both lipophilic and
water4.
soluble
esters cann be
formed.
each of the four prodrugs drawn below and determine
The synthetic
overall
drug Evaluate
water solubility.
whether a lipophilic or water soluble ester is present. Determine how prodrug formation has an
effect on overall drug water solubility.
Answer
Type of Ester Formed
Effect on Overall Drug Water Solubility
Lipophilic ester
Decreases overall water solubility of the drug
Water soluble ester salt
Increases overall water solubility of the drug
Lipophilic ester
Decreases overall water solubility of the drug
Water soluble ester salt
Increases overall water solubility of the drug
a. Provide a structural rationale for why prodrugs (e.g., B and D) are used in the preparation of
aqueous injectable products to be administered intramuscularly (IM) or intravenously (IV).
Answer
Drugs that are formulated as aqueous injectable products must be highly hydrophilic in character.
Hydrocortisone contains four hydrophilic functional groups (ketone, primary alcohol, secondary
alcohol, and tertiary alcohol); however, it is not particularly soluble in water. By forming a water
soluble ester salt with the primary alcohol at C-21, an ionizable functional group is introduced.
In the case of prodrug B, the ionizable carboxylic acid is able to interact with water through ion
dipole interactions and, therefore, significantly increase the overall water solubility of the drug
molecule.
b. Provide a structural rationale for why prodrugs (e.g., A and C) are used in the preparation of
depot injections.
Answer
Drugs that are formulated as depot injections must be highly hydrophobic in character. Hydrocortisone contains a steroid backbone (all four rings) that is highly hydrophobic; however, it still has
2.17 Hydrocortisone
181
some limited solubility in water. By forming a lipophilic ester with the primary alcohol at C-21,
the overall water solubility of the drug decreases substantially. In this case, one of the hydrophilic
groups is now masked as an ester, thereby significantly decreasing its hydrophilic character. As a
lipophilic prodrug, hydrocortisone can be formulated as a suspension for intramuscular or subcutaneous injection.
5. Lipophilic glucocorticoid esters typically do not concentrate in the urine, but rather undergo glomerular filtration followed by tubular reabsorption. Provide a brief rationale for why lipophilic glucocorticoid esters do not concentrate in the urine and determine what effect this has on duration of drug
action.
Answer
For drugs to concentrate in the urine, they need to be highly water soluble (contain functional
groups with a significant amount of hydrophilic character). We have already evaluated the overall
water solubility of hydrocortisone to be relatively poor, despite the presence of several hydrophilic
functional groups. The addition of a lipophilic ester will further decrease the water solubility of
the resulting glucocorticoid ester. Because the glucocorticoid ester suffers from poor water solubility, it is not unexpected that it does not concentrate in the urine. These lipophilic esters, however,
have sufficient hydrophobic character to undergo reabsorption in the renal tubules. Because the
drug is returned to systemic circulation via this route of absorption, the duration of drug action is
prolonged.
6. Which type of prodrug, water soluble ester salts, or lipophilic esters, would you anticipate to have
greater systemic side effects?
Answer
The more water soluble the prodrug is, the wider the systemic distribution. The greater the prodrugs
solubility in the blood, then the greater the potential is for more misadventures/side effects. Because
the water soluble ester salts are by far more water soluble than the lipophilic esters, one would
predict that the water soluble ester salts would exhibit more systemic side effects.


C
F
D
Section
4 Whole
Molecule Drug Evaluation
A
Answers
Hydrocortisone
21
17
11
Levothyroxine (T4) is a naturally produced thyroid pro-hormone.
In its active form, tri-iodo-L-thyronine (T3) is
responsible for regulating oxygen consumption and calorigenesis (think metabolism, metabolic rate, and thermogenA
molecules until it is needed. Once proteolyzed from thyroglobesis). T4 is biosynthesized and stored in thyroglobulin
ulin and transported to the desired target tissue, T4 undergoes dehalogenation catalyzed by thyroxine dehalogenase to
the active thyroid hormone T3.
1.18
2.18 remove
from on
label
1. Conduct a structural evaluation
of and
levothyroxine
(T4), bold
focusing
the boxed functional groups, and use
the information in the grid to inform your answers to the questions that follow.
HO
I
I
OH
N H2
L-Thyroxine
Answer
Function
Character
Name of
Functional
Group
A Phenol
Function
Character
Acidic, Basic,
or Neutral
Function
Hydrophilic
and/or
Hydrophobic
Provide
pKa When
Relevant
Solubility
and/or
Absorption
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
Hydrophilic (OH)
Acidic
Solubility (OH)
H-bonding (A+D)
Hydrophobic (Ar)
pKa=910
Absorption (Ar)
Dipoledipole
Amino Acids That

Can Interact with
via H-Bonding
Interactions at
pH=7.4
None Is Acceptable
Trp, His
Iondipole (as the

dipole)
B
Ether
Hydrophilic (O)
Hydrophobic (R)
Neutral
Solubility (O)
H-bonding (A)
Absorption (R)
Dipoledipole
Iondipole (as the
dipole)

183

His, Trp
184

C Halogenated
Hydrophobic
1.18 and 2.18
remove bold from
label
Neutral
Absorption
Dipoledipole
None
Iondipole (as the

dipole)
Hydrophobic
van der Waals
- Stacking
D Primary amine
Carboxylic acid
Tri-iodothyronine
Hydrophilic (NH2)
Basic
Solubility (NH2)
Iondipole (as the ion) None
Hydrophobic (R)
pKa=911
Absorption (R)
Ionic
Solubility (CO2H)
Iondipole (as the ion) None
Absorption (R)
Ionic
Hydrophilic (CO2H) Acidic

pKa=25
Hydrophobic (R)
1. Conduct a structural your answers to the questions that follow.

2. Hormone replacement therapy in the form of levothyroxine (T4) is available for those patients who
E supply of T4. Evaluate the structure of levothyroxine and
do not produce an adequate endogenous
determine if it is an enantiomer,Ddiastereomer, or geometric isomer.
O
H 2N
H
I
OH
HO
B
OH
L-Thyroxine
L-Tyrosine
O
I
OH
H NH
2
<DAVID:
I please change caption to Levothyroxine>
Levothyroxine
2.Answer
Hormone replacement, diastereomer, or geometric isomer.
Evaluation of the structure of levothyroxine reveals that there is one chiral carbon atom. Because
there is only one chiral carbon atom, levothyroxine represents an enantiomer. Diastereomers require
the presence of at least two chiral carbon atoms so levothyroxine does not represent a diastereomer.
Further inspection of the molecule reveals that there are no carboncarbon double bonds or other
conformationally restricted functional groups so geometric isomers are not possible.
3. Evaluate the chiral carbon atom in levothyroxine to determine if this drug is drawn as the R- or
Levothyroxine
S-enantiomer.
Answer
Using the Cahn-Ingold-Prelog (CIP) system (see Chapter 7 in Basic Concepts in Medicinal Chemistry),
3.theEvaluate
the chiral
carbon
this drug
is drawn
as the R- orbased
S-enantiomer.
four groups
attached
to atom
the chiral
carbon
are prioritized
on atomic number and the
described sequence rules. Using these rules, the primary amine nitrogen atom is prioritized as #1, the
Answer:
carboxylic acid #2, the methylene unit attached to the aromatic hydrocarbon has the #3 priority, and
the hydrogen atom pointing away from the reader is the #4 priority. This assessment provides the
Using the; therefore, the S-enantiomer is drawn.
evidence for the prioritization scheme indicated below. In reviewing the positions of these priorities
it is noted that they are counterclockwise in orientation; therefore, the S-enantiomer is drawn.
3

185
4. T3 is the biologically active hormone. It interacts with the thyroid hormone receptor via hydrogen
4. T3 is the biologically
identified in hydrophobic,
the structure evaluation
bonding, iondipole,
and ionic grid.
interactions. Evaluate the ribbon diagram that shows
how T3 interacts with the surface of the thyroid receptor and identify the types of interactions
possible for each of the five functional groups identified in the structure evaluation grid.
O
I
HO
OH
H N H2
O
I
Tri-iodo-L-thyronine
Tri-iodothyronine
Answer
and 2.18
removevia
bold
from labelas the H-bond donor.
A. 1.18
Phenol:
OH interacts
H-bonding
5. T4 is biosynthesized
L-tyrosine
derived
L-tryosine.as a H-bond donor and acceptor. In this case the
NOTE: from
The phenol
OHwithin
is capable
of from
participating
phenol specifically
interacts
with
the
thyroid
receptor as the H-bond donor.
O
I
O
O
B. H
Ether:
no role in binding interaction.
O
I
2N
I
OH
HO
H 2 NC. Halogenated
aromatic H
hydrocarbon:
halogens
interact via hydrophobic interaction;
aromatic
HOH
I
OH
O
hydrocarbon interacts via hydrophobic interactions or - stacking.
OH
H
H NH
2
HO N H
I
D. Primary amine: no role in binding interaction.
2
I
O
OH
I interactions.
E. Carboxylic acid: participates
in iondipole (as the ion) or ionic
OH
I
L-Tyrosine
Levothyroxine
Tri-iodothyronineLevothyroxine
L-Tyrosine
5. T4 is biosynthesized from L-tyrosine within the thyroglobulin molecule and is considered an amino
acidbased hormone. Other hormones In the body are steroid-based (e.g., estrogen) or peptideand 2.18
remove
bold from of
label
Answer:
based (e.g.,1.18
insulin).
Evaluate
the structure
T4 and justify its classification as an amino acidbased
hormone by determining which functional groups are derived from L-tyrosine.
The biosynthesis s found in the amino acid tyrosine.
O
I
O
H 2N
I
OH
HO
H
OH
B
O
A I
H NH
2
O
I
I
HO
OH
OH
I
NH2
I
O
L-Tyrosine
Levothyroxine
I
Answer
Levothyroxine
The biosynthesis of levothyroxine
occurs within the thyroglobulin molecule which is rich in L-tyrosine
residues. Iodination of the tyrosine units and phenolic coupling represent some of the biochemical
reactions that occur in the biosynthesis of the natural hormone. Box A is derived from L-tyrosine, as is

L-Tyrosine
186
Levothyroxine
Answer:
HO
evident
bybiosynthesis
the presence
of only
phenolacid
portion
of the amino acid side chain. Box B is also derived
The
s found
in the
the amino
tyrosine.
from L-tyrosine; however, the phenol has become an ether. The rest of the boxed atoms represent
each of the atoms found in the amino acid tyrosine.
A
HO
HO
I
I
O
O
OH
OH
NH2 H NH
2
HO
Levothyroxine
Levothyroxine
Levothyroxine
6. Interestingly, the dehalogenation transformation represents both an activation and deactivation

pathway for T4. The iodo substituents on the inner ring of T4 play a role not only in important hydrophobic binding interactions with the receptor, but also in maintaining the shape of the hormone in
a perpendicular orientation (see diagram below). This perpendicular shape is necessary to appro1.18 and 2.18 structure was fixed (pay no attention to the colors)
priately position the phenolic OH to participate in key receptor binding interactions. Evaluate the
metabolites produced from the dehalogenation transformations and identify which metabolite is
active and which is not. Provide a brief rationale for your answers.

I
I
HO
A
I
HO
I
O
I
OH
H NH
2
I
D
OH
H NH
2
O
I
B
Lidocaine
I
HO
O
I
OH
Levothyroxine
H NH
2
B
1.18 and 2.18 structure was fixed (pay no attention to the colors)
O
I
O
I
I
O
187
Answer
Evaluation of the dehalogenation transformation that leads to metabolite A: The outer ring of
levothyroxine is dehalogenated to produce metabolite A. This metabolite retains the two inner
ring iodo substituents; therefore, the shape of the hormone remains perpendicular. This metabolite retains its biological activity.

Evaluation of the dehalogenation transformation that leads to metabolite B: The inner ring of
levothyroxine is dehalogenated to produce metabolite B. This metabolite retains only one inner
ring iodo substituent; therefore, the shape of the hormone cannot remain perpendicular. Because
the phenol is not positioned appropriately to participate in an important binding interaction
with the thyroid hormone receptor, this metabolite is inactive.



Answers
2.19 Lidocaine
As a sodium channel blocker, lidocaine has found therapeutic use both as a local anesthetic and as a Class IB antiarrhythmic
agent. As an anesthetic, this agent demonstrates rapid onset of action (acts quickly) and a longer duration of action
(lasts longer) than most amino ester-type local anesthetics. The most frequently observed side effects are changes in
the central nervous system (CNS) (e.g., dizziness, lightheadedness, and tinnitus). Lidocaine is extensively metabolized
by the CYP1A2 isozymes to a variety of metabolites.
1. Conduct a the in the grid to inform your answers to some of the questions that follow.
1. Conduct a complete structural evaluation of lidocaine, place your answers in the grid provided, and then
use the evaluation information in the grid to inform your answers to some of the questions that follow.
C H3
CH3
O
N
C H3
C H3
Lidocaine
Lidocaine
Answer
Answer:
Function
Character
Function
Character
Acidic,
A
Basic,
or Neutral
C
Function
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
Provide
pKa When
Relevant
Solubility
and/or
Absorption
Interaction(s)
Possible with
Biological
Target
D
at Physiological
pH=7.4
Aromatic
hydrocarbon
Hydrophobic
Neutral
Absorption
Hydrophobic
Amide
Hydrophobic (R)
Neutral
Hydrophilic (CON)
None Is Acceptable
None
van der Waals
Lidocaine
- Stacking
Absorption (R)
H-bonding (A + D)
Solubility (CON)
Dipoledipole
Iondipole (as the
dipole)
2. Based on the information in the

3. Local anesthetics that have.

Amino Acids That

Can Interact with
via H-Bonding
Interactions at
pH=7.4
189
Ser, Tyr, Thr, Cys, Asn, Glu,

His, Trp,
C H3
190
CH3
O
N
N
C H3
C H3

C
Tertiary amine
Hydrophobic (R)
Hydrophilic (N)
Answer:
D
Aliphatic alkane
Hydrophobic
Basic
Absorption (R)
Solubility (N)
pKa 911Lidocaine
Neutral
Absorption
Iondipole (as the

ion)
None
Ionic
Hydrophobic
None
van der Waals
C
D
B
Lidocaine
Lidocaine
2. Based on the information in the structure evaluation grid, determine whether or not lidocaine is
likely
(pH=7.4).
2.soluble
Basedinonthe
theblood
information
in the
Answer
3. Local anesthetics that have.
Lidocaine contains functional groups that contribute to the overall hydrophobic character of the
molecule (e.g., aromatic hydrocarbon and aliphatic alkanes), as well as functional groups that
contribute to the overall hydrophilic character of the molecule (e.g., amide and tertiary amine). The
hydrophilic character of the molecule enhances its water solubility, whereas the hydrophobic character enhances its ability to be absorbed across lipophilic membranes. At pH=7.4, the tertiary amine
will be predominantly in its ionized form which will further increase the water solubility of the drug.
The possibility of H-bonding interactions between the amide and water and an iondipole interaction
between the tertiary amine and water suggests that lidocaine is likely soluble in the blood.
3. Local anesthetics that have a rapid onset of action are rapidly distributed in the body and can be
absorbed easily across lipophilic membranes. Based on the information in the structure evaluation
grid, provide a rationale for why lidocaine is rapidly distributed and can easily be absorbed across
lipophilic membranes.
Answer
Based on the information in the structure evaluation grid, we know that lidocaine is likely soluble in
the blood due to the presence of hydrophilic functional groups (amide and ionizable tertiary amine).
If the drug is soluble in the blood, then it can be readily distributed in the body.
Based on the information in the structure evaluation grid, we also know that lidocaine is composed
of functional groups with a fair amount of hydrophobic character (aromatic hydrocarbon, aliphatic
alkanes). This will enhance absorption across lipophilic membranes. Rapid distribution and absorption
across lipophilic membranes contributes to the ability of lidocaine to have a rapid onset of action.

