Drug Design:

Functional groups / Pharmacological Activity

Structure - Mechanism of action

(Interaction with target)

Structure - Physiochemical properties (Bioavailability etc)

• Acid / base properties
• Water solubility
• Partition coefficient
ADME
• (Crystal structure)
• Stereochemistry

Absorbtion. Distribution, Metabolism, Excretion

(ADMET, ADMEtox)
 Structure - Mechanism of action

Acetylcholin
(Neurotransmittor)
Acetylcholin Agonists
ca. 5Å

Carbacholin Nicotine Pilocarpine

O Me
O
N N N
O N O
H2N O H O N
N
H H
O

Protonated av phys. pH (pH≈7.4)

Det somatiske nervesystem Det autonome nervesystem

Det sympatiske Det parasympatiske

nervesystem nervesystem
Acetylcholin Antagonists
CNS CNS CNS
Atropin Cyclopentolat Tubocurarin
N H
N MeO
N
ganglion
OH Me
Acetylkolin
OH O O
Noradrenalin
O O HO
O
Synapse O
OH
Me
Reseptor
N
Effektor celle OMe
Me
 Structure - Mechanism of action
SAR: Structure Activity Relationships

Acetylcholine agonists: Small N-quartenary compds.

Acetylcholine antagonists: Larger N-quartenary compds.

N N
CO2Me NH2 N
O
O O
N
O O H
Cocaine
Procaine Lidocaine/Xylocaine
(1905) (1946)
Acid labile ester

Hydrophilic Spacer
Lipophilic
Aminogroup -Cn-X-
(Aryl)
(can be protonated) X: -CO2-
-CONH-
-NHCO-
Active compound identified Target identified
Target? Ligand?
Structure - Physiochemical properties

• Acid / base properties Human body: ca 75% water

• Water solubility pH blood ca 7.4 (physiolog. pH)
• Partition coefficient pH stomach 1 - 3.5
• (Crystal structure) pH duodenum ca. 4
• Stereochemistry pH urine ca. 6

Identification of acidic / basic functional groups

pKa determines degree of ionization different places in the body
 Acetylcholin Acetylcholin Antagonists Possible atropine analogs?
(Neurotransmittor)
ca. 5Å N
O N N N
OH
O OH OH OH
O O O O
O
N O O O
O
Cyclopentolat

H
O

N N
H
Cyclopentolate - tertiary amine, pKa ca. 10 O
OH + H20 O
OH + H3O
O O

acid form baseform

[acid form] pH=pKa; [acid]= [base]

pKa = pH + log Henderson Hasselbach pH<pKa; acid form dominates
[base form]
pH>pKa; basic form dominates
At pH 7.4

[acid form] [acid form] [acid form]

10 = 7.4 + log log = 2.6 = 398; 99.75% acid form
[base form] [base form] [base form]
N
H = active form
OH
O
O
Antibacterial sulfonamides

Old compound

At pH 6 (urine)

[acid form] [acid form] O Acid form - neutral

10.4 = 6 + log ≈ 25000 H2N S NH2 Low watersol. - crystals -
[base form] [base form] O Kidney damage

Modern compound

O O O O
N N N N
O + O O O
-H
HN S Ar N S Ar N S Ar N S Ar At pH 6 (urine)
O O O O
Sulfametoksasol [acid form]
pKa 6.1 ≈1
O base form, ionic, water sol. [base form]
N
O
N S Ar
O
 Structure - Physiochemical properties
• Acid / base properties
• Water solubility Ionisation -permanent charge
• Partition coefficient -acid / base properties
• (Crystal structure)
• Stereochemistry Hydrogen bonds

Ion - dipole bonds Intramoleculare interact. reduce water sol.

δ+
δ+
H H
O
δ-O δ+ O δ- H H
H H δ+ H
O
R N H
H CO2
R O Strong intramolec interact.
R
Acidic form of amines Basic form of carboxylic acid NH3
(carboxylate)

O
H H

Salts between weak organic acids and weak organic bases does not dissolve well in water
The more H-bonds possible - the more water sol.

