1. 1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 1: Section 10.1 (SAR)

2. 1 © Contents 1.Introduction to drug design & development 2.Structure Activity Relationships (SAR) (2 slides) 2.1.SAR on Alcohols (2 slides) 2.2.SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N) (4 slides) 2.3.SAR on Quaternary Ammonium Salts (R4N+) 2.4.SAR on Aldehydes and Ketones (2 slides) 2.5.SAR on Esters (2 slides) 2.6.SAR on Amides (3 slides) 2.7.SAR on Carboxylic Acids (3 slides) 2.8.SAR on Aromatic Rings and Alkenes (2 slides) 2.9.Miscellaneous Functional Groups in Drugs 2.10. SAR of Alkyl Groups (2 slides) [26 slides]

3. 1 © 1. Introduction to drug design & development Stages 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials

4. 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

5. 1 © NOTES ON ANALOGUES Modifications may disrupt binding by electronic / steric effectsModifications may disrupt binding by electronic / steric effects Easiest analogues to make are those made from lead compoundEasiest analogues to make are those made from lead compound Possible modifications may depend on other groups presentPossible modifications may depend on other groups present Some analogues may have to be made by a full synthesis (e.g. replacing an aromatic ring with a cyclohexane ring)Some analogues may have to be made by a full synthesis (e.g. replacing an aromatic ring with a cyclohexane ring) Allows identification of important groups involved in bindingAllows identification of important groups involved in binding Allows identification of the pharmacophoreAllows identification of the pharmacophore 2. Structure Activity Relationships (SAR)

6. 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

7. 1 © Possible effect of analogues on binding (e.g. ether) 2.1 SAR on Alcohols X Binding site X= N or O X Binding site H No interaction as HBDNo interaction as HBA steric shield O CH 3 Ether analogue O CH 3 Ether analogue

8. 1 © Possible binding interactions if amine is ionised 2.2 SAR on 1 o, 2 o & 3 o Amines (RNH 2, RNHR, R 3 N) Ionic H-Bonding HBD X Binding site X= N or O CO 2 - Binding site NH 2 R Drug + N H R2R2 + R 3 NH acts as a strong HBD +

9. 1 © Possible binding interactions for free base 2.2 SAR on 1 o, 2 o & 3 o Amines (RNH 2, RNHR, R 3 N) H-Bonding HBD X Binding site X= N or O X Binding site H HBA N H Drug R N R H Note: 3 o Amines are only able to act as HBA’s - no hydrogen available to act as HBD

10. 1 © Analogues of 1 o & 2 o amines Effect on binding 2.2 SAR on 1 o, 2 o & 3 o Amines (RNH 2, RNHR, R 3 N) CO 2 - Binding site No interaction NCH 3 O R Amide analogue 1 o and 2 o amines are converted to 2 o and 3 o amides respectively1 o and 2 o amines are converted to 2 o and 3 o amides respectively Amides cannot ionise and so ionic bonding is not possibleAmides cannot ionise and so ionic bonding is not possible An amide N is a poor HBA and so this eliminates HBA interactionsAn amide N is a poor HBA and so this eliminates HBA interactions Steric effect of acyl group is likely to hinder NH acting as a HBD (2 o amide)Steric effect of acyl group is likely to hinder NH acting as a HBD (2 o amide)

11. 1 © Analogues of 3 o amines containing a methyl substituent 2.2 SAR on 1 o, 2 o & 3 o Amines (RNH 2, RNHR, R 3 N)

12. 1 © Possible binding interactions Analogues Full synthesis of 1 o -3 o amines and amides 2.3 SAR on Quaternary Ammonium Salts (R 4 N + ) CO 2 - Binding site Ionic bonding NR 3 Drug + NR 3 Drug + Induced dipole interactions Binding site ++ --

13. 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

14. 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

15. 1 © Possible binding interactions H-bonding as HBA by either oxygen Analogues Hydrolysis splits molecule and may lead to a loss of activity due to loss of other functional groups - only suitable for simple esters.Hydrolysis splits molecule and may lead to a loss of activity due to loss of other functional groups - only suitable for simple esters. Hydrolysis leads to a dramatic increase in polarity which may influence ability of analogue to reach target if in vivo tests are usedHydrolysis leads to a dramatic increase in polarity which may influence ability of analogue to reach target if in vivo tests are used Reduction to alcohol removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction can be difficult to do if other labile functional groups are presentReduction to alcohol removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction can be difficult to do if other labile functional groups are present 2.5 SAR on Esters

