1. SAR Antidiabetic Agents X = O, S, or N

2. SAR Diuretics (2 types) hydrochlorothiazides R 2 is an electrophilic group high ceiling type

4. somatostatin agonistscaffold peptidomimetic

5. Ionic Interaction Basic groups, e.g., His, Lys, Arg (cationic) Acidic groups, e.g., Asp, Glu (anionic) Figure 3.1  G° ≈ -5 kcal/mol

6. Hydrogen Bonding Type of dipole-dipole interaction between H on X-H (X is an electronegative atom) and N, O, or F Figure 3.3  G° ≈ -3 to -5 kcal/mol

7. Conformationally rigid analog (ring-chain transformation) Less potent; therefore flexibility is important Need to separate agonist and antagonist properties - structures too similar to histamine.

8. Consider pharmacodynamics Imidazole ring can exist in 3 forms Figure 3.25

9. Hammett Study of Electronic Effect of Side Chain favored for R = e - -withdrawing favored for R = e - -donating pK a of imidazole = 6.80 pK a of imidazole in histamine = 5.90 Therefore, side chain is e - -withdrawing, favoring 3.72a. pK a of imidazole in burimamide = 7.25 Therefore, side chain is e - -donating, favoring 3.72c. Need to make side chain e - -withdrawing.

10. PLP Figure 4.5 PLP bound at active site abbreviated structure

11. First Step in All PLP-Dependent Reactions From here all of the PLP reactions occur Scheme 4.14

12. PLP Racemases All steps are reversible K eq = 1 Scheme 4.15

13. Decarboxylases Scheme 4.16

14. First Half Reaction of Aminotransferases Scheme 4.18

15. Second Half Reaction of Aminotransferases Scheme 4.19

16.  -Elimination When X is a leaving group, elimination can occur. Scheme 4.20

17. The carbon atom that is transferred is derived from serine in a PLP-dependent  - cleavage reaction. atom to be transferred Scheme 4.22

18. N 5,N 10 -Methylenetetrahydrofolate can be oxidized by a NADP + - dependent enzyme to give N 5,N 10 -methylenyltetrahydrofolate. Scheme 4.24 hydrolysis gives N 10 -formyltetrahydrofolate N 5 -formyltetrahydrofolate

19. Mechanism for P450-Catalyzed Hydroxylation Scheme 4.35 high-energy iron-oxo species

20. Some General P450 Mechanisms Hydroxylation radical lifetime is very short Scheme 4.36

21. Sulfoxidation Epoxidation Scheme 4.37 Scheme 4.38

22. Mechanism of Action Function of Zn ++ cofactor Figure 5.5 May be similar to carboxypeptidase A, another Zn ++ -dependent peptidase.

23. Binding of Enalaprilat to ACE additional binding interactions enalaprilat Figure 5.9 Poorly absorbed orally - remedied by using ethyl ester (at arrow) (enalapril) which is hydrolyzed by esterases to give enalaprilat (a prodrug).

24. Hypothetical Mechanism of Adenosine Deaminase pentostatin mimics this 2-deoxyinosine 2-deoxyadenosine Scheme 5.8

25. Multisubstrate Analog N-Phosphonoacetyl-L-Asp (PALA) Aspartate transcarbamylase - de novo biosynthesis of pyrimidines carbamoyl phosphate isostere - no longer a leaving group, mimics phosphate N-carbamoyl-L-Asp PALA tumor cells acquired ability to utilize preformed circulating pyrimidine nucleosides increased carbamoyl phosphate increased aspartate transcarbamylase Tumor resistance: Scheme 5.9

26. Aspirin causes specific acetylation of active site Ser-530. Scheme 5.17

27. Mechanism of Aminotransferases Scheme 4.18

28. Mechanism of Inactivation of GABA-AT by Vigabatrin Scheme 5.21 30% 70% vigabatrin Michael addition electrophile

29. Mechanism of Decarboxylases Scheme 4.16

30. Product-Derived Mechanism-Based Inactivator  -difluoromethyl putrescine Scheme 5.25

31. Proposed Mechanism of MAO B by Selegiline Scheme 5.27 selegiline

32. Mechanism of Thymidylate Synthase Scheme 5.29 dihydrofolate reductase tetrahydrofolate

33. Mechanism of Inactivation of Thymidylate Synthase by 5-Fluoro-2-deoxyuridylate Scheme 5.30

34. The nitrogen atom is conjugated with the cyclohexadienone which lowers the reactivity. Scheme 6.6

35. Heme-dependent Mixed Function Oxidase Scheme 4.35 Oxidizing agent Reducing agent Activated coenzyme

36. Mechanism for Arene Oxide Formation and Aromatic Hydroxylation Scheme 7.4 (favored over a)

37. Rearrangement of Arene Oxide to Arenol Called the NIH shift Scheme 7.6

38. Competing with the NIH Shift Scheme 7.7 deprotonation The more stabilized the carbocation intermediate, the less favored is a for hydride shift - more deprotonation.

39. NIH Shift with Groups Other than H Scheme 7.8 p-chloroamphetamine

40. Toxic Product of Alkene Oxygenation Scheme 7.14 aflatoxin B 1 DNA adduct

41. Reductive Reactions Table 7.6

42. Reductive Dehalogenation Scheme 7.43 Cytochrome P450 in the absence of O 2 May be the cause for Halothane hepatitis