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Medicinal Chemistry

Introduction

The science that deals with the discovery or design of new therapeutic agents and their development into useful medicines.

IT INVOLVES:

• Synthesis StructureActivity Relationships (SAR) Receptor interactions

Absorption, distribution, metabolism, and excretion (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 dislike since society views the term with suspicion.

O N H N OH OH O OH Lipitor F
O
N
H
N
OH
OH
O
OH
Lipitor
F
CH 3 N N N Zyprexa N H S CH 3
CH 3
N
N
N
Zyprexa
N
H
S
CH 3
 

HO

 
 

O

O

H

 

O

H

H

H 3 C

O

CH 3

Zocor

O H 2 N S O N N CF 3 C H 3 Celebrex
O
H 2 N
S
O
N
N
CF 3
C
H 3
Celebrex
O N H N S O N CH 3 Prevacid
O
N
H
N
S
O
N
CH 3
Prevacid

CF 3

OH

Ph HO HN HO (H 2 C) 4 O (CH 2 ) 6 OH Seretide
Ph
HO
HN
HO
(H 2 C) 4
O
(CH 2 ) 6
OH
Seretide

CO 2 H

H

N NH 2 O MeO 2 C CO 2 Et Cl CO 2 Me Cl N
N
NH 2
O
MeO 2 C
CO 2 Et
Cl
CO 2 Me
Cl
N
S
-
HSO 4
Norvasc
Plavix
NHCH 3 HCl Zoloft Cl
NHCH 3
HCl
Zoloft
Cl

Cl

N S N N O
N
S
N
N
O

MeO

) 2 Mg 2+

Nexium

What is Lipitor?

Lipitor (atorvastatin) belongs to a group of drugs called HMG CoA reductase inhibitors, or "statins." Lipitor reduces levels of "bad" cholesterol (lowdensity lipoprotein, or LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (highdensity lipoprotein, or HDL).

Lipitor is used to treat high cholesterol, and to lower the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes, coronary heart disease, or other risk factors.

What is Zyprexa?

Zyprexa (olanzapine) is an antipsychotic medication that affects chemicals in the brain.

Zyprexa is used to treat the symptoms of psychotic conditions such as schizophrenia and bipolar disorder (manic depression) in adults and children who are at least 13 years old.

Zocor

Zocor is the brand name of simvastatin, a prescription drug used to lower blood cholesterol.

Zocor belongs to a class of drugs known as statins, also called HMGCoA reductase inhibitors.

Definition of “drug ”

Drugs are defined as chemical substances that are used to prevent or cure diseases in humans, animals and plants.

Since Drugs act by interfering with biological processes, so no drug is completely safe. All drugs can act as poisons if taken in excess

For example, overdoses of paracetamol can cause coma and death.

In addition to their beneficial effects, most drugs have nonbeneficial biological effects.

• F or exampl e, overd oses of parace tamol can cause coma and death. •
• F or exampl e, overd oses of parace tamol can cause coma and death. •

Aspirin, which is commonly used to alleviate headaches, may also cause gastric irritation and bleeding.

The nonbeneficial effects of some 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, such as antibiotics, can result in the development of resistance to that drug by both the patients, microorganisms and virus the drug is intended to control.

Resistance occurs when a drug is no longer effective in controlling a medical condition. Drug resistance or tolerance, often referred to as tachyphylaxis, arises in people for a variety of reasons

For example, antimalarial drugs are proving less effective because of an increase in the proportion of drug resistant strains of the malaria parasite.

New drugs are constantly required to combat drug resistance, even though it can be minimized by the correct use of medicines by patients. They are also required for the improvement in the treatment of existin g 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

Since ancient times the peoples of the world have used a wide range of natural products for medicinal purposes.

These products, obtained from animal, vegetable and mineral sources, were sometimes ver y effective

However, many of the products were very toxic.

Initially drug development was centred around the natural products isolated from 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.

The compounds on which a development is based are now known as lead compounds, while the synthetic compounds developed from a lead are referred to as its analogues.

