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SAR Antidiabetic Agents

SAR Antidiabetic Agents. X = O, S, or N. SAR Diuretics (2 types). hydrochlorothiazides R 2 is an electrophilic group. high ceiling type. somatostatin agonist. scaffold peptidomimetic. Ionic Interaction. Basic groups, e.g., His, Lys, Arg (cationic) Acidic groups, e.g., Asp, Glu (anionic).

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SAR Antidiabetic Agents

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  1. SARAntidiabetic Agents X = O, S, or N

  2. SARDiuretics (2 types) hydrochlorothiazides R2 is an electrophilic group high ceiling type

  3. somatostatin agonist scaffold peptidomimetic

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

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

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

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

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

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

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

  11. PLP Racemases Scheme 4.15 All steps are reversible Keq = 1

  12. Decarboxylases Scheme 4.16

  13. First Half Reaction of Aminotransferases Scheme 4.18

  14. SecondHalf Reaction of Aminotransferases Scheme 4.19

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

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

  17. N5 ,N10-Methylenetetrahydrofolate can be oxidized by a NADP+-dependent enzyme to give N5 ,N10-methylenyltetrahydrofolate. Scheme 4.24 hydrolysis gives N10-formyltetrahydrofolate N5-formyltetrahydrofolate

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

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

  20. Epoxidation Scheme 4.37 Sulfoxidation Scheme 4.38

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

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

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

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

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

  26. Mechanism of Aminotransferases Scheme 4.18

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

  28. Mechanism of Decarboxylases Scheme 4.16

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

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

  31. Mechanism of Thymidylate Synthase Scheme 5.29 dihydrofolate reductase tetrahydrofolate

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

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

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

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

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

  37. 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.

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

  39. Toxic Product of Alkene Oxygenation Scheme 7.14 aflatoxin B1 DNA adduct

  40. Reductive Reactions Table 7.6

  41. Reductive Dehalogenation Scheme 7.43 Cytochrome P450 in the absence of O2 May be the cause for Halothane hepatitis

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