Non-Steroidal Anti-inflammatory Drugs NSAIDs
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Non-Steroidal Anti-inflammatory Drugs NSAIDs

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Non-Steroidal Anti-inflammatory Drugs. ???????????????????????????????? ?????????????????????????????????????????????? (analgesic)??????????????????????????????????????????????????????? (anti-inflammatory)??????????????????? (antipyretic)???????????? NSAIDs;Rhematoid arthritis (RA)Osteoarthritis (OA)Ankylosing spondylitis (AS).
Non-Steroidal Anti-inflammatory Drugs NSAIDs

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1. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) Medicinal Chemistry Taweesak Dhammaraj

2. Non-Steroidal Anti-inflammatory Drugs ???????????????????????????????? ??????????????????? ??????????????????????????? (analgesic) ??????????????????????????????????????????????????????? (anti-inflammatory) ??????????????????? (antipyretic) ???????????? NSAIDs; Rhematoid arthritis (RA) Osteoarthritis (OA) Ankylosing spondylitis (AS)

3. Biosynthesis of Prostaglandins

4. Biosynthesis of Prostaglandins (???)

5. COX-1 ????????????????????????????????????????????? ???????????????????????? ? ???????????????????????? PGs ????????????????????????? (homeostasis maintenance) ???? platelet aggregation ?????? blood flow ??????????????????? ???????????????????? gastric secretion ?????????? COX-1 ???????????????????????????? ? ???? GI side effect

6. COX-2 ????????????????????????????? ???????????? ?? ???? ?????? ????????????????????????????? neoplasia ??? ???????????????? ?????????????????????????????????????????

7. Classification 1. Non-steroidal Anti-inflammatory Agents 1.1 Non-selective COX-1 Inhibitors 1.2 Selective COX-2 Inhibitors 2. Antipyretic Analgesics

8. 1. Anti-inflammatory Agents 1.1 Non-selective Cycloxygenase (COX) -1 Inhibitors 1.1.1 Salicylates 1.1.2 Arylalkanoic Acids 1.1.2.1 Aryl- and Heteroarylacetic Acids 1.1.2.2 Aryl- and Heteroarylpropionic Acids 1.1.3 N-Arylanthranilic Acids (Fenamic Acids) 1.1.4 Oxicams 1.1.5 Phenylpyrazolones 1.2 Selective COX-2 Inhibitors

9. Mechanism ???????????????????? plostaglandins (PGs) ????????????????????????? Cyclooxygenase Aspirin ???? NSAIDs ?????????????????????????????????????? COX ??? irreversible ????????????? acetyl group ??? Serine residue (?? ?OH group) ????????? COX ???? acetyl group ????????? ?OH group ???? covalent bond ???????????? ester ????????????? ? ??????? ???????????????????? PGs ??? irreversible

10. General Structure of NSAIDs Acidic functional group ???? ?COOH; ????????????????????????? ????????????? ionic bond ?????????? arginine residue (???????? 120) ????????? COX ???????????????????? Aromatic ring ???? heteroaromatic ring (??????????????????? Acidicfunctional group); ???? hydrophobic interaction ???? wandervaal force ?????????????? flat area ????????? COX ?????????????????? double bond ???????????? 5 ??? 8 ??? arachidonic acid

11. General Structure of NSAIDs (???) ??????????????????????? lipophilic part ???? alkyl chain ???? aromatic ring ?????????????????????????????????? ????????????????????????? COX ??????????? ???????????? hydrophobic interaction ???? wandervaal force ??????? lipophilic part ????????????????????????????????????????? double bond ???????????? 11 ??? arachidonic acid

12. ????????????????? Indomethacin ?????????? COX

13. Physicochemical and Pharmacokinetic Properties of NSAIDs ??????????????? Strong organic acid; pKa ~ 3-5 ????????????????????????? physiological pH (~7.4) ???????????? plasma protein binding ????????? (~90-99%) ??????????????? ionic bond ?????????????????????????? ???????????????????????????? drug interaction ??? NSAIDs ????????????? plasma protein binding ????????????????????? carboxylic group (-COOH) ?????? metabolize ?????????? glucuronide conjugation (phase II) ????????