2.19 Lidocaine
191
4. Unless excreted unchanged, drug molecules undergo one or more metabolic transformations to
deactivate the drug and/or make the drug sufficiently water soluble to permit elimination. There are
a variety of transformations that are possible for most drugs, but only the minimum number of transformations actually occurs. The following diagram captures the metabolic pathways for lidocaine
are191:
observed
clinically.
For each transformation, identify which phase I metabolic transformation
7.that
Page
There was
a spelling
has taken place next to the relevant arrow.
Answer
C H3
C H3
O
N
N
C H3
C H3
Lidocaine
C H3
C H3
O
N
N
C H3
Aromatic
hydroxylation
HO
C H3
C H3
N
C H3
Aromatic
hydroxylation
Oxidative
N-dealkylation
H
N
C H3
Monoethylglycinexylidide
Oxidative
N-dealkylation
Amide
Hydrolysis
C H3
HO
N
C H3
H
N
C H3
3-Hydroxy-monoethylglycinexylidide
C H3
C H3
N H2
N
C H3
C H3
O
N H2
Glycinexylidide
O
HO
H
N
C H3
5. Now that you have identified the metabolic transformations that generate products that have been
identified, put your detective hat on and list any additional phase I transformations that could have
occurred.
Answer
Benzylic oxidation (on either or both of the aromatic ring methyl substituents). The resulting primary
alcohol can subsequently undergo alcohol oxidation to the corresponding aldehyde. The aldehyde
then undergoes aldehyde oxidation to the corresponding carboxylic acid.
192
6. Lidocaine suffers from CNS-based toxicities largely due to production of the N-dealkylated metabolic
product monoethylglycinexylidide once the parent drug has crossed the bloodbrain barrier.
a. Provide a structural rationale for why lidocaine is able to cross the bloodbrain barrier.
Answer
Based on the information in the structure evaluation grid, we know that lidocaine has a fair
amount of hydrophobic character (aromatic hydrocarbons with aliphatic substituents, aliphatic
alkane substituents on amine) that enhance absorption across lipophilic membranes. At pH=7.4,
the tertiary amine will be predominantly ionized. Because an equilibrium between the ionized
and unionized forms of lidocaine exists, a very small percentage of the drug will be in its unionized form at any given time. The bloodbrain barrier is highly selective. To cross this membrane
via passive diffusion, drugs typically must be in their unionized form and be highly lipophilic.
Because of the presence of the ionizable amine, only very small amounts of lidocaine will cross
the bloodbrain barrier and then undergo oxidative N-dealkylation to produce an N-dealkylated
metabolic byproductmonoethylglycinexylidide, the cause of the CNS-based toxicity observed.
b. Interestingly,
neither
1.19 and
2.19 tocainide
remove nor
boldtolycaine
from labeldemonstrates similar CNS-based toxicities. Provide a
structural rationale for why these two local anesthetics are devoid of CNS-based side effects.
Tolycaine
Tolcainide
Answer
1.25 and 2.25
remove
bold from
From a structural
perspective
tolycaine
is label
structurally identical to lidocaine with the exception
of the presence of a methyl ester instead of a benzylic methyl group. This methyl ester readily
A catalyzed ester hydrolysis, a phase I metabolic transformation, to the corresponding
undergoes enzyme
carboxylic acid. The resulting metabolic product will be ionized at physiological pH via two
B
Cacid and the tertiary amine. Even though tolycaine can undergo
functional groups, the carboxylic
oxidative N-dealkylation to produce an N-dealkylated product that closely resembles monoethylglycinexylidide, it is highly unlikely thatDthis drug will cross the bloodbrain barrier due to
the presence of these two ionizable functional groups. Again, although an equilibrium exists
between the ionized and unionized forms of both the carboxylic acid and the tertiary amine
functional groups, there is only a very small fraction of the drug that is completely unionized at
any point in time.
Sitagliptin
Tocainide contains several
of the same functional groups found in lidocaine, but does not contain
an alkylated amine. The hydrophobic character afforded by the substituted aromatic hydrocarbon and the presence of an amine-substituted aliphatic alkane will certainly contribute to the
remove
bold the
frombloodbrain
label
ability of2.25
thedrug
to cross
barrier. The primary amine will also be predominantly
ionized at pH=7.4 and, therefore, only a fraction of the time will it be available in its unionized
form. These structural characteristics are similar to lidocaine so it is possible for tocainide to cross
the bloodbrain barrier. Unlike lidocaine, tocainide cannot undergo oxidative N-dealkylation, and
the metabolic byproducts that cause CNS-based toxicity are not formed.


Answers
Shown below are the structures of montelukast and zafirlukast. These drug molecules are administered orally for the
treatment of asthma and allergic rhinitis.
Montelukast
Zafirlukast
1. The structure of montelukast contains one acidic functional group (pKa=4.4) and one basic functional
group (pKa=3.1), whereas the structure of zafirlukast only contains one acidic functional group (pKa=4.3).
1. The structure of a solution pH of 8.3.
Identify these acidic and basic functional groups and predict whether they will be primarily ionized or
primarilyAnswer:
unionized at a stomach pH=1.9, a urine pH=5.4, a cellular pH=6.1, a plasma pH=7.2, and a solution pH=8.3.
Carboxylic acid
Acidic (pKa = 4.4)
Sulfonamide
Acidic (pKa = 4.3)
Montelukast
Aromatic heterocylic amine
Basic (pKa = 3.1)
193
Zafirlukast
194
1. The structure of a solution pH of 8.3.

Answer:
Answer
Carboxylic acid
Acidic (pKa = 4.4)
Sulfonamide
Acidic (pKa = 4.3)
Montelukast
Aromatic heterocylic amine
Basic (pKa = 3.1)
Zafirlukast
Functional Group
Acidic or
Basic

1.9
5.4
6.1
7.2
8.3
Unionized
Ionized
Ionized
Ionized
Ionized
3. The
sodium saltBasic
an explanation
for this difference.
Aromatic
heterocyclic
Ionized
Unionized
amine
Unionized
Unionized
Unionized
Sulfonamide
Ionized
Ionized
Ionized
Carboxylic Acid
Acidic
2. In the previous question, we to calculate the percent of the functional group that would be ionized.
Acidic
Unionized
Ionized
2. In the previous question, we examined three pKa values in five different environments for a total of
15 different scenarios. Which of these 15 scenarios allow you to use the Rule of Nines to calculate
scenarios and use the Rule of Nines to calculate the percent of the functional group that would be
ionized.
Answer
To use the Rule of Nines, the difference between the pH and the pKa must be an integer (i.e., 1, 2, 3).
In evaluating the above 15 scenarios, there are three scenarios that meet this criterion, the carboxylic acid of montelukast (pKa=4.4) at a urine pH=5.4, the aromatic heterocyclic amine of montelukast
(pKa=3.1) at a cellular pH=6.1, and the sulfonamide of zafirlukast (pKa=4.3) at a solution pH=8.3. For
the carboxylic acid of montelukast, |pH pKa| is equal to 1; thus, there is a 90:10 ratio. Because the
carboxylic acid (pKa=4.4) would be primarily ionized in a basic environment (pH=5.4), we can use this
ratio to determine that it would be 90% ionized. For the aromatic heterocyclic amine of montelukast, |pH pKa| is equal to 3; thus, there is a 99.9:0.1 ratio. Because the aromatic heterocyclic amine
(pKa=3.1) is a basic functional group, it would be primarily unionized in a basic environment (pH=6.1).
We can use this information to predict that it would be 0.1% ionized. For the sulfonamide of zafirlukast, |pH pKa| is equal to 4; therefore, there is a 99.99:0.01 ratio. Because the sulfonamide (pKa=4.3)
is an acidic functional group, it would be primarily ionized in a basic environment (pH=8.3). Thus, we
can use this information to predict that it would be 99.99% ionized.

195
3. The sodium salt of montelukast is required for its oral administration, whereas zafirlukast can be
administered orally as its unionized free acid form. Conduct a structural analysis of these two drug
molecules and provide an explanation for this difference.
Answer
A sodium salt is an inorganic salt of the parent drug. The primary purpose of using an inorganic
salt is to enhance the water solubility of a drug molecule. This in turn enhances its solvation and
dissolution with the aqueous environment of the gastrointestinal (GI) tract. Since montelukast must
be administered as an inorganic salt, whereas zafirlukast does not have this requirement, this indicates that zafirlukast has higher water solubility than montelukast. In evaluating their structures, it
is found montelukast and zafirlukast each contain three water soluble functional groups, and the
remainder of their structures is comprised of alkyl chains, aromatic rings, a thioether, and a halogen.
All of these latter functional groups bestow lipid solubility to their respective drug molecules. A
key difference between these two structures is the overall nature of their water soluble functional
groups. The sulfonamide of zafirlukast has a wider charge distribution (four atoms) than does the
carboxylic acid of montelukast (two atoms; Comparison A). Additionally, the carbamate group of
zafirlukast has the ability to form more hydrogen bonds with water than does the tertiary hydroxyl
group of montelukast (Comparison B). The ability to act as hydrogen bond acceptors would be
expected to be similar for the methoxy group of zafirlukast and the aromatic heterocyclic amine of
Answer:
montelukast
(Comparison C). Please note that the nitrogen atom of the indole ring is an extremely
weak
base
(pK
in hydrogen bonds. This is because the lone pair of elecA sodium salt isa <
an0.1)
ilityand
o thecannot
indole participate
ring.
trons on the nitrogen atom are required for the aromaticity of the indole ring.
A O
OH
S
Cl
H3C
C H3
C
Montelukast
H3 CO
O
N
H
N
C H3
S
O
Zafirlukast
C H3
In addition, the overall lipid soluble character of montelukast is greater than that of zafirlukast.
The structure of montelukast contains 34 aromatic or aliphatic carbon atoms (as well as a halogen
whereas
structure
containsoccur
only 28
The combination
4. atom),
Montelukast
and.the
Assume
that of
all zafirlukast
binding interactions
at aatoms.
physiological
pH of 7.4. of a lower water
soluble nature and a higher lipid soluble nature is responsible for the need to utilize a sodium salt for
Answer:
the oral administration of montelukast.
Let us four nd hydrophobic interactions.
The four boxed areas could interact with a

hydrophobic pocket within the leukotriene receptors.
Ionic bond
Hydrogen bond
(as acceptor)

S
Cl
196
H3C
C H3
A
O
H3 CO
C H3
O
4. Montelukast and Montelukast
zafirlukast exert their mechanism ofBaction by interacting with cysteinyl leukotriene
). It has
receptors and blocking the normal actions of endogenous leukotrienes (LTC4, LTD4, and NLTE
4
S
been proposed that this interaction requires five key elements:
an ionic interaction, a hydrogen bond
H
O
N
interaction where the antagonist acts as the H-bonding
acceptor,
as well as the interaction O
of the
antagonist with three separate hydrophobic pockets within the receptor. Using this information and
the structures of montelukast and zafirlukast, proposeOpotential binding
interactionsZafirlukast
between these
N
drug molecules and cysteinyl leukotriene receptors. Assume that all binding interactions occur at a
C H3
physiological pH=7.4.
Answer
Let us evaluate these two drug molecules separately. The structure of montelukast contains a carboxacid that could
participate
ionic interactions
bond with the
leukotriene
receptors.
4. ylic
Montelukast
and. Assume
that in
allan
binding
occur
at a physiological
pH It
of also
7.4. contains two
functional groups, the tertiary hydroxyl group and the aromatic heterocyclic amine, that could
Answer: in a hydrogen bonding interaction as an acceptor. As shown below, the structure of
participate
montelukast
contains
four separate
regions that could interact with the three hydrophobic pockets
Let us four nd
hydrophobic
interactions.
of the receptor via van der Waals and hydrophobic interactions.
Ionic bond

hydrophobic pocket within the leukotriene receptors.
Hydrogen bond
(as acceptor)
Hydrogen bond
(as acceptor)
Montelukast
Similarly, the structure of zafirlukast contains a sulfonamide group that could participate in an ionic
interaction with the leukotriene receptor, as well as two functional groups, the methoxy group and
the carbamate, that could participate in a hydrogen bonding interaction as an acceptor. As shown
below,
the structure
of zafirlukast
four separate
regions
interact with the
Similarly,
the structure
of groupalso
that contains
could participate
in an ionic
bondthat
withcould
the leukotriene.
three hydrophobic pockets within the receptor.
Hydrogen bond
(as acceptor)
hydrophobic pocket on the leukotriene receptors.
Ionic bond
Hydrogen bond
(as acceptor)
Zafirlukast
5. Calculated log P values of montelukast or be primarily excreted unchanged?

