MedicinalChemistry

Introduction
The science that deals with the discovery or design of
new therapeutic agents and their development into
useful medicines.
ITINVOLVES:
O S
Synthesis
StructureActivityRelationships(SAR)
Structure Activity Relationships (SAR)
Receptorinteractions
Absorption,distribution,metabolism,andexcretion
(ADME)

In medicinal chemistry, the chemist

attempts to design and synthesize a
medicine or a pharmaceutical agent
which will benefit humanity.
Such a compound could also be called a
'drug', but this is a word which many
scientists
i ti t dislike
di lik since
i
society
i t views
i
th
the
term with suspicion.
p

HO

O
N

N
H

O
OH

Lipitor

N
H

O
S

H2N

CH3

O
H

OH
OH

O
Zyprexa
yp

CH3

H3C

CH3

Zocor
OH

O
N N

O
S

H
N
CF3

N
O

CF3

CH3

HO

CO2H

Seretide

Prevacid
H3C

Ph
(H2C)4
HN
O
(CH2)6 OH

HO

Celebrex
H
N

MeO2C

O
CO2Et
Cl

NH2
Cl

NHCH3

Plavix

N
MeO

N
HSO4-

Norvasc

HCl

CO2Me

Zoloft

S
O

S
Cl
Cl

Nexium

)2 Mg2+

WhatisLipitor?
Lipitor (atorvastatin) belongs to a group of drugs called HMG
CoA reductase inhibitors,
inhibitors or "statins
statins." Lipitor reduces levels of
"bad" cholesterol (lowdensity lipoprotein, or LDL) and
triglycerides in the blood, while increasing levels of "good"
good
cholesterol (highdensity lipoprotein, or HDL).
Lipitorisusedtotreathighcholesterol,andtolowertheriskofstroke,heart
Lipitor
is used to treat high cholesterol and to lower the risk of stroke heart
attack,orotherheartcomplicationsinpeoplewithtype2diabetes,coronaryheart
disease,orotherriskfactors.

WhatisZyprexa?
Zyprexa(olanzapine)isanantipsychotic
medicationthataffectschemicalsinthebrain.
Zyprexaisusedtotreatthesymptomsof
psychotic conditions such as schizophrenia
psychoticconditionssuchasschizophrenia
andbipolardisorder (manicdepression)in
adultsandchildrenwhoareatleast13years
l
hl
h
l
old.

Zocor
Zocoristhebrandnameofsimvastatin,a
p
prescriptiondrugusedtolowerblood
p
g
cholesterol.
Zocorbelongstoaclassofdrugsknownas
Zocor belongs to a class of drugs known as
statins,alsocalledHMGCoAreductase
inhibitors.
hb

Definition of drug
Definitionof
drug
Drugsaredefinedaschemicalsubstancesthat
p
areusedtopreventorcurediseasesin
humans,animalsandplants.
SinceDrugsactbyinterferingwithbiological
processes,sonodrugiscompletelysafe.
Alldrugscanactaspoisonsiftakeninexcess
All drugs can act as poisons if taken in excess

 FForexample,overdosesofparacetamolcan
l
d
f
t
l
causecomaanddeath.
Inadditiontotheirbeneficialeffects,most
drugs have nonbeneficial
drugshavenon
beneficialbiologicaleffects.
biological effects

Aspirin,whichiscommonlyusedtoalleviate
headaches,mayalsocausegastricirritation
g
andbleeding.

 The non
nonbeneficial
beneficial effects of some drugs,
drugs such
as cocaine and heroin, are so undesirable that
the use of these drugs has to be strictly
controlled by legislation.
The over-usage of the same drugs,
drugs such as
antibiotics, can result in the development of
resistance to that drug by both the patients
patients,
microorganisms and virus the drug is intended
to control
control.

 Resistanceoccurswhenadrugisnolonger
es sta ce occu s e a d ug s o o ge
effectiveincontrollingamedicalcondition.
Drug resistance or tolerance often referred to
Drugresistanceortolerance,oftenreferredto
astachyphylaxis,arisesinpeopleforavariety
ofreasons
f
For example, antimalarial drugs are proving
less effective because of an increase in the
proportion of drug resistant strains of the
malaria parasite.
parasite

 New drugs are constantly required to combat

d
drug
resistance,
it
even though
th
h it can be
b
minimized by the correct use of medicines by
patients. They are also required for the
p
in the treatment of existingg
improvement
diseases, the treatment of newly identified
diseases and the production of safer drugs by
the reduction or removal of adverse side
effects

Historical outline of drug discovery

Historicaloutlineofdrugdiscovery
Sinceancienttimesthepeoplesoftheworld
haveusedawiderangeofnaturalproductsfor
medicinalpurposes.
Theseproducts,obtainedfromanimal,
vegetableandmineralsources,were
y
sometimesveryeffective
However,manyoftheproductswerevery
to ic
toxic.

 Initially drug development was centred

products isolated from
around the natural p
plant and animal material, but as knowledge
increased a wider range of pharmaceutically
active compounds were used as the starting
point for the development of drugs.
drugs

 The compounds on which a

development is based are now
known as lead compounds,
p
while
the synthetic compounds developed
f
from
a lead
l d are referred
f
d to
t as its
it
analogues.