14. Glucuronide Conjugation

15. GI Side Effect NAIDs ????????????????????????????????????????????????????? 2 ???????? 1. ?????????????????????????????????????????????????????????????????????????????????? 2. ???????????????????? PGs ?????????????????? ???? PGs ??????? cytoprotective effect

16. 1.1.1 Salicylic acid

17. Salicylate Salts

18. Salicylate ???????? salts ????????????????????????????????????????????? ?????????????????????????????????????? ???????????????????????????????????????? aqeous solution ??????????????????????????????? ?????????????????????????????????? ? ????????????????????? Na+ ??? Mg2+ ??????????????????????????????? ???????????? Sodium salicylate, Magnesium salicylate, Choline salicylate ??? Sodium thiosalicylate

19. Aspirin or Acetylsalicylic Acid

20. Mechanism of action of Aspirin

22. Aspirin (Acetylsalicylic Acid) ?????????????????????? COX ??? irreverseble ????????????????????????????????? ????????????? hydrolysis ?????????????? salicylic acid ??? acetic acid ????????????????????????????? aspirin ???????? aqeous solution ??? ????????????????????????????????????????? ??????????????????????? ?????? hydrolysis ???????????????? plasma esterase ?????????? acetylation ????????????????????? (circulating protein) ???????? Antigen ?????????? hypersensitivity ????????????????????????????? arthritis ???????????????????????????? transient ischemic attack ??? myocardial infarction

23. Salicylamide

24. Salicylamide ???????????? analgesic ??? antipyretic ????????????? anti-inflammatory ????????????????????? salicylates ?????????? ??????? gastric irritation ??????????????? non-polar ?????????????????????????????????? salicylates ???????????????????????????????????????? sedative drowsiness ?????????????????????????? ??????????????????????

25. Salsalate

26. Diflunisal

27. 1.1.2 Arylalkanoic Acids ??????????? 2 ????? 1.1.2.1 Aryl- and Heteroarylacetic Acids 1.1.2.2 Aryl and Heteroarylpropionic Acids (?-profen?)

28. SAR

29. SAR ????????????? acidic function group ???? carboxylic acid ??? enolic functional group ???????????????????? ??????????? Cationic residue ????????? COX Acidic functional group ????????????????????????????????????????? flat surface (aromatic center) ????? C 1 atom ?????????? ????????????????????????????? ??????????????? C 1 atom ???????????????? ???????????????????????? lipophilic part ???????????????????????? aromatic (heteroaromatic) center ??????????????????????????????????

30. SAR (???) ??????? methyl group ?? C-atom (?-C) ?????????????????? acidic functional group ??? aromatic ring ????????????????????????????????????????????????????? ????????????????????????????????? ?-methyl group ?????? ?-profen? ????????????????????????? 2-substituted propionic acid ?????????????????????????????????? methyl group ??????????????????????????? ???????? chiral center ???????? ???????????????????????????? (S)-(+)-enantiomer ???????????????????? racemic mixture ????????? R-enantiomer ????????????????? S-enantiomer ????????????

31. 1.1.2.1 Aryl- and Heteroarylacetic Acids Indomethacin Sulindac Tolmetin (Sodium) Diclofenac (Sodium) Etodolac Nabumetone

32. Indomethacin

33. Indomethacin ????????????????????????????? ????????????????????????? ????? RA OA AS ?????????????????????? ???????????????????? ductus arteriosus ?????? ???????????????????????????????????? ????????????????????????????? bleeding ????????? CNS toxicity (ranging form headaches to psychoses and suicidal tendencies) ?????????????????????????????????? metabolite ??????????? serotonin Bone marrow depression; aplastic anemia and thrombocytopenia ?????????????????????????????????? ???????????????? 1-2 ?????????? T1/2 = 4.5 ???????

34. Metabolism of Indomethacin

35. Sulindac

36. Sulindac ??????????????????????? indomethacin ????????????? ???????????????? bioisosteric change ????????????? indene ring (bioisosteric ??? indole ring ??? indomethacin) Stereoisomer ??? double bond; ????????? (Z)-isomer ???????????????????????????????? (E)-isomer ???????????????? (Z)-isomer ?? conformation ???????????active conformation ??? indomethacin ??? active site ??? COX ???????????????????? pro-drug ??????????????????????? metabolize ??????? active sulfide metabolite (major metabolite) ?????????????????? aspirin ??? 8 ???? ???????????????????????????? Indomethacin ??????????????????????

37. Sulindac ?????????????????????? sulfoxide ????????????????????? prostaglandins ?????????????????? ???????? Sulindac ???????????????? GI ??????? ???????????? bleeding ??? ulceration Active metabolite ?? T1/2 ???? 2 ??????? parent compound (16 hrs and 8 hrs) ?????????????????????????? ??????? metabolite ???????? serotonin ??????????????????? CNS ???? Sulindac ???????????????????? Indomethacin ??? NSAIDs ??????? ? ???????????????????? ???? ????????????? GI (nausea, dyspepsia, diarrhea) ????? CNS (dizziness and headache) ??? ??????? ???????????? ????????????? RA OA AS acute gout ??? ????????????????????????