6. Shown below is the to perform with zafirlukast.
197
5. Calculated log P values of montelukast and zafirlukast lie in the range of 5.5 to 6.4 depending on the
computer program used to predict these values. Given this information, would these drug molecules
be predicted to be highly plasma protein bound or minimally plasma protein bound? Additionally,
would you expect these drug molecules to undergo extensive hepatic metabolism or be primarily
excreted
unchanged?
Similarly,
the structure of group that could participate in an ionic bond with the leukotriene.
Answer
Plasma proteins are used by the human body to transport endogenous
molecules
Hydrogen
bondin the plasma from
one cell to another. Given that the plasma is water soluble, these proteins
are primarily required to
(as acceptor)
carry those endogenous molecules that have a high level of lipid solubility (e.g., estradiol, cholesThe four boxedThis
areas
could
interact
with a
terol, hydrocortisone).
is also
true
for exogenously
administered drug molecules. Drug molecules
hydrophobic pocket on the leukotriene receptors.
that have a more lipid soluble character have a greater affinity for plasma proteins than do those
that have a more water soluble character. Thus, using the calculated log P values provided for montelukast and zafirlukast, it would be expected that these two drug molecules would be highly plasma
protein bound.
The primary purpose of drug metabolism is to enhance the removal of the drug molecule from the
Ionic and
bondthus can be readily
human body. Drug molecules that already possess adequate water solubility,
eliminated, generally undergo minimal or no metabolism, whereas drug molecules that are highly
lipid soluble often undergo extensive metabolic transformation. Thus, using the calculated log P
values provided for montelukast and zafirlukast, it would be expected that these two drug molecules
Zafirlukast
would undergo extensive hepaticHydrogen
metabolism.
bond
(as acceptor)
6. Shown below is the structure of zafirlukast and a list of five metabolic transformations. For each
metabolic
transformation,
if it is aorphase
I or a phase
II transformation
5. Calculated
log P valuesindicate
of montelukast
be primarily
excreted
unchanged? and if zafirlukast has
a functional group present to participate in the transformation. If you answer YES, then draw the
appropriate metabolite; if you answer NO, then provide a brief explanation as to why this metabolic
transformation
is not
possible
to perform
with zafirlukast.
6. Shown below
is the
to perform
with zafirlukast.
Metabolic Pathways
A. Methylation
B. Aromatic Oxidation
C. Hydrolysis
D. Oxidative O-Dealkylation
ReplacementStructuresforBatch3
Chapter2.20
Answer
Pleasereplacethestructureforanswer6B(page5)withtheoneshownbelow.

A. Methylation: No. Methylation is a phase II metabolic transformation that requires a catechol, a

phenol, an amine, or a sulfhydryl functional group. Because none of these functional groups are
Answer:
present
within the structure of zafirlukast, this metabolic transformation cannot occur.
B. Aromatic Oxidation: Phase I; Yes
A. Methylation: No., this metabolic transformation cannot occur.

B. Aromatic Oxidation: Phase I; Yes
Note: Aromaric hydroxylation

could also occur on these
rings; however, they are
more sterically hindered.

From: ASHP eBooks
(digital.ashp.org)
Note: Aromaric hydroxylation

could also occur on this
ring; however, it is more

198
Pleasereplacethestructureforanswer6C(page6)withtheoneshownbelow.
C. Hydrolysis: Phase I; Yes

O
H3 CO
OH
N
H
H
N
HO
C H3
S
O
Pleasereplacethestructureforanswer6D(page6)withtheoneshownbelow.
O
Note: It is also possible to

hydrolyze the sulfonamide.
N
C H3
Pleasereplacethestructureforanswer6D(page6)withtheoneshownbelow.
O
Phase I;
D. Oxidative O-Dealkylation:
O Yes
HO
H
O
H
N
O
O
H
H
N

HO
C H3
C H3
S
OO
N
H
C H3
of methoxy functional group
of methoxy functional group
S
O
N
C H3
H3 CO
O H
HO
N
O
H3 CO
H
N
HO
N
C H3
N
H
O
N
H
C H3
S
OO
N
H
O
S
O
C H3
of carbamate functional group
of carbamate functional group
N
C H3
Pleasereplacethestructureforanswer6E(page6)withtheoneshownbelow.
E. Benzylic Oxidation: Phase I; Yes
Pleasereplacethestructureforanswer6E(page6)withtheoneshownbelow.
Benzylic oxidation can occur at two sites;

however, the one in the middle of the
molecule is more sterically hindered.
Benzylic oxidation can occur at two sites;

however, the one in the middle of the
molecule is more sterically hindered.


Answers
2.21 Phenobarbital and
Other Barbiturates
Shown below are the structures of butabarbital, secobarbital, and phenobarbital. These drug molecules are used as
2.21 Phenobarbital and Other Barbiturates
sedative-hypnotic agents in the treatment of insomnia and to induce sedation prior to surgical procedures. Phenobarbital can be used in the treatment of a number of different seizure disorders. Their sedative properties are due to their
ability
to interact
thestructures
GABAA receptor
Shown
below with
are the
of buta in the central nervous system (CNS).
O and OtherOBarbiturates
2.21 Phenobarbital
HN
NH
Butabarbital
O
HN
Shown below are the structures of buta
NH
HN
NH
Secobarbital
Phenobarbital
1. Conduct a structural previously listed.

1. Conduct
aHstructural
as to why they can be
N
N H analysis of these drug
H N molecules
N H and provide an explanation
HN
NH
Answer:
administered orally for the indications previously listed.
These three drug to their site of action.
O
O
O
Answer
These three drug molecules vary only in the alkyl chains and aromatic rings located at the 5 position of barbiButabarbital
Secobarbital
Phenobarbital
turic acid. As shown below, barbituric acid is symmetrical
two identical imide functional groups (a
Only and
site contains
of
variationranges from 4.58.5, imides tend to have values
type of -dicarbonyl). While the pKa range for a -dicarbonyl
at
the
upper
end
of
this
range.
As
such,
they
can
be
ionized
in the small intestine to a limited extent and
1. Conduct a structural previously listed.
participate in hydrogen bonds with water when present in the unionized state. This provides sufficient water
Answer:
solubility
for solvation and dissolution. The alkyl chains and aromatic ring provide sufficient lipid solubility to
permit
these
drug
molecules
to cross
the gastrointestinal 5(GI) mucosal membrane and be orally absorbed. This
These three
drug
to their site
of action.
lipid solubility facilitates absorption across the bloodbrain barrier to gain access to their site of action.
Imide
Imide
Only 1site of 3
variation
Barbituric Acid
5
2. Butabarbital and secobarbital these two administered as their sodium salts.

Imide
Imide
1
3
Answer:
Barbituric Acid
199
2. Butabarbital and secobarbital these two administered as their sodium salts.
Imide
200
Imide
2. Butabarbital and secobarbital are marketed as their

sodium
Barbituric
Acidsalts and phenobarbital is marketed in its
free acid form (i.e., non-salt form). Draw the sodium salt of either butabarbital or secobarbital and
provide an explanation as to why these two drug molecules need to be administered as their sodium
salts. 2. Butabarbital and secobarbital these two administered as their sodium salts.
AnswerAnswer:
Sodium Butabarbital
Sodium Secobarbital
Phenobarbital
(Used as Free Acid)
In general the primary reason that drug molecules are administered in their inorganic salt form is to
3. Using
the information
in acting
agent solubility.
(onset of action
= 3060and
minutes;
durationneed
= 1016
hours).
enhance
solvation,
dissolution,
and water
Butabarbital
secobarbital
to be
administered as their sodium salts, whereas phenobarbital does not. This suggests that butabarbital and
secobarbital have greater lipid solubilities than phenobarbital and therefore need to be administered
in a more water soluble form. The authors do not expect the readers to know the structure-activity
relationship (SAR) of barbiturates, so the following information is offered to show how the logical
application of key concepts often explains known facts. Structural activity studies of barbiturates
have demonstrated that alkyl chains at the 5 position of barbituric acid produce more lipid solubility
than the aromatic ring in the structure of phenobarbital. Phenobarbital has a log P value=1.46, while
butabarbital and secobarbital have log P values=1.60 and 2.36, respectively.
3. Using the information in questions 1 and 2 and your answers to those questions, provide an explanation
as to why secobarbital is a short-acting agent (onset of action = 1015 minutes; duration = 34 hours),
butabarbital is an intermediate-acting agent (onset of action = 4560 minutes; duration = 68 hours), and
phenobarbital is a long-acting agent (onset of action = 3060 minutes; duration = 1016 hours).
Answer
As discussed in the previous two questions, these three drug molecules are structurally similar and
vary only in the hydrocarbon chains at position 5 of the barbituric acid ring. These minor structural
variations result in differences in their respective lipid solubilities. Drug molecules that have higher
lipid solubility (log P) traverse more quickly through lipid membranes, but are more likely to undergo
metabolic transformation than drug molecules that have lower lipid solubility. Secobarbital is the
most lipid soluble of the three drug molecules. As such, it is rapidly absorbed, can rapidly cross the
bloodbrain barrier, and has the quickest onset of action. Due to its higher lipid solubility, it is metabolized quicker than either butabarbital or phenobarbital. This rapid metabolism is responsible for the
relatively short duration of action. Butabarbital and phenobarbital are less lipid soluble than secobarbital and have similar onsets of action; however, phenobarbital has a lower lipid solubility, is metabolized at a slower rate, and thus has a longer duration of action than butabarbital.

201
4. Secobarbital contains an ionizable functional group with a pKa=7.9. Using the table shown below,
identify the functional group, provide the normal pKa range for the functional group, and identify if
4. the
Secobarbital
primarily
ionized
or unionized
at pH
of 1.5,
5.9, 6.3, 7.4, and5.9,
8.9.6.3, 7.4,
functionalbegroup
would
be primarily
ionized
or environments
unionized at pH
environments=1.5,
and 8.9.
Imide
(Acidic)
Secobarbital
Answer
5. As stated above between secobarbital and the side chains of the amino acids indicated.
Answer:
Functional Group
Acidic or
Basic
pKa Range
1.5
5.9
One
that involve
side chains4.5-8.5
of valine and
phenylalanine.
-Dicarbonyl
(Imide) the
Acidic
Unionized
Unionized
6.3
7.4
8.9
Unionized
Unionized
Ionized
<ProductionPlease change hyphens to n dashes for Dipole-Dipole in figure}

5. As stated above, barbiturates exert their mechanism of action by interacting with the GABAA receptors. Assume that the following amino acids are involved in this binding: Val, Phe, Ser, Asn, and Lys.
Using the functional groups present within the structure of secobarbital, identify five specific binding
R4 and
Phe secobarbital
vanthe
derside
Waals
interactions between
chains of the amino acids indicated.
O
Hydrophobic
Interaction
N
H
Answer
R3
One potential response
is shown below. Please note that other correct response options are available
for this particular question. The primary amine of lysine will be primarily ionized within a cell. The
imide of secobarbital has a pKa=7.9, so it would be approximately 25% ionized at a pH=7.4. The local
O
environment within a binding site may alter the acidity of this functional group. If this functional
R2
Asn
group was not
R1 ionized, it could still interact with lysine via an iondipole interaction. Asparagine can
participate in both
R5
The ability to participate in
N dipoledipole interactions as well as hydrogen
vanbonds.
der Waals
a dipoledipoleHinteraction is illustrated here to provide examples
of
different
types of interactions.
Dipole-Dipole
The
positions of the serine and asparagine could be switched
to
form
different
hydrogen bonds. The
O
O
O
O
Interaction
same
is true for the
van der Waals interactions that
involve theVal
side chains of valine and phenylalaH
N
N H2
nine.
R6
R10
H
N
H3 N
Ionic Bond
R7
Lys
Hydrogen Bond O
R9

Ser
HN
R8
One that involve the side chains of valine and phenylalanine.

<ProductionPlease change hyphens to n dashes for Dipole-Dipole in figure}
202
Phe
R4
van der Waals

NH
R3
Asn
O
R1
Dipole-Dipole
Interaction
R2
R5
N
H
O
N H2
R10
O
N
N
O
H
N
HN
van der Waals

Val
R6
H3 N
Ionic Bond
R7
Lys
Hydrogen Bond O
R9
Ser
HN
R8
Chapters1.21and2.21
6. Shown below are known metabolites of butabarbital, secobarbital, and phenobarbital. Identify the
metabolic transformations that are required to produce each metabolite and indicate if they are
PleasereplacetheindicatedstructureinQuestion6inboth1.21and2.21(theonethatispartofthequestion)
phase I or phase II transformations. Would you expect any of these metabolites to retain their
withtheonebelow.Bothstructureshadanidenticalerror.
pharmacological activity? Why or why not?
Metabolite of
butabarbital

Metabolite of
secobarbital
Metabolite of
phenobarbital
Answer
Butabarbarbital: oxidation (phase I) followed by glucuronic acid conjugation (phase II)

Secobarbital: oxidation of the double bond (water reacts with the initial epoxide to produce a diol) and
-1 oxidation; the order of these phase I transformations is unimportant
Chapter2.22

Phenobarbital: aromatic oxidation (hydroxylation, phase I) followed by sulfate conjugation
(phase II)

Intramolecular
Hydrogen Bond
203
These metabolites would not be expected to retain the pharmacological activity that was present in
the parent drug molecules. For any drug molecule to produce a pharmacological effect, it needs to
contribute complementary interactions with its biological target. The alkyl chains and aromatic ring
are important for forming van der Waals and hydrophobic interactions with hydrophobic amino acids
within the GABAA receptor. The addition of hydrophilic functional groups at this position decreases
their ability to form these key interactions. Furthermore, the addition of these hydrophilic functional
groups in the liver would greatly decrease or eliminate the ability of these metabolites to cross the
bloodbrain barrier and reach their site of action in the CNS.



