Lead Modification 1m2j6f

Lead Modification Principles of Drug design

Lead modification : Drug design and development 1. Identification of the active part : the pharmacophore 2. Functional group modification 3. SAR relationships 4. Privileged structures and drug-like molecules 5. Structure modifications to increase potency and therapeutic index

1. Identification of the active part : the pharmacophore

analgesic and addictive

3-4 times more potent analgesic and addictive

Less potent analgesic and less addictive

3200 times more potent analgesic and less addictive

2. Functional group modification

R=NH2 carbutamide Antibacterial Antidiabetic

Antidiabetic

3. Structure Activity Relationship- SAR

4. Previleged structures and drug like molecules

Benzodiazepines

5. Structure modifications to increase potency and therapeutic index a) b) c) d) e)

Homologation Chain branching Ring chain transformations Bioisosterism Combinatorial Chemistry

5.a.Homologation

5.b.Chain Branching

Promethazine – antispasmodic and antihistaminic activities predominate Promazine – reduced antispasmodic and anti-histaminic activities, enhanced sedative and tranquilizer activities Trimeprazine – reduced tranquilizing activity with increased anti-pruritic activity

5.c.Ring Chain Transformations Reasons : •Increase lipophilicity •Decrease metabolism •Contraining the groups into a particular favorable conformation

5.d.Bioisosterism • Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties. • Types i. Classical ii. Non-classical

i. Classical Bioisosteres Classical bioisosteres are functional groups that possess similar valence electron configurations. For example, oxygen and sulphur are both in column VI of the periodic table; thus, a thio–ether (-C-S-C-) is a classical bioisosteric substitution for an ether (-CO-C-) functional group.

ii. Non-classical bioisosteres • Non-classical bioisosteres are functional groups with dissimilar valence electron configurations; • for instance, a tetrazole moiety may be used to replace a carboxylate since many biological systems are unable to differentiate between these two very structurally distinctive functional groups.

Ring replacement as bioisosteric approach

Pharmacological Effects of Bioisosterism • Structural – holding other functionalities where particular geometry, then size, shape and hydrogen bonding is important • Pharmacokinetics –for E of the drug, where lipophilicity, pKa and hydrogen bonding are important • Metabolism – blocking or aiding metabolism

5.e.Combinatorial Chemistry • Chemical libraries comprising of building blocks to give a diverse array of molecules with a common scaffold • Advantages – Carried out on a solid (polymeric) to aid isolation and purification by simple flitration and washing. – Example : peptide synthesis