Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors

Journal of Medicinal Chemistry

Volumn 50, Issue 25, 2007, Pages 6367-6382

  Wey, Shiow Jyi ^a   Augustyniak, Michael E ^a   Cochran, Edward D ^a   Ellis, James L ^a   Fang, Xinqin ^a   Garvey, David S ^a   Janero, David R ^a   Letts, L Gordon ^a   Martino, Allison M ^a   Melim, Terry L ^a   Murty, Madhavi G ^a   Richardson, Steward K ^a   Schroeder, Joseph D ^a   Selig, William M ^a   Trocha, A Mark ^a   Wexler, Roseanne S ^a   Young, Delano V ^a   Zemtseva, Irina S ^a   Zifcak, Brian M ^a  

^a NitroMed Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [(4 CHLOROPHENYL)CARBONYL] 2 METHYL 3 [[N [3 (NITROOXY)PROPYL]CARBAMOYL]METHYL]INDOL 5 YL AMINOSULFONATE; 2 [1 (CYCLOHEXYLMETHYL) 5 METHOXY 2 METHYLINDOL 3 YL] N [3 (NITROOXY)PROPYL]ACETAMIDE; 2 [1 (CYCLOHEXYLMETHYL) 5 METHOXY 2 METHYLINDOL 3 YL]ACETIC ACID; 2 [1 (CYCLOHEXYLMETHYL) 5 METHOXY 2 METHYLINDOL 3 YL]ETHAN 1 OL; 2 [1 [(4 CHLOROPHENYL)CARBONYL] 5 HYDROXY 2 METHYLINDOL 3 YL] N (3 HYDROXYPROPYL)ACETAMIDE; 2 [1 [(4 CHLOROPHENYL)CARBONYL] 5 HYDROXY 2 METHYLINDOL 3 YL] N [3 (NITROOXY)PROPYL]ACETAMIDE; 2 [1 [(4 CHLOROPHENYL)CARBONYL] 5 HYDROXY 2 METHYLINDOL 3 YL]ACETIC ACID; 2 [1 [(4 CHLOROPHENYL)CARBONYL] 5 METHOXY 2 METHYLINDOL 3 YL] N (3 HYDROXYPROPYL)ACETAMIDE; 2 [1 [(4 CHLOROPHENYL)CARBONYL] 5 METHOXY 2 METHYLINDOL 3 YL] N [3 (NITROOXY)PROPYL]ACETAMIDE; 2 [5 METHOXY 2 METHYL 1 [[4 (METHYLSULFONYL)PHENYL]METHYL]INDOL 3 YL] N [3 (NITROOXY)PROPYL]ACETAMIDE; 2 [5 METHOXY 2 METHYL 1 [[4 (METHYLSULFONYL)PHENYL]METHYL]INDOL 3 YL]ACETIC ACID; 2 [6 CHLORO 1 [(4 CHLOROPHENYL)CARBONYL] 5 METHOXY 2 METHYLINDOL 3 YL] N [3 (NITROOXY)PROPYL]ACETAMIDE; 2 [6 CHLORO 1 [(4 CHLOROPHENYL)CARBONYL] 5 METHOXY 2 METHYLINDOL 3 YL]ACETIC ACID; 3 (2 BROMOETHYL) 1 (CYCLOHEXYLMETHYL) 5 METHOXY 2 METHYLINDOLE; 4 CHLOROPHENYL 3 [2 [[(3 HYDROXYPROPYL)SULFONYL]AMINO]ETHYL] 5 METHOXY 2 METHYLINDOL KETONE; 4 CHLOROPHENYL 5 METHOXY 2 METHYL 3 [2 [[[3 (NITROOXY)PROPYL]SULFONYL]AMINO]ETHYL]INDOLYL KETONE; CELECOXIB; CYCLOOXYGENASE 2 INHIBITOR; ETHYL 2 [1 (CYCLOHEXYLMETHYL) 5 METHOXY 2 METHYLINDOL 3 YL]ACETATE; ETHYL 2 [5 METHOXY 2 METHYL 1 [[4 (METHYLSULFONYL)PHENYL]METHYL]INDOL 3 YL]ACETATE; ETHYL 2 [5 METHOXY 2 METHYLINDOL 3 YL)ACETATE; INDOMETACIN; INDOMETACIN DERIVATIVE; N [2 [1 [(4 CHLOROPHENYL)CARBONYL] 5 METHOXY 2 METHYLINDOL 3 YL]ETHYL] [[3 (NITROOXY)PROPYL]AMINO]CARBOXAMIDE; NITRIC OXIDE; PHENYLMETHYL 2 [4 CHLORO 1 [(4 CHLOROPHENYL)CARBONYL] 5 METHOXY 2 METHYLINDOL 3 YL]ACETATE; PHENYLMETHYL 2 [6 CHLORO 1 [(4 CHLOROPHENYL)CARBONYL] 5 METHOXY 2 METHYLINDOL 3 YL]ACETATE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALDECOXIB;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BIOLOGICAL ACTIVITY; CONTROLLED STUDY; DRUG ACTIVITY; DRUG DESIGN; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; HUMAN; MALE; NONHUMAN; PROTON NUCLEAR MAGNETIC RESONANCE; RAT; STOMACH INJURY;