 The first rational development of

synthetic drugs was carried out by Paul
Ehrlich and Sacachiro Hata, who
produced
d d
the
h
antiprotozoal
i
l
arsphemamine
p
in 1910 byy combiningg
synthesis with reliable biological
screening
i and
d evaluation
l ti procedures.
d

 Ehrlich,atthebeginingofthe20thcentury,
g
hadrecognizedthatboththebeneficialand
toxicpropertiesofadrugwereimportantto
its evaluation
itsevaluation.
Herealizedthatthemoreeffectivedrugs
showed a greater selectivity for the target
showedagreaterselectivityforthetarget
microorganismthanitshost.

 TTocomparetheeffectivenessofdifferent
th ff ti
f diff
t
compounds,heexpressedadrugsselectivity,
andhenceitseffectiveness,intermsofits
p
chemotherapeuticindex.

 Today,Ehrlichschemotherapeuticindexhas
p
beenupdatedtotakeintoaccountthe
variabilityofindividualsandisnowdefinedas
its reciprocal the therapeutic index or ratio:
itsreciprocal,thetherapeuticindexorratio:

The important role of

drugs in human society
Drugs have irrevocably changed the fabric
y by
y improving
p
g both the individual
of society
quality of life and life expectancy.
Some examples are
Bacterial and virus infections: polio,
smallpox
smallpox,
tuberculosis
and
related
diseases have, to a very major extent,
b
become
minor
i
public
bli health
h lth concerns.

 An increase in life expectancy resulting

g therapy
py has also led to a shift in
from drug
population demographics toward a more
healthy elderly population
healthy,
population.
Drug regimens for birth control have
improved individual life choices and the
quality
q
y of life.
Cancer is also being viewed as a
potentially chronic,
chronic rather than fatal
disease
with
newer,
non-cytotoxic
approaches.
h

Origins of Medicinal
Chemistry
Early investigations of natural
p
products
Natural products having a history as folk
remedies were in use.
use Fore examples,
examples
opium, belladonna, cinchona bark, etc.
Many drugs originally used as folk
f
y
have
been
remedies,
nowadays,
abandoned.

 In the late eighteenth and early nineteenth

p
led
centuries,, chemical experimentation
ultimately to its use in the discovery of new
drugs.
drugs
In 1853, Henry, conceived the idea that
functional groups in natural products might
be modified by chemical reagents.

 He heated morphine with methyl iodide,

hoping to convert the alkaloid to codeine.
He obtained, however, a new substance of
the quaternary salt of morphine
morphine.
N

HO

OH

 In 1898,
1898 the first commercially available
semisynthetic morphine derivative (ethyl ether)
was introduced as a cough sedative in preference
to codeine or other opiates.
Meanwhile,
Meanwhile diacetylmorphine was introduced as a
safer pain reliever than morphine. It quickly
became popular throughout the world.
world
Four years passed before its addictive properties of
heroin were recognized. Laws were later passed by
governments to restrict its use.
use

Developments of MC Leading to Various Medicinal

Cl
Classes
off D
Drugs
During the 1840s, the first use of synthetic
organic chemicals were introduced for
anesthesia during a tooth removal, such as
nitrous oxide, ether, and chloroform.
In 1864, barbituric acid had been synthesized as
a useful hypnotic.

 In 1875, salicylic acid was introduced as a

possible cure for typhoid
p
yp
fever. It was
found to be an effective antipyretic.
In 1899,
1899 Aspirin was marketed as an
antipyretic without the unpleasant side
effects.
ff
This indicated that the chemical
products were
structures from natural p
changed into better drugs.
Medicinal Chemistry began.
began

Fast Development from 1900s

1900 s to 1960
1960s
s
1920s~1930s: Anesthetics, Hypnotics,
Analgesics
g
were used extensively.
y In
research for functional pharmacophore,
structure-function
structure
function
relationship
was
investigated gradually.

 After 1930s: The development of new drugs

was speeded greatly by the close combination of
Medicinal
Chemistry
and
Experimental
Pharmacology.
Theory of antimetabolite was formed by using
metabolic products as lead compounds.
Discovery of penicillin which is the first
antibiotics is an epoch
epoch-making
making achievement.
achievement
Afterward,
tetracycline,
streptomycin,
chloramphenicol erythromycin were introduced
chloramphenicol,
one after another.

 In 1940s, the first drug used for treating

g
alkylating
y
g agent
g
was
cancer as a biological
nitrogen mustard, which began tumor
chemical therapy.
therapy
In 1960s, oral steroidal contraceptive
agents were discovered. Corticosteroids
C
p
drugs.
g
have become an important

 After 1950s, aging disease, cerebrovascular

and cardiovascular diseases became first
reason for human death. New drugs design
based on enzymes or receptors as drug targets.
In 1964, first -Adrenergic blocking agent,
Propranolol, was marketed.
In 1979, Nifedipine, Calcium Channel Blocker
was marketed.
In 1981, Captopril, Angiotensin Converting
Enzyme (ACE) Inhibitor was launched.
launched