Pain relievers: aspirin

• Analgesic (pain reliever)

• Antipyritic (fever reducer)
• Anti-inflammatory
• Anticoagulent

History of Aspirin
- Hippocratus: powder made from the
bark and leaves of the willow tree to Inhibits production of
help heal headaches, pains and fevers
- Henri Leroux & Raffaele Piria: prostaglandins (pain
purification of active ingradient from
the plant messengers)
- 1899 Hoffman: formulation and patent
 Antibacterial drugs: penicillins

1941
Prevents crosslinking between proteins
and therefore cell wall synthesis (mucoproteins).
 Aspirin substitutes
Now banned Tylenol

Advil Aleve Orudis KT

Antihistamines
 Antibacterial drugs: sulfa drugs

1935
Chemical mimic-type poison for bacteria
 Other antibacterial drugs

Fluoroquinolone

bind to
bacterial
ribosomes inhibits
bacterial DNA
replication
Drugs derived from structure-based approaches

Capoten Captopril ACE Hypertension 1981 Bristol-

Myers
Squibb
Trusopt Dorzolamide Carbonic Glaucoma 1995 Merck
anhydrase

Viracept Nelfinavir HIV protease HIV/ AIDS 1999 Agouron

(Pfizer)
and Lilly
Tamiflu Oseltamivir Neuraminidase Influenza 1999 Gilead and
Roche

Gleevec Imatinib BCR- Abl Chronic 2001 Novartis

myelogenous
leukaemia
 Example Combinatorial Library
Scaffold “R”-groups Examples
R1 = OH
OCH3 OH
NH2 NH
R1 Cl
COOH
NH CN O OH
R2 = phenyl OH C
OH OH
NH
NH2 NH
Br
R2 F OH
CN CF3
R3
O
CH3
R3 = CF3
NO2 O OH
OCH3 C
For this small library, the number OH
NH
phenoxy
of possible compounds is
OH
5 x 6 x 5 = 150 O
Lead Identification by Fragment Evolution
Similarity Paradox
(hydroxyl group)

(amine group)
 Drug-drug Interactions

• Pharmacokinetic and pharmacodynamic

– With pharmacokinetic drug interactions, one drug affects the
absorption, distribution, metabolism, or excretion of another.
– With pharmacodynamic drug interactions, two drugs have interactive
effects in the brain.
– Either type of drug interaction can result in adverse effects in some
individuals.
– In terms of efficacy, there can be several types of interactions between
medications: cumulative, additive, synergistic, and antagonistic.
Cumulative Effects

Hi

Drug B
Response

Drug A
Lo
Time
The condition in which repeated administration of a drug may produce effects
that are more pronounced than those produced by the first dose.
Additive Effects

Hi

A+B
Response
A B

Lo
Time
The effect of two chemicals is equal to the sum of the effect of the two
chemicals taken separately, eg., aspirin and motrin.
Synergistic Effects

A+B
Hi

Response
A B

Lo
Time

The effect of two chemicals taken together is greater than the sum of their
separate effect at the same doses, e.g., alcohol and other drugs
Antagonistic Effects

Hi

A+B

Response
A B

Lo
Time

The effect of two chemicals taken together is less than the sum of their separate
effect at the same doses
 Agonism and Antagonism

Agonists facilitate receptor

response

Antagonists inhibit receptor

response

(direct ant/agonists)