Answers
2.22PravastatinandFluvastatin
ShownShown
belowbelow
are theare
structures
of pravastatin
and fluvastatin.
drug molecules
used
in boxed.
the treatment of
the structures
of pravastatin.
A total ofThese
six functional
groups are
have
been
various types of hyperlipidemia/dyslipidemias. A total of six functional groups have been boxed.
F
E
Pravastatin
Fluvastatin
1. Using the table below, drophilic or hydrophobic in character. for your response.
logbelow,
P values
of s and
a structural
explanation
for the
difference
in these log
P values.
1. Using2.theThe
table
identify
theprovide
six boxed
functional
groups. For
each
of the functional
groups
you
identify, indicate
if
it
is
hydrophilic
or
hydrophobic
in
character.
Also
provide
a
brief
explanation
for
your
Answer
response.
The log P value is a functional groups than the structure of fluvastatin, it has a lower log P value.
Answer
3',5'-Dihydroxy-
Hydrophobic due to its inability

to ionizeacid
or form hydrogen bonds; hydrocarbon functional
heptanoic
groups enhance lipid solubility
Alkyl group; alkyl chain; aliphatic chain
Ester
Secondary hydroxyl (secondary alcohol)
Hydrophilic due to its ability to form hydrogen bonds as either a donor or an acceptor
Halogen; fluorine
Effects can vary; fluorine can act as a hydrogen bond acceptor; however, studies have
shown that the substitution of a hydrogen atom with a fluorine atom tends to slightly
enhance lipid solubility
Aromatic ring system; heterocyclic

aromatic ring; indole
Hydrophobic due to its inability to ionize or form hydrogen bonds; the lone pair of
electrons present on the nitrogen atom are involved in the aromaticity of the ring system
and therefore are not available to form hydrogen bonds; the remaining hydrocarbons
Isopropyl chain
comprising the ring system enhance lipid solubility
Ester
Isobutyl chain
p-Fluoro-
Secondary
Carboxylic
acid
Hydroxyl
Hydrophilic due to its ability to act as a hydrogen bond acceptor
Hydrophilic due to its ability to ionize

(form
an iondipole interaction with water) and to
phenyl
ring
participate in hydrogen bonding (acceptor and donor) in its unionized formIndole ring
Pravastatin

Decalin ring
205
Fluvastatin
2.22PravastatinandFluvastatin
206
Shown below are the structures of pravastatin. A total of six functional groups have been boxed.
2. The log P values of pravastatin and fluvastatin are 1.44 and 3.62, respectively. Conduct a structural
F
analysis of these drug molecules
and provide a structural explanation for the difference
in these log P
C
values.
Answer
The log P valueBis a logarithmic expression of the ratio of a drug molecules solubility in a lipid
environment when compared to an aqueous environment
and assumes that all ionizable functional
D
groups are present in their unionized form. The log P value of any given drug molecule is the result
of
A the additive contributions and interrelationships of all of its functional groups. In evaluating the
structures of pravastatin and fluvastatin, both drug molecules contain a 3,5-dihydroxyheptanoic
acid group and differ in the ring systems attached to this group. The carboxylic acid and the two
secondary hydroxyl groups contribute to the water solubility of these drug molecules; however, it
E
would be expected that these contributions would be similar for both drug molecules. In evaluating
the different ring systems and their substituents, it can be seen that the structure of pravastatin
Pravastatin
contains an additional
secondary hydroxyl group, as well as two ester
oxygen atoms. These functional
Fluvastatin
groups are capable of forming additional hydrogen bonds and thus contribute to the overall water
solubility of pravastatin. The decalin ring and the isobutyl side chain contribute to the overall lipid
pravastatin.
In contrast,
the remaining
functional
of fluvastatinaromatic rings,
1. solubility
Using the of
table
below, drophilic
or hydrophobic
in character.
forgroups
your response.
an aliphatic chain, and a halogencontribute to its overall lipid solubility. It should be noted that
2. the
The lone
log Ppair
values
of s and provide
structural
the
difference
these
log P values.
of electrons
presenta within
theexplanation
indole ringfor
are
required
forinthe
aromaticity
of the ring
and
therefore are not available to form hydrogen bonds or accept protons. Because the structure
Answer
of pravastatin contains more hydrophilic functional groups than the structure of fluvastatin, it has a
The log P value is a functional groups than the structure of fluvastatin, it has a lower log P value.
lower log P value.
3',5'-Dihydroxyheptanoic acid
Ester
Isobutyl chain
Secondary
Hydroxyl
Isopropyl chain
p-Fluorophenyl ring
Pravastatin
Decalin ring
Indole ring
Fluvastatin
3. The normal pKa range for carboxylic acids is 2.5 to 5. The pKa values for the carboxylic acids present
within the structures of pravastatin and fluvastatin are 4.21 and 4.56. Conduct a structural analysis
and provide a reason why these pKa values are at the high end of the normal range.
Answer
The presence or absence of specific functional groups can affect the acidity or basicity of ionizable
functional groups. In the case of pravastatin and fluvastatin, as well as other drug molecules within
this chemical/pharmacological class, the 3-hydroxyl group affects the acidity of the carboxylic acid. In
general, non-aromatic hydroxyl groups are electron withdrawing due to the high electronegativity of
the oxygen atom; however, in the case of pravastatin and fluvastatin, the position of the 3-hydroxyl
group orients it to form intramolecular hydrogen bonds with the carboxylic acid. These hydrogen
bonds decrease the ability of the proton of the carboxylic acid to dissociate, therefore decreasing its
acidity and increasing its pKa value.

Chapter2.22
207

3. The normal pKa range for at the high end of the normal range.
Answer
The presence or absence of its pKa value.
Intramolecular
Hydrogen Bond
Intramolecular
Hydrogen Bond
Intramolecular
Hydrogen Bone
H
O
H3C
HO
O
COOH
OH
OH
H
O
H
O
O
H3C
Intramolecular
Hydrogen Bone
H
F
H Pravastatin
C H3
N
Fluvastatin
4. Pravastatin and fluvastatin exert their anti-hyperlipidemic effects by inhibiting the enzyme HMG
CoA reductase. AsPravastatin
shown below, HMG CoA reductase converts 3-hydroxy-3-methylglutaryl
CoA
Fluvastatin
(HMG CoA) to mevalonic acid. This conversion is required for the synthesis of cholesterol and acts as
a primary control site for production of this endogenous steroid. Using the structures of HMG CoA,
acid,
and fluvastatin,
provide
an explanation
to how
4. mevalonic
Pravastatin
andpravastatin,
fluvastatin fluvastatin,
provide
an d fluvastain
inhibitas
HMG
CoApravastatin
reductase. and fluvastatin
inhibit HMG CoA reductase.
HMG CoA
Reductase
HMG CoA
Mevalonic Acid
Answer
In the reaction catalyzed by HMG CoA reductase, the thioester of HMG CoA is reduced to a primary
hydroxyl group. The 3,5-dihydoxyheptanoic acid found within the structures of pravastatin and
fluvastatin very nicely mimic the structure of mevalonic acid, the product of this reaction. Unlike the
natural substrate, pravastatin and fluvastatin cannot be reduced. Because they bear structural similarity to both the substrate and the product, they can interact with the enzyme in a similar manner as
the substrate; however, because they lack the functional group that is normally reduced, they are not
transformed by the enzyme and act as enzyme inhibitors. The respective ring systems of pravastatin
and fluvastatin most likely occupy binding sites that are adjacent to the active site of the enzyme.

208

Answer
Answer
In the reaction most likely occupy binding sites that are adjacent to the active site of the enzyme.
In the reaction most likely occupy binding sites that are adjacent to the active site of the enzyme.
HMG CoA
HMG CoA
Reductase
Reductase
Thioester
Thioester
Mevalonic Acid
Mevalonic Acid
HMG CoA
HMG CoA
HO 3
HO
O
H3 C
O
H
H3 C
O
H3 C
H
H3C
HO
HO
COOH
3
COOH
5 OH
5 OH
H
H
Pravastatin
Pravastatin
Primary
Primary
Hydroxyl
Hydroxyl
C H3
C H3
HO 3
HO
COOH
COOH
5 OH
5 OH
H
H
3
Fluvastatin
Fluvastatin
5. Shown below are the structures of fluvastatin and a conformationally restricted analog. The addition
of another carbon atom and the conformational restriction essentially abolish the therapeutic activity
5. Shown below are the structures why this structural change results in a loss in activity.
of 5.
fluvastatin.
Usingare
these
postulate
a reason
why this
structural
change
results in a loss in
Shown below
the structures,
structures why
this structural
change
results
in a loss
in activity.
activity.
Fluvastatin
Fluvastatin
Conformationally
Conformationally
Restricted
Analog
Analog
ofRestricted
Fluvastatin
of Fluvastatin
Answer
The addition of a functional group will affect the overall electronic distribution, water/lipid solubility balance, and steric dimensions of the parent drug molecule. The electronic effects would be
expected to be minimal due to the low electronegativity values of carbon and hydrogen. The additional carbon atom will increase lipid solubility and this could affect the ability of the analog to
dissolve; however, the use of a sodium salt (similar to what is done with fluvastatin) should still allow
for adequate dissolution. This then leaves the steric effect as the most probable cause for the loss
209
of activity with this analog. There are two aspects to consider. First, the addition of an extra carbon
atom may not be permitted due to the steric dimensions of the target enzyme, HMG CoA reductase.
The simple addition of a methyl group (or carbon atom) can significantly alter the interaction of a
drug molecule with its biological target. Although this may be the cause for the loss of activity, a
much bigger alteration in the steric dimension of fluvastatin has been introduced with this conformational restriction. In evaluating the structure of fluvastatin, it is found that there is free rotation
about the bond that connects the indole ring to the para-fluoro aromatic ring. This allows flexibility
and the opportunity for these two rings to be oriented in a manner that allows optimal interactions
with HMG CoA reductase. In contrast, the conformational restriction introduced in the fluvastatin
analog creates a large, planar, tetracycline ring system with no flexibility. The ability of this analog to
interact with HMG CoA reductase would therefore be dependent on the availability of a complementary large, flat, hydrophobic area within the active site of the enzyme. Receptor binding studies have
shown that the para-fluoro aromatic ring of fluvastatin cannot be coplanar with the indole ring and
that conformational restriction, such as that shown in this question, abolishes therapeutic activity.
6. Pravastatin
is primarily
metabolite
inactive.
6. Pravastatin
is primarily
metabolized
to itsis3
epimer. This metabolite is completely inactive as an
HMG CoA reductase inhibitor. Identify the metabolic transformations required to produce this
metabolite and provide an explanation as to why this metabolite is inactive.
3D epimer
Answer
The epimer results from the oxidation of the 3 hydroxyl group by alcohol dehydrogenase followed
by reduction to the 3 epimer. The loss of activity results from the fact that the compound no longer
mimics HMG CoA or mevalonic acid. The epimeric hydroxyl group is oriented in the opposite direction and either fails to form a crucial hydrogen bond or sterically inhibits interaction with the active
site of HMG CoA reductase.



Answers
2.23 Quinapril
2.23 Quinapril
Shown
belowbelow
is the is
structure
of quinapril.
It is an
enzyme (ACE) inhibitor that is used in the
Shown
the structure
of quinapril.
It angiotensin
is an groupsconverting
are identified.
treatment of hypertension and heart failure. Five functional groups are identified.
B
H3C
O
D
O
H
N
N
C H3
OH
E
1. Using the table below, identify the five boxed functional groups. For each of the functional groups you
1. Using
the table
below,
identifyor
thehydrophobic
five explanation
for your response.
identified,
indicate
if it is
hydrophilic
in character.
Also provide a brief explanation for
your response.
2. Using the h functional ionized or unionized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
Answer

hydrocarbon
groups enhance lipid solubility.
Ethyl ester
Contains both hydrophilic and hydrophobic properties. The two oxygen atoms can act as
hydrogen bond acceptors and can contribute to water solubility. The ethyl group can neither
ionize nor form hydrogen bonds and thus contributes to lipid solubility.
Secondary amine
participate in hydrogen bonding (acceptor and donor) in its unionized form.
Amide
Carboxylic acid
Secondary amine
Hydrophilic due to its ability to form hydrogen

bonds as a hydrogen
Carboxylic
acid bond acceptor. (Note:
Does not participate as a hydrogen bond donor due to the lack of hydrogen atom.)
participate in hydrogen bonding (acceptor and donor) in its unionized form.

2. Using the unmodified structure of quinapril and the following table, identify all of the acidic and basic
functional groups present in the structure, provide the normal pKa range for each functional group, and
identify if each functional group would be primarily ionized or unionized at pH environments=1.5, 4.8,
6.3, 7.4, and 8.1.

211
H3C
212
1.Medicinal
Using the
table below,
identify theOfive explanation
for your response.
Chemistry
Self Assessment
O
D
2. Using the h functional ionized
or unionized atOpH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
A
H
N
N
C H3
OH
E
1. Using the table below, identify the five explanation for your response.
2. Using the h functional ionized or unionized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
Secondary amine
Functional Group
Acidic or
Basic
Carboxylic acid

pKa Range
1.5
4.8
6.3
7.4
Secondary amine
Basic
911
Ionized
Ionized
Ionized
Ionized
Ionized
Carboxylic acid
Acidic
2.55
Unionized
Ionized*
Ionized
Ionized
Ionized
8.1
*There is a possibility that this functional group could be > 50% unionized at a pH=4.8; however,
because the pKa values of carboxylic acids present in the structures of other drug molecules within
Secondary amine class tend to range from 2.3 to 3.5, Carboxylic
this chemical/pharmacological
this functional
acid group will most
likely be primarily ionized at this pH value.
3. Quinapril is a prodrug. It is administered as an oral tablet and converted in vivo to its active metabo3. quinaprilat.
Quinapril is Identify
a is administered
orally instead
of quinaprilat.
lite,
the metabolic
pathway
that converts quinapril to quinaprilat, and offer a
reason why quinapril is administered orally instead of quinaprilat.
Quinapril
Quinaprilat
Quinapril
Quinaprilat
Answer
Ester hydrolysis converts quinapril to quinaprilat. Esterases are ubiquitous within the human body
and can readily convert ester prodrugs to their active forms. In evaluating the structures of quinapril
and quinaprilat, the only difference in these two molecules is the presence of a second carboxylic
acid in quinaprilat instead of the ethyl ester present in quinapril. Both of these molecules possess
a sufficient number of water soluble functional groups to allow for their dissolution within the
aqueous content of the GI tract. Quinaprilat has three ionizable functional groups (two carboxylic
acids and a secondary amine) along with an amide that is capable of forming hydrogen bonds. This
greatly enhances the water solubility of quinaprilat to the extent that it has difficulty traversing the
GI membrane despite the presence of hydrophobic rings and alkyl chains. To optimize the water/lipid
balance, an ester prodrug is used. The ethyl ester is more hydrophobic than the carboxylic acid and in
combination with the other hydrophobic groups allows for better passage across the GI membrane.