The first rational development of

synthetic drugs was carried out by Paul Ehrlich and Sacachiro Hata, who

produced

the

antiprotozoal

arsphemamine in 1910 by combining

synthesis

with

reliable biological

screening and evaluation procedures.

Ehrlich, at the begining of the 20th century, had recognized that both the beneficial and toxic properties of a drug were important to its evaluation.

He realized that the more effective drugs showed a greater selectivity for the target microorganism than its host.

To compare the effectiveness of different compounds, he expressed a drug’s selectivity, and hence its effectiveness, in terms of its chemotherapeutic index.

• To compare th e eff ec ti veness of differen t compounds, he expressed a

Today, Ehrlich’s chemotherapeutic index has been updated to take into account the variability of individuals and is now defined as its reciprocal, the therapeutic index or ratio:

• Today, Ehrlich’s chemotherapeutic index has been updated to take into account the variability of individuals

The important role of drugs in human society

• Drugs have irrevocably changed the fabric of society by improving both the individual quality of life and life expectancy.

• Some examples are

• Bacterial

and

virus

infections:

smallpox, tuberculosis

and

polio,

related

diseases have, to a very major extent,

become minor public health concerns.

• An increase in life expectancy resulting from drug therapy has also led to a shift in population demographics toward a more healthy, elderly population.

Drug

regimens

for

birth

control

have

improved individual life choices and the

quality of life.

• Cancer

is

also

being

viewed

as

a

potentially

chronic,

rather

than

fatal

disease

with

approaches.

newer,

non-cytotoxic

Origins of Medicinal Chemistry

Early investigations of natural products

Natural products having a history as folk examples,

remedies

were

in

use. Fore

opium,

belladonna,

cinchona

bark,

etc.

Many

drugs

originally

used

as

folk

remedies,

nowadays,

have

been

abandoned.

In the late eighteenth and early nineteenth centuries, chemical ex perimentation led ultimately to its use in the discovery of new 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.

N
N

O

H

• He heated morphine with methyl iodide, h opin g to co nv ert the a
• He heated morphine with methyl iodide, h opin g to co nv ert the a

HO

OH

In

1898,

the

first commercially available

semisynthetic morphine derivative (ethyl ether) was introduced as a cough sedative in preference to codeine or other opiates.

• Meanwhile, diacetylmorphine was introduced as a safer pain reliever than morphine. It quickly became popular throughout the world.

Four years passed before its addictive properties of heroin were recognized. Laws were later passed by governments to restrict its use.

Developments of MC Leading to Various Medicinal Classes of 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

fever.

It

was

found to be an effective antipyretic.

In

1899,

Aspirin

was marketed

as

an

antipyretic without the unpleasant side effects. This indicated that the chemical

structures from natural products were changed into better drugs.

Medicinal Chemistry began.

Fast Development from 1900s to 1960s

1920’s~1930’s: Anesthetics, Hypnotics,

Analgesics were used extensively. In research for functional “pharmacophore”,

structure-function relationship investigated gradually.

was

After 1930’s: The development of new drugs

was speeded greatly by the close combination of

Medicinal

Chemistry

Pharmacology.

and

Experimental

Theory of antimetabolite was formed by using metabolic products as lead compounds.

• Discovery

of

penicillin

which

is

the

first

antibiotics is an epoch-making achievement.

Afterward,

tetracycline,

streptomycin,

chloramphenicol, erythromycin were introduced

one after another.

In 1940’s, the first drug used for treating cancer as a biological alkylating agent was nitrogen mustard, which began tumor chemical therapy.

In 1960’s, oral steroidal contraceptive agents were discovered. Corticosteroids have become an important drugs.

After 1950’s, 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

β-Adrenergic

Propranolol, was marketed.

blocking agent,

In 1979, Nifedipine, Calcium Channel Blocker was marketed.

In

1981,

Captopril,

Angiotensin

Converting

Enzyme (ACE) Inhibitor was launched.