1. Drug Discovery & Development
Lec 3

2. II. Special approach 1. Variation of alkyl substituents.
2. Extention of the structure.
3. Ring closure or ring opening
4. Ring expansion and ring contraction
5. Homologation and chain branching
6. Introduction of unsaturation center
7. Introduction, removal or replacement of bulky
groups
8. Changes of substitution position
9. Introduction of chiral center
10. Conformation restriction (molecular rigidification)
11. Isosteres and bioisosteres

3. 1. Variation of alkyl substituents.
The length and size of alkyl substituents can be modified to fill up on hydrophobic pockets in the binding site or to introduce selectivity for one target over another. Alkyl groups attached to heteroatoms are most easily modified.

4. Rationale: Alkyl group in lead compound may interact with hydrophobic
region in binding site
Vary length and bulk of group to optimise interaction

5. Vary length and bulk of alkyl group to introduce selectivity
Rationale:
Vary length and bulk of alkyl group to introduce selectivity
Binding region for N
Receptor 1
Receptor 2

6. Example:
Salbutamol
(Anti-asthmatic)
Adrenaline

7. 2. Extension of structure
RECEPTOR
RECEPTOR
Extra
functional
group
DRUG
DRUG
Unused
binding
region
Drug
Extension

8. Example: ACE Inhibitors
Hydrophobic pocket
Vacant
EXTENSION
Hydrophobic pocket
Binding
site
Binding
site

9. Extension - extra functional groups
Example: Nerve gases and medicines
Sarin
(nerve gas)
Ecothiopate
(medicine)
Notes:
Extension - addition of quaternary nitrogen
Extra ionic bonding interaction
Increased selectivity for cholinergic receptor
Mimics quaternary nitrogen of acetylcholine
Acetylcholine

10. Extension - extra functional groups
Example: Second-generation anti-impotence drugs
Viagra
Notes:
Extension - addition of pyridine ring
Extra van der Waals interactions and HBA
Increased target selectivity

11. 3. Ring closure or ring opening
Diethylstilbesterol may be regarded as a ``ring opening`` modification of estradiol

12. Closure of a chain or opening of a ring

13. Ring chain transformation

15. 4-Ring expansion and ring contraction
Hydrophobic regions

16. Carboxylate ion out of range
Ring expansion / contraction
vary
ring size
Example:
Binding regions
Binding site
Binding site
Two interactions
Carboxylate ion out of range
Three interactions
Increased binding

17. 5- Homologation A homologous series is a group of compounds that
differ by a constant unit, generally a CH2 group

18. This phenomenon corresponds to Increased lipophilicity of the molecule to permit penetration into cell membranes until its lowered water solubility becomes problematic in its transport through aqueous media.
e.g. 1: Hypnotic activity of alcohols
The maximum effect occurred for 1-hexanol to 1-octanol.
The potency declined on chain lengthening until no activity
was observed for hexadecanol.
e.g. 2: 4-alkyl substituted resorcinol derivatives
[Antibacterial effect is maximum in case of 4-n-hexyl resorcinol]

19. Chain branching
Chain branching lowers the potency of a compound because a branched alkyl chain is less lipophilic than the corresponding straight alkyl chain.
in case of [Homologation]
lipophilic relationship is important
The lowered potency may be due to
 pharmacokinetics
(Absorption, metabolism, excreation,……..etc)
 pharmakodynamics
Chain branching may interfere with receptor binding

21. The primary pharmacologic activity of promethazine is that of an antihistamine, whereas promazine is an antipsychotic. The only difference between the two molecules is the alkylamine side chain. In the case of promethazine, there is an isopropylamine side chain, whereas promazine contains an n-propylamine.
Promethazine
Promazine

22. 6. Introduction of unsaturation center

24. The double bond in prednisolone increases its antirheumatic activity over its parent compound, cortisol by about 30 fold
Cortisol
Prednisolone

25. Thank you & have a nice vacation