Drug Discovery & Development

Lec 3

II. Special approach1 .Variation of alkyl substituents.

2 .Extention of the structure.3 .Ring closure or ring opening

4 .Ring expansion and ring contraction5 .Homologation and chain branching6 .Introduction of unsaturation center

7 .Introduction, removal or replacement of bulkygroups

8 .Changes of substitution position9 .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.

ANALOGUE

C

CH3

CH3H3C

van der Waals interactions

LEAD COMPOUND

CH3

Hydrophobicpocket

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

Rationale: Vary length and bulk of alkyl group to introduce selectivity

Binding region for N

Receptor 1 Receptor 2

Fit

Fit

NCH3

N CH3 Fit

No Fit

StericBlock

N CH3

CH3

N

Example:

HO

HO

HN

CH3

OHH

HOCH2

HO

HN

CCH3

OH

CH3

H

CH3

Adrenaline Salbutamol (Anti-asthmatic)

2 .Extension of structure

RECEPTOR

DRUG

DrugExtension

Unusedbindingregion

RECEPTOR

DRUGExtrafunctionalgroup

Example: ACE Inhibitors

Bindingsite

NH

N

O CO2

O

O

CH3

(I)

EXTENSION

Hydrophobic pocket

Bindingsite

NH

N

O CO2

O

O

CH3

Hydrophobic pocket

Vacant

Example: Nerve gases and medicines

Extension - extra functional groups

Notes:• Extension - addition of quaternary nitrogen • Extra ionic bonding interaction• Increased selectivity for cholinergic receptor• Mimics quaternary nitrogen of acetylcholine

Sarin(nerve gas)

O

PF

O(CHMe2)

CH3

Ecothiopate(medicine)

O

PS

N

CH3

H3C

H3C

OEt

OEt

Acetylcholine

ON

CH3

H3C

H3C

CH3

O

O

PS

N

CH3

H3C

H3C

OEt

OEt

Example: Second-generation anti-impotence drugs

Extension - extra functional groups

Notes:• Extension - addition of pyridine ring• Extra van der Waals interactions and HBA• Increased target selectivity

ViagraN

N

CH3

S OO

CH3

N

HN

O

N

N

CH3

CH3

N

N

CH3

S OO

CH3

N

HN

O

N

HN

CH3

N

N

N

CH3

S OO

CH3

N

HN

O

N

HN

CH3

N

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

R R RR

Ringexpansion

Hydrophobic regions

Example:

Ring expansion / contraction

Binding regions

Binding site Binding site

varyring size

NH

(CH2)n

N

N

CO2O

O2C

Ph

N

N

CO2ONH

Ph

O2CNH

N

N

CO2O

O2C

Ph

I

Three interactionsIncreased binding

Two interactionsCarboxylate ion out

of range

5- Homologation

A homologous series is a group of compounds thatdiffer 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.

N

S

N

Promethazine Promazine

N

S

N

6. Introduction of unsaturation center

HO

O

O

OHOH HO

O

O

OHOH

The double bond in prednisolone increases its antirheumatic

activity over its parent compound, cortisol by about 30 fold

Cortisol Prednisolone

Thank you & have a nice

vacation