2.23 Quinapril
213
Chapters1.23and2.23
4. Quinapril inhibits ACE. This enzyme is a relatively nonspecific dipeptidyl carboxypeptidase. It is a zinc
protease that converts angiotensin I, a decapeptide, to angiotensin II, an octapeptide. The peptide
catalyzed
the zinc
atom andare
is shown
below.
Quinapril,
providedbelow.
4. cleavage
Quinapril isinhibits
ACE.by
binding
interactions
occurring
at a pH
of 7.4. along with other ACE inhibi
tors, is a tripeptide mimic that can interact with the enzyme resulting in enzyme inhibition rather
than hydrolysis. Using this information and the structures provided below, identify how quinapril can
interact with ACE. Assume that all drug binding interactions are occurring at a pH=7.4.
Leu
Leu
Phe
Phe
His
His
Quinaprilat
Quinaprilat
Angiotensin I
R = Asp-Arg-Val-Tyr-Ile-His
Angiotensin I
Answer
Answer
D
B
C
A
Because ACE is a nonspecific dipeptidyl carboxypeptidase, it is able to hydrolyze a dipeptide sequence
from the carboxylic acid end of a peptide. For this enzyme to be able to cleave a dipeptide sequence
(i.e., two amino acids), substrates must have a minimum length of three amino acids. Quinaprilat and
other ACE inhibitors act as tripeptide mimics. These drug molecules retain key peptide features (i.e.,
peptide bonds, side chains similar to those found on amino acids), but are not able to be hydrolyzed.
Thus, they are able to interact in a similar manner as the substrate does. The table below lists five key
interactions of quinaprilat with ACE.
Drug Binding
Interaction
Explanation
Ionic interaction
This carboxylic acid mimics the C-terminal carboxylic acid of an ACE substrate and
will participate in an ionic interaction with the side chain of either Asp or Glu.
van der Waals and/or hydrophobic

binding with hydrophobic amino
acids (e.g., Phe, Tyr, Leu, Ile)
Because ACE is a nonspecific carboxypeptidase, quinapril does not need to exactly

mimic Leu, the C-terminal amino acid of angiotensin I. Similar to the side chain of
Leu, this ring system is hydrophobic and can participate in similar types of interactions as Leu.

214

C
Hydrogen bond acceptor
Because ACE is a dipeptidyl carboxypeptidase, it does not cleave the terminal

peptide bond. Instead, the terminal peptide bond can participate in hydrogen
bonds. The carbonyl of the amide bond can act as a hydrogen bond acceptor and
interact with Ser, Thr, Tyr, Trp, Gln, Asn, or Cys.
Ionic bond (metal complexation)
This carboxylic acid would be located very close to the zinc atom shown participating in the mechanism of angiotensin I metabolism. As such, at pH=7 it can
form an ionic bond with the zinc atom.
van der Waals and/or hydrophobic

binding with hydrophobic amino
acids (e.g., Phe, Tyr, Trp)
This aromatic ring mimics the Phe side chain of angiotensin I and can participate
in similar interactions.
5. Shown below are in these pathways.

5. Shown below are four possible metabolic pathways for quinapril. Identify the metabolic transformaAnswer
tions involved in these pathways.
Quinapril
C
Answer
Pathway A: Aromatic oxidation followed by sulfate conjugation of the resulting phenol
Pathway B: Ester hydrolysis
.Pathway C: Amino acid conjugation (with glycine)
Pathway D: Benzylic oxidation followed by oxidation of the resulting secondary alcohol
2.23 Quinapril
215
6. Although it is possible for quinapril to undergo all of the above metabolic transformations, pathway
B is the major pathway. Other metabolites have been identified, but only at very low levels. Provide
an explanation for this finding.
Answer
Remember that the major purpose of drug metabolism is to enhance the removal of the drug from
the body, and the number of metabolic transformations required to achieve this goal varies from
drug molecule to drug molecule. In the case of quinapril, ester hydrolysis can occur quickly and at
many locations within the body. The resulting metabolite, quinaprilat, contains three ionizable functional groups and is easily eliminated from the body without the need for further metabolism.



Answers
2.24 Rivastigmine
2.24Rivastigmine
Shown below is the structure of rivastigmine. Four of its functional groups have been identified.
Shown below is the structure of rivastigmine. Four of its functional groups have been identified.
C H3
H3C
C
O
CH3 D
C H3
N
C H3
Rivastigmine
tableidentify the four boxed functional groups. For each of the functional groups you
1. Using1.theUsing
tablethe
below,
identified,
indicate
if it induction.
is hydrophilic or hydrophobic in character. Also provide a brief explanation for
2. Based on their
your response.
3. Rivastigmine is an acetylcholinesterase with acetylcholine.
Answer
Alkyl chain; alkyl group; aliphatic chain
Carbamate
Hydrophilic due to its ability to act as a hydrogen bond acceptor

hydrocarbon
Tertiary amine
participate in hydrogen bonding (acceptor) in its unionized form
Labile ester bond
Rivastigmine
2. Based on their electronic properties AND their relative positions in the molecule, identify
if functional
groups A and B are electron withdrawing or electron donating. Additionally, identify if this effect is due
to resonance or induction.
Answer
Functional group
A is an alkyl (ethyl) group and has a lower electronegativity than the nitrogen atom
of the carbamate; therefore, it acts as an electron donating group through induction. The same is true
for the twoA.methyl
groups
attached analysis
to the tertiary
Conduct
a structural
of howamine.
it could interact with acetylcholinestase.

Functional group
B is a carbamate
group
that is directly
attached
to an
aromatic
ring. Based
onsite.
its
Answer:al
groups to orient
themselves
in a similar
manner
within
the enzyme
binding
position, it can donate electrons into the aromatic ring through resonance.

217
Key structural similarities
2.24Rivastigmine
218
C H3
B
Shown below is the structure of rivastigmine. FourRivastigmine
of its functional groups have been identified.
3. Rivastigmine is an acetylcholinesterase inhibitor. Inhibition of this enzyme prolongs the half-life of

CH3 D
C H3
1.acetylcholine,
Using the table
allowing for higher concentrations
at muscarinic and nicotinic recepC of acetylcholine
tors.
This
action
is
useful
in
the
treatment
of
Alzheimers
disease,
myasthenia
gravis, and glaucoma.
C H3
O
N
A H3C
2. Based on their induction.
Shown below is the structure of acetylcholine interacting Nwith the active site of acetylcholinesterase.
3.Glutamic
Rivastigmine
is an acetylcholinesterase
with acetylcholine.
acid, histidine,
and serine are involved
in the mechanism
of ester hydrolysis and can form
C H3
O
specific interactions with acetylcholine.
B
Labile ester bond
Rivastigmine
1. Using the table

2. Based on their induction.
3. Rivastigmine is an acetylcholinesterase with acetylcholine.
Labile ester bond

Rivastigmine

a. Conduct
structural
analysis of
rivastigmine
indicate
how
it acetylcholinestase.
could interact with acetylcholinA. aConduct
a structural
analysis
of how and
it could
interact
with
esterase.
Answer:al groups to orient themselves in a similar manner within the
enzyme binding site.
Rivastigmine

Answer
The structure of rivastigmine contains a tertiary amine that will be primarily ionized at a physiB amine mimics the quaternary nitrogen present
ological pH=7.4. This ionized
within the structure
B
A the glutamic acid or with the side chain
of Acetylcholine
acetylcholinebound
and can
form site
an ionic interaction with
to
active
A
of another
acidic amino acid (comparison A). The carbamate present within the structure of
rivastigmine is isosteric to the acetate ester of acetylcholine and thus can form similar hydrogen
bonds (comparison B). The distance between the tertiary amine and the carbamate of rivastigA.
Conduct a structural analysis of how it could interact with acetylcholinestase.
mine is two carbon atoms longer than the quaternary nitrogen and the acetate of acetylcholine;
Answer:al
groups to orient
themselves
in astructure
similar manner
within the allows
enzymethese
binding
site.
however,
conformational
rotation
within the
of rivastigmine
functional
Key structural similarities
groups to orient themselves in a similar manner within the enzyme binding site.
B
A
Key structural
similarities
Similar distances
after conformational
rotation
(Note: The length of the lines are identical)
Similar distances after conformational rotation

(Note: The length of the lines are identical)
2.24 Rivastigmine
219
b. The serine residue of acetylcholinesterase attacks the ester bond of acetylcholine causing hydrolysis and acetylation of the serine. A similar reaction occurs between the carbamate group of
rivastigmine and the serine residue; however, while acetylcholine is a substrate of acetylcholinB.
The
serine residue
acetylcholinesterase.
esterase,
rivastigmine
is aninhibits
inhibitor.
Compare the functional groups involved and provide an
explanation as to how rivastigmine inhibits acetylcholinesterase.
B.
The serine residue inhibits acetylcholinesterase.
acetylcholine

rivastigmine
4. Answer
Neostigmine is a structural analog in routes of administration.
In both cases, acetylcholinesterase catalyzes the hydrolysis of a functional group. As part of this
mechanism, serine makes a bond that is similar to that which was hydrolyzed. In the case of
acetylcholine, serine is esterified (i.e., an ester is added to the serine side chain). Esters can be
very rapidly hydrolyzed; therefore, acetylcholinesterase is very quickly regenerated and acetylcholine acts as a substrate. In the case of rivastigmine, serine is carbamylated (i.e., a carbamate
group is added to the serine side chain). Unlike esters, carbamates are hydrolyzed much slower;
thus, the intermediate shown above persists for much longer than the millisecond that it takes to
hydrolyze an ester. As a result, the carbamate +
portion of rivastigmine remains attached to acetylcholinesterase for a longer time resulting in inactivation of the enzyme.
Neostigmine Bromide
4. Neostigmine is a structural analog of rivastigmine. Similar to rivastigmine, neostigmine is able to
interact with acetylcholinesterase and cause inhibition due to the presence of a carbamate functional
5. group.
Rivastigmine
has aindifference
results
durationand
of action.
Intermediate
the hydrolysis
of in a longer
The primary
differences
between
rivastigmine
neostigmine are their routes of adminAnalogousorally
intermediate
formed withof
acetylcholine
istration and their
therapeutic indications. Rivastigmine is administered
in the treatment
rivastigmine
Alzheimers disease, whereas neostigmine is administered intramuscularly (IM) or subcutaneously
Methyl of myasthenia gravis. Conduct structural analyses of these drug molecules and
(SC) in the treatment
Methyl
4. provide
Neostigmine
is a structural
routes of administration.
an explanation
foranalog
these in
differences
in routes of administration and therapeutic indications.
Methyl
Neostigmine
Ethyl
+
Rivastigmine
+
Neostigmine Bromide
Purchased by palm
atlantic university,
Nordine results in a longer duration of action.
5. beach
Rivastigmine
has aEd
difference
220
Intermediate
in the
hydrolysis
of
Medicinal
Chemistry
Self
Assessment

rivastigmine
acetylcholine
Answer
4. Neostigmine is a structural analog in routes of administration.
Unlike rivastigmine, the structure of neostigmine contains a permanently charged ammonium salt.
Similar to the tartrate salt of rivastigmine, this will enhance water solubility; however, it will hinder
the ability of the neostigmine to be absorbed within the gastrointestinal (GI) tract and to cross the
bloodbrain barrier. Therefore, neostigmine cannot be administered orally nor can it be used to treat
Alzheimers disease because it is unable to reach its site of action in the central nervous system (CNS).
Neostigmine is well suited for IM and SC administration and can be used to treat myasthenia gravis,
a chronic autoimmune neuromuscular disorder that is characterized by fluctuating weakness of the
voluntary muscle groups in the periphery. The beneficial
effects of acetylcholinesterase inhibition
+
observed in the treatment of myasthenia gravis do not require that the drug molecule enter the CNS.
Neostigmine Bromide
5. Rivastigmine has a longer duration of action than neostigmine. A comparison of the structures of
rivastigmine and neostigmine reveals that the carbamate group present in rivastigmine is slightly
than that
in neostigmine.
mechanism
of action given in question 3, provide
5. larger
Rivastigmine
haspresent
a difference
results in a Using
longer the
duration
of action.
a reason why this structural difference results in a longer duration of action.
Methyl
Methyl
Methyl
Ethyl
+
Neostigmine
Rivastigmine
Answer
The mechanism of action of these two drug molecules involves the carbamylation of the serine
residue found within the active site of acetylcholinesterase and the subsequent slow hydrolysis of
the carbamate. As the size of the carbamate increases, hydrolysis and regeneration of acetylcholinesterase decreases. So in this case, the additional carbon atom present within the structure of rivastigmine provides steric hindrance to the hydrolysis of the carbamate resulting in a longer duration of
action.
6. Evaluation of the structure of rivastigmine reveals that the aliphatic chain containing the tertiary
amine is located meta to the carbamate group. Similar orientations can be seen with neostigmine.
Using the information from the previous questions, provide an explanation as to why a para
orientation
of these
groups would lead to a significant decrease in the ability to inhibit
6. Evaluation
of thefunctional
to inhibit acetylcholinesterase.
acetylcholinesterase.
para orientation
meta orientation
H3 C
C H3
C H3
C H3
C H3
C H3
Rivastigmine
O
H3C
N
C H3
C H3
C H3
para Analog of
Rivastigmine
Answer
Answer:
For rivastigmine to interact with acetylcholinesterase, it must contain structural features that mimic
For rivastigmine
to interact
with acetylcholinesterase,
it must contain
structural
features 3,
that
mimic
acetylcholine,
the natural
substrate
for this enzyme. As previously
explained
in question
the
H3 C
C H3
C H3
O
H3C
C H3
CH
2.24
Rivastigmine
3
221
C H3
para Analog of
Rivastigmine
Rivastigmine
tertiary amine and carbamate of rivastigmine can mimic the quaternary
nitrogen atom and ester of
acetylcholine respectively. The aromatic ring provides structural rigidity; however, conformational
flexibility of its substituents allows these functional groups to be properly oriented when they are
Answer:
located meta to one another. As shown below, para orientation of these substituents does not allow
forrivastigmine
proper orientation.
the requisite functional
groupsstructural
are present,
they that
are located
For
to interactAlthough
with acetylcholinesterase,
it must contain
features
mimic too far
apart from one another and, therefore, cannot interact effectively with acetylcholinesterase.
The meta orientation allows for similar distances
The para orientation places the functional groups

too far apart from one another



Answers
2.25 Sitagliptin
Sitagliptin is an inhibitor of dipeptidyl peptidase IV (DPP-IV), a serine protease that catalyzes the deactivation/degra2.25 Sitagliptin
dation of GLP-1. GLP-1 is a 36-amino acid peptide that is responsible for promoting insulin secretion in response to
an increase in blood glucose levels. Currently there are four DPP-IV inhibitors on the market, all of which contain an
essential basic amino functional group that represents the penultimate amino-terminal alanine residue found within
GLP-1.Sitagliptin is an inhibitor of dipeptidyl represents the amino-terminal alanine residue found within GLP-1.
N H2 O
N
F
N
CF3
Sitagliptin
Sitagliptin
1. Conduct a structural evaluation of sitagliptin, focusing on the boxed functional groups, and use the information1.in the
grid to
inform
your answers
to the
questions
that
follow.
Conduct
a grid
to inform
the answers
to the
questions
that
follow.
Answer
2. Sitagliptin is group and modify the structure to show the phosphate salt form.
Function
Character
Character
Acidic, Basic,
F
or Neutral
Name of
Functional
Group
Hydrophilic
and/or
Hydrophobic
FProvide
Halogenated
aromatic
hydrocarbon
Hydrophilic (F)
Neutral
pKa When
Relevant
Hydrophobic (R)
Function
Function
Solubility
N H2 O
and/or
Absorption
N
Solubility (F)
Absorption (R)
Sitagliptin
Interaction(s)
Possible with
Biological Target
at Physiological
pH=7.4
N
van der Waals
N
Amino Acids That

at pH=7.4
None Is Acceptable
Asp, Glu, Lys, Arg
N
Hydrophobic
H-bondingCF
(A)
Dipoledipole
Iondipole (as the

dipole)
Answer:
- stacking
The pKa the primary amine is the most basic functional group within the structure of sitagliptin.
Primary amine Hydrophilic (NH2)

