1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 5: Section

1 © Contents 4.9.Rigidification -Methods - Introduce rings (2 slides) -Methods - Introduce rigid functional groups -Examples -Examples - Combretastatin (anticancer agent) -Methods - Steric Blockers -Steric Blockers – Examples (2 slides)

1 © Rationale : Endogenous lead compounds often simple and flexible (e.g. adrenaline)Endogenous lead compounds often simple and flexible (e.g. adrenaline) Fit several targets due to different active conformations (e.g. adrenergic receptor types and subtypes)Fit several targets due to different active conformations (e.g. adrenergic receptor types and subtypes) 4.9 Rigidification Rigidify molecule to limit conformations - conformational restraintRigidify molecule to limit conformations - conformational restraint Increases activity (more chance of desired active conformation)Increases activity (more chance of desired active conformation) Increases selectivity (less chance of undesired active conformations )Increases selectivity (less chance of undesired active conformations )Disadvantage: Molecule more complex and may be more difficultMolecule more complex and may be more difficult to synthesise

1 © 4.9 Rigidification RECEPTOR 1 RECEPTOR 2

1 © Methods - Introduce rings Bonds within ring systems are locked and cannot rotate freely 4.9 Rigidification

1 © Methods - Introduce rings Bonds within ring systems are locked and cannot rotate freely 4.9 Rigidification Test rigid structures to see which ones have retained active conformation

1 © Methods - Introduce rigid functional groups 4.9 Rigidification

1 © Important binding groups Rigid Rigid Rigid Examples 4.9 Rigidification Inhibits platelet aggregationAnalogues

1 © Examples - Combretastatin (anticancer agent) 4.9 Rigidification More active Less activeRotatablebond

1 © Methods - Steric Blockers 4.9 Rigidification Flexible side chain Coplanarity allowed Orthogonal rings preferred Introduce steric block Introduce steric block

1 © Steric clash Steric Blockers - Examples 4.9 Rigidification Increase in activity Active conformation retained Serotonin antagonist Introduce methyl group

1 © Steric clash Steric Blockers - Examples 4.9 Rigidification D 3 AntagonistInactive Active conformation disallowed