38. Metabolism of Sulindac

39. Edotolac Analogue ??? Indomethacin ???????????????????????????? ?????????????????? ??? ??????????? (uricosuric action) ????? RA OA ??? ????????????????????????? ??????????????????????????????????????????????????? ???????????????????????????????????? T1/2 ~ 7 ???????

40. Tolmetin (Sodium)

41. Tolmetin ???????? RA OA ??? AS ??????????????????????????????? ????????????????????????? phase I oxidation ?????????????????? ??????? dicarboxylic compound ??????? glucuronide conjugation ?????????????? ??????? T1/2 ???????? 5 ???????

42. Metabolism of Tolmetin

43. Ketorolac (Tromethamine) ??????????????????? Tolmetin ?? T1/2 ????????????????????????????? dicarboxylic metabolite (4-6 ???????) ?????????????????????????? oral ??? IM ?????????????????????? ????????????????????????????????????? ?????????????????????? narcotic analgesic ??? (?????? 15-30 mg ??? ketorolac ????????? 12mg ??? morphine)

44. Diclofenac (Sodium) ????????????? o-chloro group ????????? anilino-phenyl ring ????????????????????? phenylacetic acid ??????????? conformation ????????????????????? active site ?????????? COX ????????????????????????????????????????????????? ????????????????????? 1.5-2.5 hrs. ?????? plasmaprotein ?????? ???????? RA, OA ??? ankylosing spondylitis

45. Nabumetone

46. Nabumetone ????????????????????????????? non-acidic pro-drugs ??? metabolize ????????????????????????? ??????? major active metabolite ??? 6-methoxynaphthalene-2-acetic acid (6MNA) ???????????????????????????? PGs ?? joints ?? T1/2 ~ 24 ??????? ????????????????????????????????????????????????????????????? ??????? pro-drug ?????????????????????????? PGs ?? gastric mucosa ?????????????????????????????????????????? ?????????????????????????? NSAIDs ??????? ? ????????????????????????????????????????????????????????? ???????? RA ??? OA

47. 1.1.2.2 Aryl- and Heteroarylpropionic Acids Ibuprofen Fenoprofen (Calcium) Ketoprofen Naproxen Flurbiprofen Ketorolac (Tromethamine) Oxaprozin

48. ?????????????????????????? COX-1 ??????? ??? naproxen ?????????????????? COX-2 ?????????????????????????? ????????????? RA OA ???AS ???????????????????????????????? ??????????????????????????????????? ??????????????????????????????????????????? ??????????????????????????????????????? salicylates ??????????????? thrombocytopenia headache dizziness ??? fluid retention edema ??????????????????????????????????????? ???????????????? 1-2 ??????? ?????? ketoprofen ER ??? Naproxen ????????????????????????????? ?????????????? plasma protein ?????????? 99% ?????????? (?????? flurbiprofen ??? naproxen ) ?? T? ???????? 4 ???????

49. Stereochemistry ??????????? ?-methyl group ????????? acetic acid ??????????????????? 1 chiral center Stereoisomer ??????????????????????????? S-(+)-enantiomer ??? R-(-)-enantiomer S-(+)-enantiomer ????????????????????????????????? R-(-)-enantiomer ?? in vitro ??? R-(-)-enantiomer ????????????????? S-(+)-????????? (in vivo)??????????????????? isomerization ???????????? ????? R-isomer ??????????? S-isomer ???????????? ??????????????????? ??????????? racemic mixture ????????????

50. Isomerization

54. ???????????? Anthranilic Acid (Fenamic Acid)

55. ?????????????????????????????????????? ?????????????????? Meclofenamate ????? RA (as secondary agent) ??? Mefenamic acid ??????????? Dysmennorhea ???????????????? GI (N/V, diarrhea, ulceration, headache, drowsiness ??? hematopoietic toxicity) ??????????????????? ????????????????????????? ???????????????? 2-4 ???????(Meclofenamate ??????????????????????????? non-polar ???????) ?????? plasma protein ?????????? 99% N-Anthranilic Acid

56. SAR ??????????????????? anthranilic acid ?????????????????????? ???????????? N-aryl ring ??????????????????????? ??????????????????? N-aryl ring ????????? 2? 3? ??? 6? ????????????????????????????????????? ???????????????? N-aryl ring ???????????????? anthranilic ring ??????????? active site ?????????????????????????? Meclofenamic acid ??????????????????????????? Mefenamic acid ~ 25 ????; ????????? Meclofenamic acid ?? ortho- substituents 2 ???? ?????????????? N-aryl ring ?????????? anthranilic ring ?????????????????? Mefenamic acid ?????? ortho-substituents ??????????????