16. 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

17. 1 © Possible binding interactions The nitrogen of an amide cannot act as a HBA - lone pair interacts with neighbouring carbonyl groupThe nitrogen of an amide cannot act as a HBA - lone pair interacts with neighbouring carbonyl group Tertiary amides unable to act as HBD’sTertiary amides unable to act as HBD’s 2.6 SAR on Amides Binding site (X= N or O) X H X HBA HBD N Drug H O R N H O R

18. 1 © Analogues Hydrolysis splits molecule and may lead to loss of activity due to loss of other functional groups - only suitable for simple amides.Hydrolysis splits molecule and may lead to loss of activity due to loss of other functional groups - only suitable for simple amides. Hydrolysis leads to dramatic increase in polarity which may affect ability of analogue to reach target if in vivo tests are doneHydrolysis leads to dramatic increase in polarity which may affect ability of analogue to reach target if in vivo tests are done Reduction to amine removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction may be difficult to do if other labile groups are presentReduction to amine removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction may be difficult to do if other labile groups are present 2.6 SAR on Amides

19. 1 © N-Methylation prevents HBD interaction and may introduce a steric effect that prevents an HBA interactionN-Methylation prevents HBD interaction and may introduce a steric effect that prevents an HBA interaction No binding as HBD X N CH 3 O R Analogue binding site Binding of O as HBA hindered X H N CH 3 R O steric shield AnalogueAnalogues

20. 1 © Possible binding interactions as free acid 2.7 SAR on Carboxylic Acids Binding site (X= N or O) X H HBA Binding site (X= N or O) X H HBA C O H Drug O C O H O Binding site (X= N or O) X H C O Drug O HBD

21. 1 © Possible binding interactions as carboxylate ion 2.7 SAR on Carboxylic Acids Binding site (X= N or O) X H HBA Binding site (X= N or O) NHR 2 + Ionic bonding O C O Drug - O C O - Charged oxygen atoms are strong HBA’sCharged oxygen atoms are strong HBA’s Group could interact both as an ion and as a HBA at the same timeGroup could interact both as an ion and as a HBA at the same time

22. 1 © Possible analogues Possible effects Reduction removes carbonyl oxygen as potential HBA and prevents ionisationReduction removes carbonyl oxygen as potential HBA and prevents ionisation Esterification prevents ionisation, HBD interactions and may hinder HBA by a steric effectEsterification prevents ionisation, HBD interactions and may hinder HBA by a steric effect 2.7 SAR on Carboxylic Acids No ionic bonding possible NHR 2 binding site C O O Analogue CH 3 + H-Bonding hindered X H steric shield C O O Analogue CH 3

23. 1 © Possible binding interactions Possible analogues 2.8 SAR on Aromatic Rings and Alkenes binding site Drug R R hydrophobicregion vdw hydrophobicpocket

24. 1 © Possible effects on binding 2.8 SAR on Aromatic Rings and Alkenes binding site hydrophobicregion hydrophobicpocket Analogue H H No fit Analogue R R H H ‘Buffers’

25. 1 © Acid chlorides - too reactive to be of useAcid chlorides - too reactive to be of use Acid anhydrides- too reactive to be of useAcid anhydrides- too reactive to be of use Alkyl halides-present in anticancer drugs to form covalent bonds with nucleophiles in targetAlkyl halides-present in anticancer drugs to form covalent bonds with nucleophiles in target Aryl halides -commonly present. Not usually involved in binding directlyAryl halides -commonly present. Not usually involved in binding directly Nitro groups -sometimes present but often toxicNitro groups -sometimes present but often toxic Alkynes -sometimes present, but not usually important in binding interactionsAlkynes -sometimes present, but not usually important in binding interactions Thiols -present in some drugs as important binding group to transition metals (e.g. Zn in zinc metalloproteinases)Thiols -present in some drugs as important binding group to transition metals (e.g. Zn in zinc metalloproteinases) Nitriles - present in some drugs but rarely involved in bindingNitriles - present in some drugs but rarely involved in binding Functional groups may be important for electronic reasons (e.g. nitro, cyano, aryl halides)Functional groups may be important for electronic reasons (e.g. nitro, cyano, aryl halides) Functional groups may be important for steric reasonsFunctional groups may be important for steric reasons (e.g. alkynes) 2.9 Miscellaneous Functional Groups in Drugs

26. 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

27. 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