ANIMALS; ASPIRIN; CYCLOOXYGENASE 2 INHIBITORS; DRUG DESIGN; DRUG SYNERGISM; FEMALE; GASTRIC MUCOSA; HUMANS; HYDROXAMIC ACIDS; INDOMETHACIN; MALE; NITRIC OXIDE DONORS; PYRAZOLES; RATS; RATS, SPRAGUE-DAWLEY; STOMACH ULCER; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 37048998977     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0611861     Document Type: Article

References (70)

1. Mitchell, J. A.; Akarasereenont, P.; Thiemermann, C.; Flower, R. J.; Vane, J. R. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 11693-11697.
2. Masferrer, J. L.; Zweifel, B. S.; Manning, P. T.; Hauser, S. D.; Leahy, K. M.; et al. Selective inhibition of inducible cyclooxygenase-2 in vivo is antiinflammatory and nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3228-3232.
3. Seibert, K.; Zhang, Y.; Leahy, K.; Hauser, S.; Masferrer, J.; et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 12013-12017.
4. Smith, W. L.; Garavito, R. M.; DeWitt, D. L. Prostaglandin endoperoxide H synthase (cyclooxygenase)-1 and -2. J. Biol. Chem. 1996, 271, 33157-33160.
5. Hoffmann, C. COX-2 in brain and spinal cord - Implications for therapeutic use. Curr. Med. Chem. 2000, 7, 1113-1120.
6. Tibbie, J.; Sigthorsson, G.; Caldwell, C.; Palmer, R. H.; Bjarnason, I. Effects of NSAIDs on cryoprobe-induced gastric ulcer healing in rats. Aliment. Pharmacol. Ther. 2001, 15, 2001-2008.
7. Rodriguez, F.; Llinas, M. T.; Gonzalez, J. D.; Rivera, J.; Salazar, F. J. Renal changes induced by a cyclooxygenase-2 inhibitor during normal and low sodium intake. Hypertension 2000, 36, 276-281.
8. Zhang, J.; Ding, E. L.; Song, Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: Meta-analysis of randomized trials. J. Am. Med. Assoc. 2006, 296, 1619-1632.
9. McGettigan, P.; Henry, D. Cardiovascular risk and inhibition of cyclooxygenase: A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. J. Am. Med. Assoc. 2006, 296, 1633-1644.
10. Silverstein, F. E.; Faich, G.; Goldstein, J. L.; Simon, L. S.; Pincus, T.; et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis. J. Am. Med. Assoc. 2000, 284, 1247-1255.
11. Goldstein, J. L.; Lowry, S. C.; Lanza, F. L.; Schwartz, H. I.; Dodge, W. E. The impact of low-dose aspirin on endoscopic gastric and duodenal ulcer rates in users of a non-selective non-steroidal anti-inflammatory drug or a cyclo-oxygenase-2-selective inhibitor. Aliment. Pharmacol. Ther. 2006, 23, 1489-1498.
12. Wallace, J. L.; Miller, M. J. S. Nitric oxide in mucosal defense: A little goes a long way. Gastroenterology 2000, 119, 512-520.
13. Elliott, S. N.; McKnight, W.; Cirino, G.; Wallace, J. L. A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology 1995, 109, 524-530.
14. Radomski, M. W.; Palmer, R. M.; Moncada, S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem. Biophys. Res. Commun. 1987, 148, 1482-1489.
15. Bandarage, U. K.; Chen, L.; Fang, X.; Garvey, D. S.; Glavin, A.; et al. Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs. J. Med. Chem. 2000, 43, 4005-4016.
16. Mizoguchi, H.; Hase, S.; Tanaka, A.; Takeuchi, K. Lack of small intestinal ulcerogenecity of nitric oxide-releasing indomethacin, NCX-530, in rats. Aliment. Pharmacol. Ther. 2001, 15, 257-267.