Hydrophobic (R)

Basic
Solubility (NH2)
pKa 911
Absorption (R)
Iondipole (as the

ion)
Ionic
223

Trp, His
Sitagliptin is an inhibitor of dipeptidyl represents the amino-terminal alanine residue found within GLP-1.
A
224
Medicinal
Assessment
Sitagliptin
is anChemistry
inhibitor ofSelf
dipeptidyl
represents the amino-terminal alanine residue found within GLP-1.
F

C
Amide
Hydrophilic F
(CON)
Aromatic
Heterocycle
(1, 3, 4
triazole)
N H2 O
Neutral
Hydrophobic (R)
B
B
N
H-bonding
(A)
Asp, Glu, Lys, Arg
N H-bonding (A)
Asp, Glu, Lys, Arg
Solubility (CON)
N
N H Absorption
2 O
(R)
Dipoledipole
D N
N
Iondipole
(as the
N
dipole)
N CF3
Hydrophilic (N)
F
Basic
Hydrophobic (R)
pKa ~1-5
Sitagliptin
Solubility (N)
Absorption (R)
Dipoledipole
CF
3
Sitagliptin
Iondipole (as the

dipole)
1. Conduct a grid to inform the answers to the questions that follow.
1. Conduct
a grid to inform
the answers
to the
questions
that follow.
2. Sitagliptin
is formulated
as a phosphate
salt.
Identify
the most
basic functional group and modify the
structure to show the phosphate salt form.
F
F
N H2 O
F
F
F
N H2 O
N
N
Sitagliptin
Sitagliptin
N
N
N CF3
CF3
Answer
Answer:
Sitagliptin
The pKa of the aromatic heterocycle (1,3,4-triazole) is much lower than the pKa of the primary amine.
amine
is thethat
most
basic
functional
group within
structure ofnitrogen
sitagliptin.
a the primary
There is The
one pK
additional
nitrogen
atom
you
might
be considering.
Be the
carefulthat
atom
Answer:
is directly attached to a carbonyl (to form an amide) and is neutral in character! With the analysis
complete,
that the
primary
amine
the most
basicgroup
functional
withinofthe
structure of
The it
pKisa clear
the primary
amine
is the
most isbasic
functional
within group
the structure
sitagliptin.
sitagliptin.
Sitagliptin phosphate
Sitagliptinphosphate
phosphate
Sitagliptin
3. Sitagliptin is marketed as the R-enantiomer. Evaluate the structure of sitagliptin and provide a structural rationale for the R-enantiomer designation.
Answer
Using the Cahn-Ingold-Prelog (CIP) (see Chapter 7 in Basic Concepts in Medicinal Chemistry), the four
groups attached to the chiral carbon atom need to be prioritized based on atomic number and the
described sequence rules. Using these rules, the primary amine nitrogen atom is prioritized as #1 as it
has the highest atomic number, the methylene unit attached to the amide carbonyl is prioritized as
#2, the methylene unit attached to the halogenated aromatic hydrocarbon is prioritized as #3, and
the hydrogen atom pointing away from the reader is the #4 priority. NOTE: it is important to recognize that although the methylene units are identical, the rules state that atoms attached to each of
these methylene units are the next to be evaluated. Evaluation of the methylene to the right of the
2.25 Sitagliptin
225
3. Sitagliptin is designation.
primary amine reveals that the carbon atom is attached to the equivalent of two oxygen atoms and a
nitrogen atom. Evaluation of the methylene to the left of the primary amine reveals that the carbon
Answer:
atom is attached to the equivalent of three carbon atoms. The atomic number of both oxygen and
nitrogen
is higher
than carbon; therefore,
the #2 and
#3 prioritization
is reflective ofisthat
analysis.
Using
the Cahn-Ingold-Prelog
(are clockwise
in orientation
and the R-enantiomer
drawn.
Reviewing the positions of these priorities, it is noted that they are clockwise in orientation and the
R-enantiomer is drawn.
2
4
Sitagliptin
Sitagliptin
4. At 38%, the fraction of sitagliptin reversibly bound to plasma proteins is relatively low. By way of
4. At 38%,
(e.g.,fraction
warfarin).
reminder,
only the
thebound
unbound
of drug is able to exert its biological activity and undergo
metabolism. Describe the relative risk of a plasma protein binding interaction between sitagliptin
5.another
Approximately
79%
of urine.
Provide
a abolic
transformation
and
drug that
is highly
protein
bound
(e.g.,
warfarin). (i.e., excreted unchanged).
Answer
Based on the information from the structure evaluation grid, sitagliptin is a basic drug (see discussion
of the
liptin and
determine
which
phase
I metabolic
transformation
hasfor
occurred.
of 6.
the Assess
plasma each
binding
proteins
in Chapter
3 of
Basic
Concepts
in Medicinal
Chemistry
information
about albumin and 1-acid glycoprotein). Generally albumin tends to bind to acidic drugs, whereas
the plasma protein 1-acid glycoprotein has an affinity for basic drugs and some neutral drugs.
Warfarin is an acidic drug and is greater than 90% plasma protein bound. In this scenario, warfarin
would be bound to albumin and sitagliptin would be bound to 1-acid glycoprotein. Because the
two drugs are not competing for the same plasma binding protein, there is very, very little risk of a
plasma protein binding interaction.
5. Approximately 79% of sitagliptin is excreted unchanged in the urine. Provide a structural rationale
that supports this observation.
Answer
Based on the information in the structure evaluation grid, sitagliptin contains a number of functional groups that contribute to the overall water solubility of the drug. The fluorinated aromatic
hydrocarbon, amide, and aromatic heterocycle (1,3,4 triazole) will be able to participate in important
hydrogen bonding interactions with water. The primary amine, likely to be predominantly ionized in
the plasma and urine, significantly enhances this water solubility by participating in the strong ion
dipole interactions with water. The drug is sufficiently hydrophilic in character for it to be excreted
without the need for metabolic transformation (i.e., excreted unchanged).

226
6. Assess each of the possible metabolic products generated from sitagliptin and determine which
phase I metabolic transformation has occurred.
A
B
Answer
A
Benzylic oxidation
Amide hydrolysis


Answers
2.26 Sorafenib
Because protein tyrosine kinases regulate cellular proliferation, differentiation, and survival, it is no surprise that
several neoplastic disorders can be tied to altered activity of protein tyrosine kinases. Clinically relevant antineoplastic
tyrosine kinase inhibitors interact with the active site of the enzyme via several types of binding interactions. The
adenosine triphosphate (ATP) binding domain of the tyrosine kinases contains a hydrophobic domain that includes
a significant number of isoleucine, leucine, alanine, and valine residues. There are at least five binding pockets that
flank this region in which van der Waals, hydrophobic, hydrogen bonding, and electrostatic interactions occur.
Sorafenib is a tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma, a highly vascularized
tumor.2.26
The Sorafenib
drug specifically targets vascular endothelin growth factor 2 (VEGF2) that is instrumental in the generation ofBecause
new blood
vessels.
protein
tyrosine kinases owth is instrumental in the generation of new blood vessels.
C
E
A
B
D
Sorafenib
Sorafenib
1. Conduct
structural
evaluation
of sorafenib,
1. aConduct
a to
the questions
that follow.focusing on the boxed functional groups, and use the information in the grid to inform your answers to the questions that follow.
2. Sorafenib interacts with in the local environment of the enzyme.
3. Nilotinib, another and Leu298/Val299/Phe359 in each of the respective five binding pockets.
A
B
Nilotinib
227
A. Consider the side chains of the. Assume pH=7.4.
228
Answer
Character
Name of
Functional Group
A
Halogenated aromatic
hydrocarbon
Function
Character
Acidic, Basic,
or Neutral
Function
Hydrophilic
and/or
Hydrophobic
Provide
pKa When
Relevant
Solubility
and/or
Absorption
Interaction(s)
pH=7.4
Hydrophobic
Neutral
Absorption
Cl:
Dipoledipole
Ar:
van der Waals
Hydrophobic
- Stacking
Halogenated aliphatic
alkane
Hydrophilic (F)
Neutral
Solubility
H-bonding (A)
Dipoledipole
Urea
Hydrophilic (HNCONH)
Neutral
Hydrophobic (R)
Solubility (HNCONH)
H-bonding (A + D)
Absorption (R)
Dipoledipole
Ether
Hydrophilic (O)
Neutral
Hydrophobic (R)
Solubility (O)
H-bonding (A)
Absorption (R)
Dipoledipole
Pyridine
Hydrophilic (N)
Basic
Solubility (N)
Pyridine N atom:
(Azine)
Hydrophobic (R)
(pKa 15)
Absorption (R)
H-bonding (A)
Dipoledipole
R:
van der Waals
Hydrophobic
- Stacking
Amide
Hydrophilic (CONH)
Hydrophobic (R)
Neutral
Solubility (CONH)
H-bonding (A+ D)
Absorption (R)
Dipoledipole
2. Sorafenib interacts with Cys919, Phe1047, and Asp1046 via hydrogen bonding and hydrophobic interactions.
Identify which functional groups could interact with the side chains of these amino acids. Assume
that Asp1046 is unionized in the local environment of the enzyme.

2.26 Sorafenib
229
2.26 Sorafenib
Because
Answer protein tyrosine kinases owth is instrumental in the generation of new blood vessels.
Interacts with Cysteine919
Interaction
Functional
Group
Yes or No
Interacts with Aspartic Acid1046

F
Interaction
Interacts with
Phenylalanine1047 via a
Yes or No
Yes or No
No
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Sorafenib
Yes
No
No
Yes
No
1. Conduct a to the questions that follow.

3. Nilotinib, another tyrosine kinase inhibitor (via Bcr-Abl) indicated for the treatment of PhiladelSorafenib interacts
with in the
localmyelogenous
environment ofleukemia,
the enzyme.
phia2.Chromosome
(Ph+) positive
chronic
also interacts with each of the five
binding pockets found within this
target. This drug interacts with Leu285/Val289, Asp391/Glu286,
298 biological
299
3. , Met
Nilotinib,
another
Leu
/Phe359
in each
of the respective
fivepockets.
binding pockets.
318
359
Thr315
, and
Leu298and
/Val299
/Phe/Val
in each
of the
respective
five binding
A
B
Nilotinib
Nilotinib
a. Consider the side chains of the amino acids indicated and determine which type(s) of binding
interactions are possible in each of the five binding pockets. Assume pH=7.4.
Answer
A. Consider the side chains of the. Assume pH=7.4.
Leu285/Val289
Asp391/Glu286
Thr315
Met318
Hydrophobic
Ionic
H-bonding
Hydrophobic
Hydrophobic
B. Determine which of the side chains are both at pH=7.4.
van der Waals

the ion)
Dipoledipole
Dipoledipole
der Waals
C. It has beenIondipole
atom(s) (as
within
the structure
of methionine
participate in thisvaninteraction.
Iondipole (as the
dipole)
Methionine

van der Waals
B
230
Sorafenib
Conductwhich
a to the
follow. groups (AE) can interact with the side chains of the
b. 1.
Determine
of questions
the boxedthat
functional
amino acids found in each of the five binding pockets. Indicate the type of interaction(s) possible
2. Sorafenib interacts with in the local environment of the enzyme.
in the appropriate box. None is an acceptable answer. Assume that the drug and the amino acid
side chains are both at pH=7.4.
3. Nilotinib, another and Leu298/Val299/Phe359 in each of the respective five binding pockets.
Leu285/Val289
A
B
Hydrophobic
Hydrophobic
AAsp
391
/Glu286
Iondipole (functional
group as the dipole)
None
van der Waals
Thr315
Met318
H-bonding (A)
Hydrophobic
Hydrophobic
Dipoledipole
H-bonding (A)
Hydrophobic
Dipoledipole
- Stacking
Hydrophobic
van der Waals
- Stacking
None
H-bonding (A+D)
D*
None
H-bonding (A+D)
Hydrophobic
Iondipole (functional Nilotinib

H-bonding (A)
E**
None
None
None
None
Hydrophobic
Dipoledipole
Dipoledipole
None
- Stacking
Dipoledipole
* Aniline-like nitrogen atom will not be ionized at physiological pH.