H H
O O H H
H O
H

Alchohol O 3 H-Bonds H H
R H
Primary amine R N H O
3 H-Bonds
O H
H H
H H
O
H H
O O
H H

Aldehyde / ketone O 2 H-Bonds

R' H
R R' Secondary amine R N H O
2 H-Bonds
H

H H H H
O O O
H H
R'
Ester O 3 H-Bonds 1 H-Bonds
Secondary amine R N R''
R
R O
H H
H H O
O
Prediction of water solubility - Empirical

Water solubilization of functional groups

Functional group Monofunctional comp. Polyfunctional
Ex. monofuctional comp.
comp. methanol - pentanol/hexanol
are solubile
Alchohol 5 – 6 carbons 3 – 4 carbons

Phenol 6–7 3–4

Terbinafine
Antifungal agent
Ether 4–5 2

Aldehyde 4–5 2 N

Ketone 5–6 2

Amine 6–7 3
21 C-atom, tertiary amine solubilize 6 - 7 C atoms
Carboxylic acid 5–6 3
Insolubile (neutral form)
Ester 6 3
Corresponding acid (cationic) solubile
Amide 6 2-3

(solubile: >10 mg/mL)

Charge: 1 charge - 20-30 C
 Water solubilization of functional groups

Functional group Monofunctional comp. Polyfunctional

comp.
Ex. polyfunctional comp.
Alchohol 5 – 6 carbons 3 – 4 carbons

Phenol 6–7 3–4 Betaxolol

Betablokker
Ether 4–5 2
Ether: 2
O N
Aldehyde 4–5 2 H Ether: 2
OH
Alchohol: 3-4
Ketone 5–6 2
Amine 2
Amine 6–7 3 O
Tot: 9 - 10

Carboxylic acid 5–6 3 18 C-atomer (not solubile)

Ester 6 3

Amide 6 2-3

Charge: 1 charge - 20-30 C

Structure - Physiochemical properties
• Acid / base properties
• Water solubility
• Partition coefficient
• (Crystal structure) logP P: Partition coefficient between n-octanol and water
• Stereochemistry
Experimental: MlogP or logPmeas
logP ∝ Rt (HPLC, TLC reverse phase)
Fragment π-value
C (aliphatic +0.5
Phenyl +2.0 Calcd: ClogP
-Cl +0.5 π-value: hydrophilic - lipophilic value
-ONO2 +0.2 Betaxolol
Betablokker
-S- 0.0
12 x C aliphat: +6.0
O=C-O- (carboxyl) -0.7
O N
H Ph: +2.0
O=C-N- (amide) -0.7 OH
3 x O: -3.0
-O- (hydroxyl, ether) -1.0
N: -1.0
N (amine) -1.0 O
logP +4.0
-NO2 (aliphat.) -0.85
ClogP (SciFinder): 2.69
-NO2 (aromat.) -0.28
 Absorbtion of Bioactive Compounds

Absorbtion from GI tract

Membrane

GI-tract
Blood
Stomach
pH 1-3
Often
rate limiting
Drug

Acidic /
Enzymatic break down
Duodenum
pH 5-7

+ digestive enzymes Binding to

biomolecules

Small Jejunum
intestine

Ileum
pH 7- 8
Most drugs: Passive diffusion

Lipophilic pKa pH
Membrane
Stomach Blood
pH 1 - 3 R-H R-H
Amount un ionized drug
R-CO2H R-CO2H

[acid form]
R-NH3 pKa = pH + log Henderson Hasselbach
[base form]

Low lipophilicity unionized form - low absorbtion

Water phase - extracellular fluid
logP - P: Partition coefficient between n-octanol and water
Lipophilic phase - cell membrane
Crossing the membrane

Passive transport / diffusion

High conc.

Chanel protein
Low conc.

