1 © 2. Structure Activity Relationships (SAR) Alter, remove or mask a functional groupAlter, remove or mask a functional group Test the analogue for activityTest the analogue for activity Conclusions depend on the method of testing in vitro - tests for binding interactions with target in vivo - tests for target binding interactions and/or pharmacokineticsConclusions depend on the method of testing in vitro - tests for binding interactions with target in vivo - tests for target binding interactions and/or pharmacokinetics If in vitro activity drops, it implies group is important for bindingIf in vitro activity drops, it implies group is important for binding If in vivo activity unaffected, it implies group is not importantIf in vivo activity unaffected, it implies group is not important AIM - Identify which functional groups are important for binding and/or activity METHOD

1 © HBD 2.1 SAR on Alcohols Possible binding interactions Possible analogues X Binding site X= N or O O H Drug O H X Binding site H HBA Ether Ester Alkane

1 © Possible binding interactions Analogues 2.4 SAR on Aldehydes and Ketones Dipole-dipole interaction Binding site (X= N or O) X H H-BondingHBA O Drug Binding site O Drug

1 © Effect on binding Change in stereochemistry (planar to tetrahedral) May move oxygen out of range If still active, further reactions can be carried out on alcohol to establish importance of oxygen 2.4 SAR on Aldehydes and Ketones Binding site (X= N or O) X H H OH Alcohol analogue

1 © Esters are usually hydrolysed by esterases in the bloodEsters are usually hydrolysed by esterases in the blood Esters are more likely to be important for pharmacokinetic reasons i.e. acting as prodrugsEsters are more likely to be important for pharmacokinetic reasons i.e. acting as prodrugs 2.5 SAR on Esters Ester masking polar groups allowing passage through fatty cell membranes

1 © Possible interactions 2.10 SAR of Alkyl Groups hydrophobic slot binding site Drug CH 3 van der Waals interactions binding site hydrophobic ‘pocket’ Drug CH 3 H3CH3C

1 © Analogues Easiest alkyl groups to vary are substituents on heteroatomsEasiest alkyl groups to vary are substituents on heteroatoms Vary length and bulk of alkyl group to test space availableVary length and bulk of alkyl group to test space available 2.10 SAR of Alkyl Groups Drug Analogue

1 © 3. PHARMACOPHORE Defines the important groups involved in bindingDefines the important groups involved in binding Defines the relative positions of the binding groupsDefines the relative positions of the binding groups Need to know Active ConformationNeed to know Active Conformation Important to Drug DesignImportant to Drug Design Important to Drug DiscoveryImportant to Drug Discovery

1 © O NMe HO MORPHINE

1 © O NMe HO MORPHINE IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

1 © O NMe HO MORPHINE IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

1 © N HO ANALGESIC PHARMACOPHORE FOR OPIATES

1 © MORPHINE O NMe HO NMe HO LEVORPHANOL NMe HO METAZOCINE CH 3 H3CH3C

1 © MORPHINE O NMe HO NMe HO LEVORPHANOL NMe HO METAZOCINE CH 3 H3CH3C

1 © O NMe HO

1 ©

1 © O N Ar

1 © O N Ar 11.3 o 150 o 18.5 o A A A

1 © 4. DRUG DESIGN - OPTIMISING BINDING INTERACTIONS AIM - To optimise binding interactions with target To increase activity and reduce dose levels To increase activity and reduce dose levels To increase selectivity and reduce side effects To increase selectivity and reduce side effects STRATEGIES Vary alkyl substituentsVary alkyl substituents Vary aryl substituentsVary aryl substituents ExtensionExtension Chain extensions / contractionsChain extensions / contractions Ring expansions / contractionsRing expansions / contractions Ring variationRing variation IsosteresIsosteres SimplificationSimplification RigidificationRigidification REASONS

1 © Salbutamol(Ventolin)(Anti-asthmatic) Adrenaline Propranolol (  -Blocker) 4.1 Vary Alkyl Substituents

1 ©  -Adrenoceptor H-Bonding region H-Bonding region H-Bonding region Van der Waals bonding region Ionic bonding region

1 © ADRENALINE  -Adrenoceptor

1 ©

1 ©  -Adrenoceptor ADRENALINE

1 © SALBUTAMOL

1 ©

1 ©  -Adrenoceptor SALBUTAMOL

1 © SALBUTAMOL

1 © SALBUTAMOL

1 © SALBUTAMOL

1 © SALBUTAMOL

1 © SALBUTAMOL

1 © SALBUTAMOL

1 ©

1 © 4.1 Vary Alkyl Substituents Notes on synthetic feasibility of analogues Feasible to remove alkyl substituents on heteroatomsFeasible to remove alkyl substituents on heteroatoms and replace with other alkyl substituents Difficult to modify alkyl substituents on the carbon skeleton of a lead compound. Full synthesis is usually requiredDifficult to modify alkyl substituents on the carbon skeleton of a lead compound. Full synthesis is usually required

1 © 4.1 Vary Alkyl Substituents Methods

1 © Example : ACE Inhibitors 4.3 Extension - Extra Functional Groups EXTENSION Hydrophobic pocket Binding site Binding site Hydrophobic pocket Vacant

1 © Example 4.5 Ring Expansion / Contraction Binding regions Binding site Vary n to vary ring size

1 © Useful for SAR Replacing OCH 2 with CH=CH, SCH 2, CH 2 CH 2Replacing OCH 2 with CH=CH, SCH 2, CH 2 CH 2 eliminates activity Replacing OCH 2 with NHCH 2 retains activityReplacing OCH 2 with NHCH 2 retains activity Implies O involved in binding (HBA)Implies O involved in binding (HBA) 4.7 Isosteres and Bio-isosteres Propranolol (  -blocker)

1 © Methods : Retain pharmacophoreRetain pharmacophore Remove unnecessary functional groupsRemove unnecessary functional groups 4.8 Simplification

1 © Methods: Remove asymmetric centresRemove asymmetric centres 4.8 Simplification

1 © Methods: Simplify in stages to avoid oversimplificationSimplify in stages to avoid oversimplification 4.8 Simplification Simplification does not mean ‘pruning groups’ off the leadSimplification does not mean ‘pruning groups’ off the leadcompound Compounds usually made by total synthesisCompounds usually made by total synthesis Pharmacophore

1 ©

1 ©

1 ©

1 ©

1 ©

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Target binding site Rotatable bonds

1 © Different binding site - side effects Rotatable bonds

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 Test rigid structures to see which ones have retained active conformation

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

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