A. (azine)
Consider
the sideatom
chains
of not
the. be
Assume
pH=7.4.
**Pyridine
nitrogen
will
ionized
at physiological pH.
B. Determine
which
the pyridyl
side chains
are both
at (functional
pH=7.4.
c. It has been
documented
thatofthe
nitrogen
atom
group E) of nilotinib participates in a hydrogen bonding interaction with methionine. Draw a diagram that clearly shows
C. It has
beenthe
atom(s)
withinofthe
structure ofparticipate
methionineinparticipate
in this interaction.
which atom(s)
within
structure
methionine
this interaction.
Answer:
Methionine
Methionine
Answer
H-Bond
Acceptor
Nilotinib
Nilotinib
H-Bond
Donor
Methionine
Methionine
2.26 Sorafenib
231
4. Sorafenib enters cells via passive diffusion. Using the information in the structure evaluation grid as a
starting point, identify which functional groups contribute to the ability of this drug to enter cells via
passive diffusion.
Answer
The halogenated aromatic hydrocarbon, aromatic hydrocarbon, and the pyridine ring carbon atoms
all contribute significantly to the hydrophobic character of sorafenib. It is important to note that
the basic pyridine ring is unlikely to be ionized at physiological pH (pKa = 6 < pH = 7.4). Although
there appears to be significant hydrophilic character (halogenated aliphatic alkane, urea, ether, the
nitrogen atom of the pyridine, amide) present in this molecule, sorafenib is practically insoluble in
water. The lack of water solubility and clearly identifiable hydrophobic character allows for passive
diffusion of the drug across the cellular lipid bilayer membrane.
5. Nilotinib is considered significantly more hydrophobic than sorafenib (distribution coefficient log D is
2.4 and 0.8, respectively). Provide a structural rationale for this property difference.
Answer
Based on the information found in the structure evaluation grid for sorafenib, there are several
functional groups that contribute to the overall hydrophobic character of the molecule (e.g., halogenated aromatic hydrocarbon, aromatic hydrocarbon, carbon atoms of pyridine/azine ring). Similar
evaluation of nilotinib yields two aromatic rings, a pyrimidine ring (between functional groups D and
E), a pyridine ring (functional group E), and even some hydrophobic character in the histidine ring
(functional group A) that contribute to the overall hydrophobic character of the molecule. When you
compare the sheer number of functional groups that contribute to the overall hydrophobic character
for each drug, nilotinib wins!
6. Sorafenib is marketed as a tosylate salt, a lipid-soluble organic salt. Nilotinib is marketed as a hydrochloride monohydrate salt, an inorganic salt. In general, what is the value of each of these types of
salts?
Answer
The value of lipid-soluble organic salts is to decrease the water solubility and increase the lipid solubility of the parent drug (in this case sorafenib) (see Chapter 5 of Basic Concepts in Medicinal Chemistry). Typically lipid-soluble salts are used in the formation of lipid-soluble suspensions. In addition,
they can improve the oral bioavailability of acid labile drug molecules and improve the palatability
of liquid solutions. p-Toluenesulfonic acid (tosylic acid) is considered a strong organic acid and forms
a strong counter-ion when dissociated from the drug molecule. Sorafenib is administered as a filmcoated tablet for adults and as a liquid suspension for children.
The value associated with the formation of inorganic salts is due to the improved aqueous solubility,
solvation, and dissolution that results. In general, inorganic salts enhance the absorption of drugs
that are administered orally because they improve both solvation and dissolution properties.



Answers
Shown
below
is the
of zanamivir.
This drug
via oral inhalation for the treatment of
Shown
below
is structure
the structure
for the treatment
of molecule
influenza is
A administered
and B infections.
influenza A and B infections.
Zanamivir
Chapter2.27
1. Identify
all of the
acidic
1. Identify
all of
the ofand
7.2.basic functional groups, provide the normal pKa range for each functional
group,
and
identify
if
each
functional group would be primarily ionized or unionized at a pulmonary
PleasereplacethestructurefortheanswerofQ1withtheonebelow.
Answer:
pH=7.2.
Answer
Carboxylic acid (Acidic functional group)

Carboxylic
Normalacid
pH (Acidic
range =functional
2.5 to 5 group)
Normal
pH range
= 2.5 toionized
5
Would
be primarily
at a pH of 7.2
Guanidine (Basic functional group)

Guanidine
(Basic
functional
group)
Normal
pH range
= 12 to
13
Would
be primarily
at a pH of 7.2
Normal
pH range
= 12 toionized
13
2.
Identify all other water soluble functional groups that are present within the structure of zanamivir.
Answer:
Please replace the structure for the answer to Q6, part a with the one below (page 4, middle structure)
Primary hydroxyl group
Secondary hydroxyl group
(or primary alcohol)
(or secondary alcohol)
secondary
alcohol)
Purchased by palm beach(or
atlantic
university,
Ed Nordine
233
Ether oxygen
234

Would be primarily ionized at a pH of 7.2
2. Identify all
other water soluble functional groups that are present within the structure of zanamivir.
Answer:
Answer
Primary hydroxyl group

(or primary alcohol)


Ether oxygen
Amide
The amide and hydroxyl groups can act as hydrogen bond donors and acceptors and thus can form
hydrogen bonds with water. The ether oxygen most likely contributes the least to water solubility;
however,
it can on
function
a hydrogenasbond
acceptor.
3. Based
your isas
administered
an oral
inhaler instead of an oral tablet or capsule.
3. Based on your answers to questions 1 and 2, explain why zanamivir is administered as an oral inhaler
instead of an oral tablet or capsule.
Answer
The structure of zanamivir contains multiple hydrophilic functional groups that will allow it to easily
dissolve within the aqueous contents of the gastrointestinal (GI) tract. The carboxylic acid and the
guanidine functional groups will be extensively ionized at an intestinal pH=5 which further increases
the overall water solubility of the molecule. Although the structure of zanamivir contains a hydrocarbon chain and ring, the overall balance between water and lipid solubility hinders its ability
to effectively cross the GI membrane. The oral absorption of zanamivir has been reported to be
between 1% and 5%. Due to this, zanamivir must be administered via oral inhalation.
4. Zanamivir exerts its antiviral action by inhibiting neuraminidase, a viral enzyme that is required for
the spread of the viral infection. A key component of neuraminidases action is the hydrolysis of
4. Zanamiviracid
exerts
his, provide
an explanation Shown
how zanamivir
inhibits
neuraminidase.
N-acetylsialic
fromitssurface
viral glycoproteins.
below is
the structure
of N-acetylsialic acid
bound to a glycoprotein. Using this structure and the structure of zanamivir, provide an explanation
of how zanamivir inhibits neuraminidase.
Glycosidic bond
Zanamivir
Answer
Answer:
Zanamivir is a stable mimic of N-acetylsialic acid. As shown below, the structure of zanamivir retains
is a stable
a cleavable
glycosidic bond.
many Zanamivir
of the structural
features
of N-acetylsialic
acid, but lacks a cleavable glycosidic bond.
Structurally identical
to N-acetylsialic acid
(with exception of
Zanamivir
Answer:
235
Zanamivir is a stable a cleavable glycosidic bond.
Glycosidic bond
Answer:
Zanamivir is a stable a cleavable glycosidic bond.
Zanamivir
Structurally identical
to N-acetylsialic acid
(with exception of
the double bond)
Zanamivir
Lacks glycosidic bond
identical
The structural similarity allows zanamivir to interact withStructurally
neuraminidase
in the same manner as
5. N-acetylsialic
Shown below acid.
is a activity
is
likely
to
be
more
active,
less
active,
or
similar
toremain
that of zanamivir?
to
N-acetylsialic
acid
Ionic or iondipole interactions with the carboxylic acid
the same, as does
(with
exception
of
the ability to form hydrogen bonds with the hydroxyl groups and the amide. Because zanamivir lacks
the double
bond)
a cleavable glycosidic bond, it can occupy the binding site without
being
metabolically transformed.
The most significant difference between zanamivir and N-acetylsialic acid is the substitution of a
secondary hydroxyl group with a guanidine group. Studies have shown that this basic functional
group can form ionic interactions with neuraminidase. In summary, zanamivir structurally mimics the
natural substrate for neuraminidase and is able to bind to the active site of the enzyme. This binding
inhibits the ability of neuraminidase to cleave N-acetylsialic acid from viral glycoproteins, thus inhibLacks glycosidic bond
iting the spread of a viral infection.
Zanamivir
5. Shown below is a stereoisomer of zanamivir. Identify if the stereoisomer is an enantiomer, a diastereomer,

5. aShown
belowisomer,
is a activity
is likelyand/or
to be more
active, less active,
similarwhether
to that ofthis
zanamivir?
geometric
an epimer,
a conformational
isomer.orPredict
stereoisomers
pharmacological activity is likely to be more active, less active, or similar to that of zanamivir?
6. Shown below is the structure of for oseltamivir
Answer
stereoisomer
the opposite
stereochemical configuration at all five chiral centers and has the
6. This
Shown
below is thehas
structure
of for oseltamivir
exact same conformation as zanamivir; therefore, this is the enantiomer of zanamivir. None of the
other stereochemical designations are correct.
Given that zanamivir as well as oseltamivir exert their antiviral activity by mimicking N-acetylsialic
acid, alteration of the stereochemistry decreases the resemblance to N-acetylsialic acid and would be
predicted to cause a decrease in binding affinity to neuraminidase and a decreased antiviral effect.

236
6. Shown below is the structure of oseltamivir and a list of five metabolic transformations. For each
Chapter2.27
metabolic transformation, indicate if it is a phase I or a phase II transformation and if oseltamivir has
a functional group present that can undergo the indicated transformation. When evaluating these
PleasereplacethestructurefortheanswerofQ1withtheonebelow.
metabolic transformations, consider functional groups that are initially present within the structure
of oseltamivir as well as those that can be added/revealed through phase I metabolism. If you answer
YES, then draw the appropriate metabolite; if you answer NO, then provide a brief explanation as to
why this metabolic transformation is not possible for oseltamivir.
w is the structure of for oseltamivir
Carboxylic acid (Acidic functional group)

Normal pH range = 2.5 to 5
Metabolic Pathways
A. Hydrolysis
B. Allylic Oxidation
C. Glucuronide Conjugation

D. -Oxidation
E. Oxidative O-Dealkylation
Answer
Answer:
Please
replace the structure for the answer to Q6, part a with the one below (page 4, middle structure)
A. Hydrolysis: Phase I transformation. Both the ester and amide functional groups can undergo
A. Hydrolysis:
Phasehydrolysis
I oseltamivir.
hydrolysis. Ester
produces the active metabolite of oseltamivir.
Product of
hydrolysis
esterEster
hydrolysis
Product of
Amide
hydrolysis
amide
hydrolysis
Product of ester
amide
and Ester
amideand
hydrolysis
hydrolysis
B. Allylic Oxidation: Phase I transformation. It is not possible because both allylic carbon atoms are
B. Allylic
oxidation:
a hydrogenAdditionally,
atom that is required
for carbon
oxidation.
already
attached Phase
to heteroatoms.
one allylic
atom lacks a hydrogen atom
that is required for oxidation.
Already attached
to a heteroatom
Lacks a hydrogen atom
Already attached
to a heteroatom

C. Glucuronide conjugation: Phase II.
Oseltamivir
Already attached
to a heteroatom
Oseltamivir
237
C. Glucuronide conjugation: Phase II.

C. Glucuronide Conjugation: Phase II transformation. It can occur directly with the secondary amine
or with the carboxylic acid that results from phase I ester hydrolysis.
D. Oxidation: Phase I, Yes

D. Oxidation: Phase I, Yes
D. -Oxidation: Phase I, Yes
E. Oxidative O-Dealkylation: Phase I, Yes

+
+


Index
Angiotensinogen, 27, 129
Acebutolol, 21, 117-119

Acetylcholine, 79-80, 218-219
Acetylcholinesterase inhibitor, 79-81,
218-221
Acidic functional group, 7-9, 11-12, 31, 36,
40, 55, 66, 69, 75, 81, 91, 99-103,
105-106, 137, 151, 155, 174, 190,
193-194, 211-212, 233
Anticholinergic agents, 18, 114-115

Antidiabetic agent, experimental, 7-8, 99,
101, 102
Antihistamine, 39, 149-152
Anti-hyperlipidemic agents, 47, 165
Anxiolytic effect, 53, 172
Arformoterol, 13-14, 109
Argatroban, 9, 103
Arginine, 8, 102
duration of, 81, 220
Aripiprazole, 31-33, 137-142
onset, 66, 190
metabolites, 33, 141
Active metabolite, 63, 186-187
Aromatic oxidation, 70, 141, 197
Active product, 58-59, 179
Aspartic acid, 88, 98, 228
Adenosine triphosphate (ATP) binding, 87,

227
Atenolol, 11, 105, 105-106
Alanine, 87, 227

Alendronate, 15, 111
Aliskiren, 27-30, 129-135
Allylic oxidation, 92, 236
Alprazolam, 53, 172
Amiloride, 9, 103
Amino acid binding interactions, 32, 139-140
Amino acid side chain interactions, 30, 44-45,
56, 58, 72, 88, 134, 163, 175, 178,
201-202, 228-229, 230
C-11 oxidation, 58, 179

C-17 oxidation, 58, 179
C-21, 60, 179-180
Cahn-Ingold-Prelog (CIP) system, 22,
119-120, 184
Carbamate group, 81, 219-220
Carboxylic acid, 73, 185, 194, 206
Cefamandole, 21, 117-119
Action
Administration routes, 14-15, 109-110
Atrial fibrillation, 43, 159
Cefotaxime, 11, 105-106

Cefprozil, 35-38, 143-147
Cephalosporin, 35, 143
Cetirizine, 39-40, 149-152
Chemical hydrolysis, 147
Chiral carbon atom, 62, 184
Chiral centers, 21-22, 119
Chlorimipramine, 24, 124
B
Baclofen, 13-14, 24, 109, 129
Barbiturates, 71-72, 199-203
Barbituric acid, 199
Basic functional group, 7-9, 11, 12, 31, 36,
40, 55, 69, 75, 91, 99-103, 105-106,
137, 144, 151, 155, 174, 193-194,
211-212, 233
Chlorpropamide, 41-42, 153-157

Ciprofloxacin, 13-14, 109
Class IB anti-arrhythmic agent, 65, 189
Clonidine, 8, 102-103
CNS-based toxicities, 67, 192
Conformational isomer, 92, 235
Conjugate elimination, 48, 168
Benzodiazepines, 53, 172
Cucumber flavor, 20, 116
Amino acid-based hormone, 62, 185
Benzylic oxidation, 56, 70, 141, 176, 191,