Rate ∝ Conc. absortion site (1. order kinetics)

% Drug absorbed ∝ lipophilicity

Size of molecule
Certain ionic compounds may go thru as ion-pair
Active transport / Carrier mediated transport
•Less common
•Structural recemblanse with for instance nutritional compound
•Transport against conc. gradient
•Mechanism saturated at high conc.
•Competition for carrier molecules, compounds with structural resemblance

Energy
The Lipinski "Rule of Five"

states that compounds are likely to have good absorption and permeation
in biological systems and are more likely to be successful drug candidates
if they meet the following criteria:

five or fewer hydrogen-bond donors

Not too polar
ten (2 x 5) or fewer hydrogen-bond acceptors

molecular weight less than or equal to 500 Not too big

calculated logP less than or equal to 5 Not too hydrophobic

*Compound classes that are substrates for biological transporters

are exceptions to the rule.
 Structure - Physiochemical properties
• Acid / base properties
• Water solubility
• Partition coefficient
• (Crystal structure)
• Stereochemistry

Biomolecules (reseptors, enzymes): Asymmetric

D A
A D
C Drug
B B
Enantiomers may behave differently:
•Absorbtion (membrane selectivity)
•Metabolism
•Binding to other reseptors than target
C (loss, side effects)
•Binding to target reseptor

Biomolecular
target

No desired resonce
Desired responce Side effects??
Restricted rotation - optically active rotamers

P P

P P

(R)-(+)-BINAP (S)-(-)-BINAP

X-ray contrast agent

* CO2H
Chiral C-atom
O 4 stereoisomers
I I Chiral axis (restrict. tot.)
NH2
I
•Screening/Design/Serendipity/Natural products
•Lead compound
•Structure Optimisation Refinement of lead structure:
•Actual Drug •Determining pharmacophore
•Functional group modification

Pharmacophore:
The part of the molecule that contains the functional groups that actually binds to the reseptor

Morfin Petidine Dextropropoxyphene

N
N N
OH
O
O
O O
OH O
Antimycobacterials
Ar
Lead compound Rel high activity
N N
Y
O X N N

N Z
N
Cl N N

O R

N N
N N
N N
N N
R

R ≠ CH2Ph R=H, alkyl

Inactive

Pharmacophore??

Ar Ar
Azapurines?? Ar Ar
N N N
Deazapurines?? N
N R X
N N N
N
??
?? ??
Improvement of lead by functional group modification
•Activity
•Toxicity
•Bioavailability
•Metabolism

Isosters:
Functional groups that results in approx. the same properties
Steric and electronic similarities

S
bp 81 oC bp 84 oC bp 116 oC

-CH=CH- and -S- are isosters -C= and -N= not isosters

(at least with respect to bp)

Bioisosters:
Functional groups that results in approx. the same biological properties

Classical bioisosters
Steric and electronic similarities

Tetravalente
Monovalent Divalent
N
-F, -H -C=S, -C=O, -C=NH, -C=C- C

-OH, -NH2
Rings
-H, -F, -OH, -NH2, -CH3 Trivalente
-SH, -OH -CH=, -N=
-Cl, -Br, -CF3 N S O
 -X π σp % Inhib at MIC
6.25 µg/mL (µg/mL)
-H 0.00 0.00 >90 3.13
O -F 0.15 0.06 >90 6.25
-Cl 0.70 0.23 >90 6.25
N N -OH -0.61 -0.37 79 n.d.
N
-OMe -0.04 -0.27 >90 1.56
N
-NH2 -1.23 -0.66 23 n.d.
-NMe2 0.18 -0.83 >90 12.5
X -CH3 0.60 -0.17 >90 3.13
-t-Bu 1.98 -0.20 >90 12.5
-SO2Me -1.63 0.72 23 n.d.
Bioisosters

σ: electronic effects; σ>0 electron withdrawing, σ<0 electron donating

π: Lipophilicity, π>0 increased lipophil. rel to H

Angiotensin II antagonists
Non-classical bioisosters (Hypertention)
Not strong steric or electronic similarities
O N
N

N
N HO2C
NH
N
N N N N N
N N N
N N N N
H H H H
N
pKa 14.2 pKa 10.3 pKa 9.2 pKa 4.9 ≈ karboksylsyrer
N
O
HO N
N