17. Lolli, M. L.; Cena, C.; Medana, C.; Lazzarato, L.; Morini, G.; et al. A new class of Ibuprofen derivatives with reduced gastrotoxicity. J. Med. Chem. 2001, 44, 3463-3468.
18. Takeuchi, K.; Mizoguchi, H.; Araki, H.; Komoike, Y.; Suzuki, K. Lack of gastric toxicity of nitric oxide-releasing indomethacin, NCX-530, in experimental animals. Dig. Dis. Sci. 2001, 46, 1805-1818.
19. Minuzi, P.; Degani, M.; Gainol, S.; Meneguzzii, A.; Zuliani, V.; et al. NCX4016 (NO-aspirin) inhibits thromboxane biosynthesis and tissue factor expression and activity in human monocytes. Med. Sci. Monit. 2001, 7, 573-577.
20. Muscará, M. N.; Lovren, F.; McKnight, W.; Dicay, M.; Soldato, P. D.; et al. Vasorelaxant effects of a nitric oxide-releasing aspirin derivative in normotensive and hypertensive rats. Br. J. Pharmacol. 2001, 133, 1314-1322.
21. Keeble, J.; Al-Swayeh, O. A.; Moore, P. K. Vasorelaxant effect of nitric oxide releasing steroidal and nonsteroidal anti-inflammatory drugs. Br. J. Pharmacol. 2001, 133, 1023-1028.
22. Kartasasmita, R. E.; Laufer, S.; Lehmann, J. NO-Donors (VII [I]): Synthesis and cyclooxygenase inhibitory properties of N- and S-nitrooxypivaloyl-cysteine derivatives of naproxen - A novel type of NO-NSAID. Arch. Pharm. Pharm. Med. Chem. 2002, 8, 363-366.
23. Napoli, C.; Ackah, E.; Nigris, F. D.; Soldato, P. D.; D'Armiento, F. P.; et al. Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 12467-12470.
24. Hawkey, C. J.; Jones, J. I.; Atherton, C. T.; Skelly, M. M.; Bebb, J. R.; et al. Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: Proof of concept study in humans. Gut 2003, 52, 1537-1542.
25. Fiorucci, S.; Santucci, L.; Wallace, J. L.; Sardina, M.; Romano, M.; et al. Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 10937-10941.
26. Cena, C.; Lolli, M. L.; Lazzarato, L.; Guaita, E.; Morini, G.; et al. Antiinflammatory, gastrosparing, and antiplatelet properties of new NO-donor esters of aspirin. J. Med. Chem. 2003, 46, 747-754.
27. Huledal, G.; Jonzon, B.; Malmenas, M.; Hedman, A.; Andersson, L. I.; et al. Renal effects of the cyclooxygenase-inhibiting nitric oxide donator AZD3582 compared with rofecoxib and naproxen during normal and low sodium intake. Clin. Pharmacol. Ther. 2005, 77, 437-450.
28. Muscará, M. N.; Wallace, J. L. COX-inhibiting nitric oxide donors (CINODs): Potential benefits on cardiovascular and renal function. Cardiovasc. Hematol. Agents Med. Chem. 2006, 4, 155-164.
29. Ranatunge, R. R.; Augustyniak, M.; Bandarage, U. K.; Earl, R. A.; Ellis, J. L.; et al. Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles. J. Med. Chem. 2004, 47, 2180-2193.
30. Engelhardt, F. C.; Shi, Y.-J.; Cowden, C. J.; Conlon, D. A.; Pipik, B.; et al. Synthesis of a NO-releasing prodrug of rofecoxib. J. Org. Chem. 2006, 71, 480-491.
31. COX-1 numbering was used.
32. Mancini, J. A.; Riendau, D.; Falgueyret, J.-P.; Vickers, P. J.; O'Neill, G. P. Arginine 120 of prostaglandin G/H synthase-1 is required for the inhibition by nonsteroidal anti-inflammatory drugs containing a carboxylic acid moiety. J. Biol. Chem. 1995, 270, 29372-29377.
33. Greig, G. M.; Francis, D. A.; Falgueyret, J.-P.; Ouellet, M.; Percival, M. D.; et al. The interaction of arginine 106 of human prostaglandin G/H synthase-2 with inhibitors is not a universal component of inhibition mediated by nonsteroidal anti-inflammatory drugs. Mol. Pharmacol. 1997, 52, 829-838.