198
Cysteine, 88, 228
Amino acids, 5, 98
Beta-lactam bond instability, 38, 147
Amlodipine, 30, 134-135
Beta-lactamases, 38, 147
Amphoteric drug, 9, 36, 103, 144
Binding interactions, 56, 175
Anesthetic, 65, 189
Bioavailability, 132
Angiotensin converting enzyme, 27, 129
Biological targeting, 14-15, 19, 110, 115
Angiotensin converting enzyme (ACE)

inhibitor(s), 17, 75-78, 113, 211-215
Blood soluble, 65, 190
Angiotensin I, 27, 77, 129-130, 213
Butabarbital, 71, 199-200
Angiotensin II, 27, 129-130
Bromfenac, 3, 7-8, 37, 99, 101, 102

metabolite, 72, 202-203
Angiotensin II receptor blockers (ARBs), 41,

153
239
Cysteinyl leukotriene receptors, 70, 196
D
Dabigatran etexilate, 43-45, 159-164

mesylate, 45, 164
Dehalogenation, 61, 63, 183, 186-187

Delapril, 17, 113
Depot injections, 60, 180
Dexfenfluramine, 24, 125
Diastereomer(s), 21, 28, 52, 62, 92, 117-119,
130-131, 170, 184, 235
240
Dihydropyridine calcium channel blocker,

30, 134
Diltiazem, 9, 103
Fluvoxamine metabolites, 53, 171

Functional groups, 3-9, 11, 95-98, 99
Dipole-dipole interaction, 202
GABAA, 71, 72, 199, 201, 203
Drug action

duration, 60, 181
stereochemistry and, 21-22, 117-121
Drug binding interactions, 17-20, 113-116

Drug interaction, 32, 139
Drug metabolism, 23-24, 123-125
Gemfibrozil, 47-49, 165-168

Geometric isomer(s), 21, 28, 52, 62, 92,
117-119, 130-131, 170, 184, 235
GI drug absorption compartments, 36, 145
Glucocorticoid, 57-58, 177-178
Glucuronide conjugation, 53, 92, 172, 237
Glutamate, 20, 116
Glutamic acid, 20, 79, 116, 218
Glutamine, 98
E-geometric isomer, 170
Electron donation, 4, 55, 79, 96, 173, 217
Gram (-) activity, 35, 143
Electron withdrawing, 4, 55, 79, 96, 97,

173-174, 217
Gram (+) activity, 35, 143
Glyburide, 42, 158
Elimination, 48, 167

half-life, 49, 168
unchanged, 70, 197
Embeconazole, 15, 111-112

Enantiomer(s), 21-22, 52, 62, 92, 117-121,
170, 184, 235
Enterohepatic recycling, 23, 123, 124
Enzymatic hydrolysis, 147
Epimer, 92, 235
Ibuprofen, 4, 96
Imipramine analogs, 5, 97
Dipeptidyl peptidase IV, 83, 223

D-Phe-Pro-Arg tripeptide sequence, 43-45,
159-163
metabolite, 42, 158
Green pepper flavor, 20, 116

Guanidine functional group, 8, 102
H
Half-life, 42, 156
Inactive metabolite, 63, 186-187

Inactive product, 58-59, 179
Induction, 4, 55, 79, 96, 173-174, 217
Inosinic acid, 20, 116
Insulin, 62, 185

structure, 14, 111
Interactions, 62, 185

Intermediate-acting agent, 71, 200
Intestine pH, 14, 109
Ion channels, 20, 116
Ion-dipole interaction(s), 19, 58, 62, 115,
185, 178
Ionic bond, 202
Ionic interaction, 62, 185
Ionization percentage, 12, 106-108
Ionized, 31, 36, 55, 69, 71, 76, 91, 137, 145,
174, 193-194, 201, 211-212, 233
Irbesartan, 13-14, 109
Isoleucine, 87, 227
Halogenated aromatic hydrocarbon, 185
Haloperidol, 55-56, 173-176
Leu-Val peptide bond, 30, 134
Henderson-Hasselbalch equation, 12,

106-107, 108, 155
Levothyroxine (T4), 61-63, 183-187
Hepatic metabolism, 70, 197
Hepatic oxidation, 53, 172
Lidocaine, 65-67, 189-192

Sodium channel blocker, 65, 189-192
Heroin, 23, 123
Lipid solubility, 31, 138, 195
Histidine, 79, 218
Lipid soluble esters, 174
HMG CoA reductase, 74, 207-209
Lipophilic absorption, 66, 190
HMG-CoA reductase inhibitor, 22, 119-120
Lipophilic ester, 60, 180-181
Hormone replacement therapy, 62, 184
Lisinopril, 17, 113
Hydrochloride monohydrate salt, 89, 231
Lomitapide, 9, 103
Hydrochloride salt, 13-14, 109
Long-acting agent, 71, 200
Hydrocortisone, 57-60, 177-181
Loperamide, 14, 109-110
Fesoterodine, 18, 114, 115
Hydrogen bond(s), 18-19, 58, 62, 88-89,

115, 178, 185, 195, 202, 207, 228
Lorazepam, 53, 172
Fibrin, 43, 159
Hydrolysis, 56, 70, 92, 176, 198, 236
Fibrinogen, 43, 159
Hydrolytic reactions, 44, 161-162
Flavors, 20, 116
Hydrolyzable peptide bond, 30, 134
Fluvastatin, 22, 73-74, 119-120, 205-209
Hydrophilic reaction, 4, 55, 73, 75, 79, 96,

173, 205, 211, 217
Ester hydrolysis, 79-80, 218-219

Estradiol, 21, 23, 117-119, 123
Estrogen, 62, 185
Ether, 185
Ezetimibe, 11, 105-106
F
Fenofibrate, 47-49, 165-168

as active drug, 48, 166
as prodrug, 48, 166
conformationally restricted analog of,

74, 208-209
Fluvoxamine, 24, 51-53, 125, 169-172

Fluvoxamine + alprazolam, 53, 172

Fluvoxamine + lorazepam, 53, 172
Losartan, 32, 41, 139, 153

L-tyrosine, 62, 185-186
M
Maleate salt, 52, 170-171
Hydrophobic reaction, 4, 19, 55, 62-63,

73, 75, 79, 88-89, 96, 114-115, 173,
185-186, 196, 202, 205, 211, 217,
228, 231
Mechanism of action, 42, 155-156
Hydroxyzine, 39-40, 149-152
Methionine, 89, 230
Metabolic transformation, 28-29, 53, 77-78,

171-172, 214-215
Metabolites, 24, 124
Index
Methylation, 70, 197
Phenol, 185
Serotonin receptor modulator, 31, 137
Mevalonic acid, 74, 207-208
Phenylalanine, 88, 228
Serotonin reuptake transporter, 51, 169
Montelukast, 69-70, 193-198
Phenytoin functional groups, 3, 37
Morphine, 23, 123
Phosphate salt, 84, 224
Serotonin selective reuptake inhibitors

(SSRI), 51, 169
pKa, 71, 201
N-acetylsialic acid, 91-92, 234-235

Natamycin, 12, 106-107
N-dealkylated monoethylglycinexylidide,
67, 192
Neostigmine bromide, 81, 219-220
Nerolidol, 19, 115
Neuraminidase, 91, 234-235
Nifedipine, 21, 117-119
Nilotinib, 88-89, 229, 231
Nitrofurantoin, 11, 105-106
Nonelectrolyte, 9, 103
Non-hydrolyzable hydroethylene, 30, 134
Non-peptidomimetic prodrug, 44, 161
Norepinephrine reuptake, 24, 125
Shitaki mushrooms, 20, 116
range, 6, 31, 73, 76, 91, 101-102, 137,

206-207, 211-212, 233
Short-acting agent, 71, 200
values, 42, 69, 154-155, 193, 194-195
Sodium salt(s), 70, 71, 195, 200
Sitagliptin, 83-85, 223-226
Plasma pH, 11, 14, 105, 109
Solubility, 13-15, 109-112
Plasma protein binding, 30, 32, 41-42, 70,

84, 134-135, 139, 153, 197, 225
Sorafenib, 87-89, 227-231
Potassium salt, 13-14, 109

Pravastatin, 9, 73-74, 103, 205-209
Stereochemistry, drug action and, 21-22,

117-121
Primarily ionized, 11, 105-106
Steroid-based hormone, 62, 185
Primarily unionized, 11, 105-106
Stomach pH, 11, 14, 105, 109
Primary amine, 185
Sulfamethoxazole, 4, 96
Prodrug(s), 44, 48, 60, 76, 161-162, 174,

180-181, 212
Sulfate conjugation, 23, 56, 123, 176
Protein tyrosine kinases, 87-89, 227-231
Sulfonylureas, 41-42, 153-157
Pyridyl nitrogen, 89, 230
Sorbinil, 7-8, 99, 101, 102
Sulfonamide, 194
Nucleophilic side chain, 38, 147
Quinapril, 76-78, 211-215
Tetracycline, 13-14, 109
Quinaprilat, 76-77, 212-213
Tetrapeptide side chains, 5, 98
Oral anticoagulant, experimental, 7-8, 99,

101, 102
Thrombin active site, 43, 159
Oral bioavailability, 52, 171
R-A double bond reduction, 58, 179
Thyroglobulin molecules, 61, 183
Oseltamivir, 91-92, 233-237
Ranitidine, 12, 108
Tocainide, 67, 192
Oxidative N-dealkylation, 56, 142, 176
Reactions, 58-59, 179
Tolbutamide, 32, 41, 139, 153-156
Oxidative O-dealkylation, 48-49, 70, 92,

168, 198, 236, 237
Reduction, 56, 176
Tolterodine, 18, 114-115
R-enantiomer, 62, 84, 184, 224-225
Tolycaine, 67, 192
Oxidative transformation, 28-29, 132-133
Renin, 30, 134
Tosylate salt, 89, 231
Oxybutynin, 18, 114-115
Resonance, 4, 55, 79, 96, 217
Transformations, 58-59, 179
Ring A ketone reduction, 58, 179
Tricyclic antidepressant, 24, 124
Odorant molecules, 19, 115
Taste receptors, 20, 116
Thrombin inhibitor, 43, 159
Rivastigmine, 79-81, 217-221
Passive diffusion, 89, 231

Penicillins, 38, 147
Routes of administration, biological targets

and, 14-15, 109-110
Peptide cleavage, 76, 213
Rule of Nines, 12, 69, 106, 194
Peptide-based hormone, 62, 185
pH/pKa, 11-12, 105-106
Phase I transformation, 23-24, 33, 37,

40, 48, 53, 56, 66-67, 70, 72, 85, 92,
123-125, 141-142, 146, 150-151,
167-168, 172, 175-176, 191-192,
197-198, 202, 226, 236-237
Phase II transformation, 23, 33, 37, 40, 48,
56, 70, 72, 92, 123, 125, 141, 146,
151, 167-168, 175, 197, 202, 236-237
Salmeterol functional groups, 3, 37
Tyrosine kinase inhibitor, 87-89, 227-231
Umami receptor, 20, 116
Scents, 19, 115
Unionized, 31, 36, 55, 69, 71, 76, 91, 137,

145, 174, 193-194, 201, 211-212,
233
Sclareol, 19, 115
Urinary pH, 11, 105
Salts, 13-15, 109-112
Scopolamine, 14, 109-110

Secobarbital, 71, 199-200, 201
Valine, 87, 98, 227
S-enantiomer, 62, 184
Serine, 79, 80, 218-219

Tri-iodo-L-thyronine (T3), 61, 63, 183, 185

Tyrosine, 98
Phenobarbital, 71-72, 199-203

241
Van der Waals, 19, 87, 114-115, 140, 196,

202-203, 227
242
Vanillin, 19, 115

Vascular endothelin growth factor 2, 87,
227
W
Warfarin, 3, 37, 84, 225
Water solubility, 31, 138, 195
Water soluble ester, 60, 180-181
-oxidation, 92, 236, 237
Z
Zafirlukast, 69-70, 193-198
Zanamivir, 91-92, 233-237


Review of Organic Chemistry Functional Group Solutions Manual

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Robin M.

Marc W. Harrold, PhD

Purchased by palm beach atlantic university, Ed Nordine

Director, Special Publishing: Jack Bruggeman

2015, American Society of Health-System Pharmacists, Inc. All rights reserved.

Purchased by palm beach atlantic university, Ed Nordine

Purchased by palm beach atlantic university, Ed Nordine

Purchased by palm beach atlantic university, Ed Nordine

Functional Group Characteristics and Roles........................................................................................................................ 1

Section 2 Whole Molecule Drug Evaluation

Solving pH/pKa Problems................................................................................................................................................ 105

Section 4 Whole Molecule Drug Evaluation

INDEX .................................................................................................................................................................................... 239

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Purchased by palm beach atlantic university, Ed Nordine

Purchased by palm beach atlantic university, Ed Nordine

Purchased by palm beach atlantic university, Ed Nordine

Section 1 - General Self Assessment

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Functional Group Characteristics and Roles.................... 3

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Section 1 General Self Assessment

Structures for 1.1 and 2.1

1.1 Functional Group Characteristics

copies in the event you wanted that.

Functional Group Name

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Medicinal Chemistry Self Assessment

Structures for 1.1 and 2.1

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3. Shown below is the structure of imipramine as well

Answers can be found in Section 2.1

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Section 1 General Self Assessment

1.2 Identifying Acidic and Basic

Experimental oral anticoagulant

Acidic Functional Groups

Basic Functional Groups

Medicinal Chemistry Self Assessment

Experimental Oral Anticoagulant

Basic Functional Group

Experimental Oral Anticoagulant

1.2 Identifying Acidic and Basic Functional Groups

Acid/Base Character of Drug Molecule

Answers can be found in Section 2.2

Medicinal Chemistry, American Society of Health-System Pharmacists, 2013.

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Section 1 General Self Assessment

1.3 Solving pH/pKa Problems

Drug (pKa Value)

The pKa values for natamycin are 4.6 and 8.4.

Medicinal Chemistry Self Assessment

The pKa values for natamycin are 4.6 and 8.4.

Answers can be found in Section 2.3

Section 1 General Self Assessment

1.4 Salts and Solubility

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Medicinal Chemistry Self Assessment

Biological Targets and Routes of Administration

O H Asn Tyr Cys Asn COOH

Leu Cys Gly Ser His