1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 1 © O NMe HO MORPHINE

10. 1 © O NMe HO MORPHINE IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

11. 1 © O NMe HO MORPHINE IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

12. 1 © N HO ANALGESIC PHARMACOPHORE FOR OPIATES

13. 1 © MORPHINE O NMe HO NMe HO LEVORPHANOL NMe HO METAZOCINE CH 3 H3CH3C

14. 1 © MORPHINE O NMe HO NMe HO LEVORPHANOL NMe HO METAZOCINE CH 3 H3CH3C

15. 1 © O NMe HO

16. 1 ©

17. 1 © O N Ar

18. 1 © O N Ar 11.3 o 150 o 18.5 o 7.098 A 2.798 A 4.534 A

19. 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

20. 1 © Salbutamol(Ventolin)(Anti-asthmatic) Adrenaline Propranolol (  -Blocker) 4.1 Vary Alkyl Substituents

21. 1 ©  -Adrenoceptor H-Bonding region H-Bonding region H-Bonding region Van der Waals bonding region Ionic bonding region

22. 1 © ADRENALINE  -Adrenoceptor

23. 1 ©

24. 1 ©  -Adrenoceptor ADRENALINE

25. 1 © SALBUTAMOL

26. 1 ©

27. 1 ©  -Adrenoceptor SALBUTAMOL

28. 1 © SALBUTAMOL

29. 1 © SALBUTAMOL

30. 1 © SALBUTAMOL

31. 1 © SALBUTAMOL

32. 1 © SALBUTAMOL

33. 1 © SALBUTAMOL

34. 1 ©

35. 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

36. 1 © 4.1 Vary Alkyl Substituents Methods

37. 1 © Example : ACE Inhibitors 4.3 Extension - Extra Functional Groups EXTENSION Hydrophobic pocket Binding site Binding site Hydrophobic pocket Vacant

38. 1 © Example 4.5 Ring Expansion / Contraction Binding regions Binding site Vary n to vary ring size

39. 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)

40. 1 © Methods : Retain pharmacophoreRetain pharmacophore Remove unnecessary functional groupsRemove unnecessary functional groups 4.8 Simplification

41. 1 © Methods: Remove asymmetric centresRemove asymmetric centres 4.8 Simplification

42. 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

43. 1 ©

44. 1 ©

45. 1 ©

46. 1 ©

47. 1 ©

48. 1 © Target binding site Rotatable bonds

49. 1 © Target binding site Rotatable bonds

50. 1 © Target binding site Rotatable bonds

51. 1 © Target binding site Rotatable bonds

52. 1 © Target binding site Rotatable bonds

53. 1 © Target binding site Rotatable bonds

54. 1 © Target binding site Rotatable bonds

55. 1 © Target binding site Rotatable bonds

56. 1 © Target binding site Rotatable bonds

57. 1 © Target binding site Rotatable bonds

58. 1 © Target binding site Rotatable bonds

59. 1 © Different binding site - side effects Rotatable bonds

60. 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

61. 1 © 4.9 Rigidification RECEPTOR 1 RECEPTOR 2

62. 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

63. 1 © Examples - Combretastatin (anticancer agent) 4.9 Rigidification More active Less activeRotatablebond

64. 1 © Steric clash Steric Blockers - Examples 4.9 Rigidification Increase in activity Active conformation retained Serotonin antagonist Introduce methyl group