34. Bhattacharya, D. K.; Lecomte, M.; Rieke, C. J.; Garavito, R. M.; Smith, W. L. Involvement of arginine 120, glutamate 524, and tyrosine 355 in the binding of arachidonate and 2-phenylpropionic acid inhibitors to the cyclooxygenase active site of ovine prostaglandin endoperoxide H synthase-1. J. Biol. Chem. 1996, 271, 2179-2184.
35. Gierse, J. K.; McDonald, J. J.; Hauser, S. D.; Rangwala, S. H.; Koboldt, C. M.; et al. A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J. Biol. Chem. 1996, 271, 15810-15814.
36. Kurumbail, R. G.; Stevens, A. M.; Gierse, J. K.; McDonald, J. J.; Stegeman, R. A.; et al. Structural basis for selective inhibition of cycloxygenase-2 by anti-inflammatory agents. Nature 1996, 384, 644-648.
37. Kalgutkar, A. S.; Rowlinson, S. W.; Crew, B. C.; Marnett, L. J. Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 521-524.
38. Luong, C.; Miller, A.; Barnett, J.; Chow, J.; Ramesha, C.; et al. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nat. Struct. Biol. 1996, 3, 927-933.
39. Copeland, R. A.; Williams, J. M.; Giannaras, J.; Nurnberg, S.; Covington, M.; et al. Mechanism of selective inhibition of the inducible isoform of prostaglandin G/H synthase. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 11202-11206.
40. Callan, O. H.; So, O.-Y.; Swinney, D. C. The kinetic factors that determine the affinity and selectivity for slow binding inhibition of human prostaglandin H synthase 1 and 2 by indomethacin and flurbiprofen. J. Biol. Chem. 1996, 271, 3548-3554.
41. Houtzager, V.; Ouellet, M.; Falgueyret, J.-P.; Passmore, L. A.; Bayly, C.; et al. Inhibitor-induced changes in the intrinsic fluorescence of human cyclooxygenase-2. Biochemistry 1996, 35, 10974-10984.
42. Gierse, J. K.; Koboldt, C. M.; Walker, M. C.; Seibert, K.; Isakson, P. C. Kinetic basis for selective inhibition of cyclo-oxygenases. Biochem. J. 1999, 339, 607-614.
43. Timofeevski, S. L.; Prusakiewicz, J. J.; Rouzer, C. A.; Marnett, L. J. Isoform-selective interaction of cyclooxygenase-2 with indomethacin amides studied by real-time fluorescence, inhibition kinetics, and site-directed mutagenesis. Biochemistry 2002, 41, 9654-9662.
44. So, O.-Y.; Scarafia, L. E.; Mak, A. Y.; Callan, O. H.; Swinney, D. C. The dynamics of prostaglandin H synthases. Studies with prostaglandin H synthase 2 Y355F unmask mechanisms of time-dependent inhibition and allosteric activation. J. Biol. Chem. 1998, 273, 5801-5807.
45. Walker, M. C.; Kurumbail, R. G.; Kiefer, J. R.; Moreland, K. T.; Koboldt, C. M.; et al. A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors. Biochem. J. 2001, 357, 709-718.
46. Kalgutkar, A. S.; Kozak, K. R.; Crews, B. C.; Hochgesang, G. P. J.; Marnett, L. J. Covalent modification of cyclooxygenase-2 (COX-2) by 2-acetoxyphenyl alkyl sulfides, A new class of selective COX-2 inactivators. J. Med. Chem. 1998, 41, 4800-4818.
47. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; Sorcek, R.; Wong, H.-C.; et al. Effect of structure modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity. J. Med. Chem. 1997, 40, 980-989.
48. Julémont, F.; Leval, X. D.; Michaux, C.; Renard, J.-F.; Winum, J.-Y.; et al. Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors. J. Med. Chem. 2004, 47, 6749-6759.
49. Palomer, A.; Pascual, J.; Cabré, M.; Borràs, L.; González, G.; et al. Structure-based design of cyclooxygenase-2 selectivity into ketoprofen. Bioorg. Med. Chem. Lett. 2002, 12, 533-537.
50. Bayly, C. I.; Black, W. C.; Léger, S.; Ouimet, N.; Ouellet, M.; et al. Structure-based design of COX-2 selectivity into flurbiprofen. Bioorg. Med. Chem. Lett. 1999, 9, 307-312.
51. Black, W. C.; Bayly, C.; Belly, M.; Chan, C. C.; Charleson, S.; et al. From indomethacin to a selective COX-2 inhibitor: Development of indolalkanoic acids as potent and selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 725-730.
