Drug Discovery & Development Lec 3

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

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.

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

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

Example: Salbutamol (Anti-asthmatic) Adrenaline

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

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

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

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

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

Closure of a chain or opening of a ring

Ring chain transformation

4-Ring expansion and ring contraction Hydrophobic regions

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

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

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]

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

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

6. Introduction of unsaturation center

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

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