57. 1.1.4 Oxicams ?????? Piroxicam ??? Meloxicam ??????? NSAIDs ??????? enolic acid ??????????????? 4-hydroxy-1,2-benxothiazine carboxamides ????????????????????????????????????????? ????????????????????????????????????? ???????????????? 3-5 ??????? ?????????????? carboxylic group ?????????? glucuronide conjugaton ????? ?????????????? T1/2 ?????? (20-50 ???????) ???????????????????????? Meloxicam ??????? selective COX-2 inhibitors

58. SAR

60. ????????? piroxicam ??? meloxicam?? R gr. ?? amide ???? heterocyclic ring ????? heteroatom (N-atom) ????????????? ortho- ??? amide group ????? hydrogen atom ?? amide N-atom =>?????????????????????????????????????????????????????????????????????????????????????????????????????????????? R gr. ???? aromatic ring ??? ????? H- ?? amide N-atom

61. Stabilization of Enolate Anion

62. Piroxicam

63. Meloxicam

64. 1.1.5 Phenylpyrazolones ?????? Phenylbutazone ??? Oxyphenbutazone ????????????????????????????? ????????????????????? ???????? RA ??? OA ??????????????? GI irritation ????????????????????????? Na+ ??? blood dyscrasia ??????????????? 7-10 ??????????????????????

65. ???????????? phenylbutazone

66. Phenylbutazone

67. Oxyphenbutazone

68. 2. Selective COX-2 Inhibitors NSAIDs ??????????????????? COX-1, COX-2 ??? thromboxane synthetase ?????????????????????? ????? - ?? gastric mucosal protection ???????????????????????????????????????????????? - stress-induced decreased renal perfusion - ??????????????????????? thromboxane (TBX) ??????????? platelet aggregation ????????????????????????? bleeding NSAIDs ????????????????????????????? COX-1 ??????????????????? gastrointestinal bleeding ??? renal toxicity ??????? selective COX-2 inhibitors

69. Selective COX-2 Inhibitors ???????????????????? ?????????????? ???????? OA RA acute pain ??? Dysmenorrhea ????????????? 2 ???????????????????? Sulides ???? Nimesulide Coxibs ???? Celecoxib Rofecoxib Valdecoxib ??? Parecoxib

70. Nimesulide

71. ???????????? Coxibs ???????????????????????????????????? diaryl-5-membered heterocyclic compond ?????? Celecoxib Rofecoxib Valdecoxib Parecoxib

74. Active binding sites of COX-1 and COX-2 active binding site COX-2 ????????????????? COX-1 ???????????????????????????? 523 ?? COX-2 ???? valine ????? COX-1 ???? isoleucine (valine ????????? R- group ??????????? isoleucine) ???????????????????????????????????????????? COX-2 active binding site ?????????????? COX-2 ????????? COX-1 (???????? COX-1??????????????????? steric effect ??? isoleucine residue) ?? COX-1 ??????? isoleucine ?????????????????????????? active site ????????????????????????????? rigid ??? bulky ???????? sulfonamide ???? sulfonyl side chain ?????????????????????????????????????? selective cox-2 inhibitors

75. COX-1 and COX-2

76. Flurbiprofen; Non-Selective COX inhibitors

77. ????????????? COX-1 ??? COX-2 ??? Non-selective COX inhibitor

78. Celecoxib;Selective COX-2 inhibitors

79. ????????????? COX-1 ??? COX-2 ??? Selective COX-2 inhibitor

80. 2. Antipyretic Analgesic ??????????????????????????????? ?????????????????????????? ???? Acetaminophenol (Acetanilide ??? Phenacetin; ????????????????????? ?????????????????????????) ?????????????????? Acetaminophen ????????????; ??????????????????????????????????????????? antagonist ???? bradykinin ?????? peripheral pain receptor ??????????????????????????????????? endogenous pyrogen ??? hypothalamic thermoregulatory centers ???????????????????????????????????????? ??????????????? PGs ????????????????????????????????????

81. acetaminophenol ???????????????????????? ??????????????????????????????? aspirin Acetaminophen ????????????? aqeous solution ??????? Aspirin ????????????????????????? liquid formulation ???? ? ???????????????????????????????

82. ????????? antipyretic analgesics

83. SAR p-aminophenol derivatives ????????????????????? aniline derivatives ?????????????????? p-aminophenol ???????????????????????? ??????? methyl- ??? propyl- group ??? phenolic hydroxyl group ????????????? (derivatives) ?????????????????????????????????????? ethyl group ???????????????????????????????????? nitrogen atom ???????????????? ???????????????????????????????????????????? amino group ????????????????????????????? ???? acetyl group ???????????????? amide ??? aromatic ring (acyl group ??? aromatic ring) ?????? hydrolysis ??????? ???????????????????????

84. Metabolism and Toxicity

85. Metabolism and Toxicity

86. Metabolic Intoxicification


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