52. Leblanc, Y.; Black, W. C.; Chan, C. C.; Charleson, S.; Delorme, D.; et al. Synthesis and biological evaluation of both enantiomers of L-761,000 as inhibitors of cyclooxygenase-1 and -2. Bioorg. Med. Chem. Lett. 1996, 6, 731-736.
53. Woods, K. W.; McCroskey, R. W.; Michaelides, M. R.; Wada, C. K.; Hulkower, K. I.; et al. Thiazole analogues of the NSAID indomethacin as selective COX-2 inhibitors. Bioorg. Med. Chem. Lett. 2001, 11, 1325-1328.
54. Kalgutkar, A. S.; Marnett, A. B.; Crew, B. C.; Remmel, R. P.; Marnett, L. J. Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. J. Med. Chem. 200043, 2860-2870.
55. Kalgutkar, A. S.; Crews, B. C.; Rowlinson, S. W.; Marnett, A. B.; Kozak, K. R.; et al. Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent highly selective COX-2 inhibitors. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 925-930.
56. Kozak, K. R.; Prusakiewicz, J. J.; Rowlinson, S. C.; Marnett, L. J. Enantiospecific, selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 1315-1318.
57. Myers, G. S.; Winthrop, S. O. Poly-nitrate esters and salts thereof. U.S. Patent 2, 975, 208, 1961.
58. Kawashima, Y.; Ikemoto, T.; Horiguchi, A.; Hayashi, M.; Matsumoto, K.; et al. Synthesis and pharmacological evaluation of (nitrooxy)alkyl apovincaminates. J. Med. Chem. 1993, 36, 815-819.
59. McOmie, J. F. W.; Watts, M. L.; West, D. E. Demethylation of aryl methyl ethers by boron tribromide. Tetrahedron 1968, 24, 2289-2292.
60. Okada, M.; Iwashita, S.; Koizumi, N. Efficient general method for sulfamoylation of a hydroxyl group. Tetrahedron Lett. 2000, 41, 7047-7051.
61. Blair, J. B.; Kurrasch-Orbaugh, D.; Marona-Lewicka, D.; Cumbay, M. G.; Watts, V. J.; et al. Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines. J. Med. Chem. 2000, 43, 4701-4710.
62. Kelley, J. L.; Linn, J. A.; Selway, J. W. T. Synthesis and antirhinovirus activity of 6-(dimethylamino)-2-(trifluoromethyl)-9-(substituted benzyl)-9H-purines. J. Med. Chem. 1989, 32, 1757-1763.
63. Flynn, D. L.; Capiris, T.; Cetenko, W. J.; Connor, D. T.; Dyer, R. D.; et al. Nonsteroidal antiinflammatory drug hydroxamic acids. Dual inhibitors of both cyclooxygenase and 5-lipoxygenase. J. Med. Chem. 1990, 33, 2070-2072.
64. Sebesta, D. P.; O'Rourke, S. S.; Martinez, R. L.; Pieken, W. A.; McGee, D. P. C. 2′-Deoxy-2′-alkoxylaminouridine: Novel 2′-substituted uridines prepared by intramolecular nucleophilic ring opening of 2,2′-O-anhydrouridines. Tetrahedron 1996, 52, 14385-14402.
65. McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M.-C. The facile dealkylation of phosphonic acid dialkyl esters by bromotrimethylsilane. Tetrahedron Lett. 1977, 155-158.
66. Young, J. M.; Panah, S.; Satchawatcharaphong, C.; Cheung, P. S. Human whole blood assays for inhibition of prostaglandin G/H synthases-1 and -2 using A23187 and lipopolysaccharide stimulation of thromboxane B2 production. Inflamm. Res. 1996, 45, 246-253.
67. Riendeau, D.; Percival, M. D.; Brideau, C.; Charleson, S.; Dube, D.; et al. Etoricoxib (MK-0663): Preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J. Pharmacol. Exp. Ther. 2001, 296, 558-566.
68. 2 synthase cyclooxygenase active site. Biochemistry 1996, 35, 7330-7340.
69. Hawkey, C. J.; Skelly, M. M. Gastrointestinal safety of selective COX-2 inhibitors. Curr. Pharm. Des. 2002, 8, 1077-1089.
70. Remmel, R. P.; Crews, B. C.; Kozak, K. R.; Kalgutkar, A. S.; Marnett, L. J. Studies on the metabolism of the novel, selective cyclooxygenase-2 inhibitor indomethacin phenethylamide in rat, mouse, and human liver microsomes: Identification of active metabolites. Drug Metab. Dispos. 2004, 32, 113-122.