In Vitro Structure-Activity Relationship and in Vivo Studies for a Novel Class of Cyclooxygenase-2 Inhibitors: 5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone Derivatives

Journal of Medicinal Chemistry

Volumn 47, Issue 4, 2004, Pages 792-804

  Shin, Song Seok ^a   Byun, Youngjoo ^a,b   Lim, Kyung Min ^a   Choi, Jin Kyu ^a   Lee, Ki Wha ^a   Moh, Joo Hyun ^a   Kim, Jin Kwan ^a   Jeong, Yeon Su ^a   Kim, Ji Young ^a   Choi, Young Hoon ^a   Koh, Hyun Ju ^a   Park, Young Ho ^a   Oh, Young Im ^a   Noh, Min Soo ^a,c   Chung, Shin ^a  

^a AmorePacific Corporation   (South Korea)

^b OHIO STATE UNIVERSITY   (United States)

^c MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,2 DIMETHYL 4 (3 FLUOROPHENYL) 5 [4 (METHYLSULFONYL)PHENYL] 3 (2H) FURANONE; 2,2 DIMETHYL 4 (3,5 DIFLUOROPHENYL) 5 [4 (METHYLSULFONYL)PHENYL] 3(2H) FURANONE; 4 PHENYL 3(2H) FURANONE DERIVATIVE; 5 [4 (AMINOSULFONYL)PHENYL] 2,2 DIMETHYL 4 (3 FLUOROPHENYL) 3(2H) FURANONE; CELECOXIB; CYCLOOXYGENASE 2 INHIBITOR; ETORICOXIB; INDOMETACIN; MELOXICAM; ROFECOXIB; UNCLASSIFIED DRUG; VALDECOXIB;

ADJUVANT ARTHRITIS; ANALGESIC ACTIVITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG INHIBITION; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYPERALGESIA; IC 50; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; RAT; RAT STRAIN; STOMACH ULCER; STRUCTURE ACTIVITY RELATION;

ADULT; ANIMALS; ARTHRITIS, EXPERIMENTAL; CARRAGEENAN; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITORS; CYCLOOXYGENASE INHIBITORS; EDEMA; FURANS; HUMANS; ISOENZYMES; MACROPHAGES, PERITONEAL; MALE; MEMBRANE PROTEINS; MICE; MODELS, MOLECULAR; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; RATS; RATS, SPRAGUE-DAWLEY; STOMACH ULCER; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 10744228435     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm020545z     Document Type: Article

References (65)

1. (a) Roth, S. H. Nonsteroidal Anti-inflammatory Drugs: Gastropathy, Deaths, and Medical Practice. Ann. Intern. Med. 1988, 109, 353-354.
2. (b) Jones, R. Nonsteroidal Anti-inflammatory Drug Prescribing: Past, Present, and Future. Am. J. Med. 2001, 110, 4S-7S.
3. (a) Singh, G. Recent Considerations in Nonsteroidal Antiinflammatory Drug Gastropathy. Am. J. Med. 1988, 105, 31S-38S.
4. (b) Wolfe, M. M.; Lichtenstein, D. R.; Singh, G. Gastrointestinal Toxicity of Nonsteroidal Anti-inflammatory Drugs. N. Engl. J. Med. 1999, 340, 1888-1899.
5. 2 Synthase (Cyclooxygenase) in Human Monocytes. J. Biol. Chem. 1990, 265, 16737-16740.
6. (b) Xie, W.; Chipman, J. G.; Robertson, D. L.; Erikson, R. L.; Simmons, D. L. Expression of a Mitogen-responsive Gene Encoding Prostaglandin Synthase is Regulated by mRNA Splicing. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 2692-2696.
7. (a) Smith, W. L.; DeWitt, D. L. Prostaglandin Endoperoxidase H Synthase-1 and -2. Adv. Immunol. 1996, 62, 167-215.
8. (b) Pariet, M.; Churchill, L.; Engelhardt, G. In New Targets in Inflammation: Inhibitors of COX-2 or Adhesion Molecules; Bazan, N.; Botting, J. ; Vane, J., Eds.; Kluwer Academic: London, 1996; pp 23-38.
9. Morham, S. G.; Langenbach, R.; Loftin, C. D.; Tiano, H. F.; Vouloumanos, N.; Jennette, J. C.; Mahler, J. F.; Kluckman, K. D.; Ledford, A.; Lee, C. A.; Smithies, D. Prostaglandin Synthase-2 Gene Disruption Causes Severe Renal Pathology in the Mouse. Cell 1995, 83, 473-482.
10. For animal safety data of COX-2 inhibitors, see the FDA NDA reports as follows: (a) Celecoxib: Pharmacology Review, Application Number 20-998. (b) Rofecoxib: Pharmacology Review, Application Number 21,042. (c) Valdecoxib: Pharmacology Review, Application Number 21-341.
11. For animal safety data of COX-2 inhibitors, see the FDA NDA reports as follows: (a) Celecoxib: Pharmacology Review, Application Number 20-998. (b) Rofecoxib: Pharmacology Review, Application Number 21,042. (c) Valdecoxib: Pharmacology Review, Application Number 21-341.
12. For animal safety data of COX-2 inhibitors, see the FDA NDA reports as follows: (a) Celecoxib: Pharmacology Review, Application Number 20-998. (b) Rofecoxib: Pharmacology Review, Application Number 21,042. (c) Valdecoxib: Pharmacology Review, Application Number 21-341.
13. (a) Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M. B.; Hawkey, C. J.; Hochberg, M. C.; Kevin, T. K.; Schnitzer, T. J. The VIGOR Study Group. Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Reumatoid Arthritis. N. Engl. J. Med. 2000, 343, 1520-1528.
14. (b) Silverstein, F. E.; Faich, G.; Goldstein, J. L.; Simon, L. S.; Pincus, T.; Whelton, A.; Makuch, R.; Eisen, G.; Agrawal, N. M.; Stenson, W. F.; Burr, A. M.; Zhao, W. W.; Kent, J. D.; Lefkowith, J. B.; Verburg, K. M.; Geis, G. S. Gastrointestinal Toxicity with Celecoxib vs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS Study: A Randomized Controlled Trial. JAMA 2000, 284, 1247-1255.
15. (c) Distel, M.; Mueller, C.; Bluhmki, E.; Fries, J. Safety of Meloxicam: A Global Analysis of Clinical Trials. Br. J. Rheumatol. 1996, 35 (Suppl. 1), 68-77.
16. (a) Mukherjee, D.; Nissen, S. E.; Topol, E. J. Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors. JAMA 2001, 286, 954-959.
17. (b) Barkin, R. L.; Sable, K. S. Caution Recommended for Prescribing and Administering COX1/COX2 and COX2 Specific NSAIDs. P&T 2000, 25, 196-202.
18. 2. Science 2002, 296, 539-541.
19. (d) Khan, K. N. M.; Paulson, S. K.; Verburg, K. M.; Lefkowith, J. B.; Maziasz, T. J. Pharmacology of Cyclooxygenase-2 Inhibition in the Kidney. Kidney Int. 2002, 61, 1210-1219.
20. (a) Prasit, P.; Wang, Z.; Briedeau, C.; Chan, C.-C.; Charleson, S.; Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson, A. W.; Gauthier, J. Y. ; Gordon, R.; Guay, J.; Gresser, M.; Kargman, S.; Kennedy, B.; Leblanc, Y.; Legar, S.; Mancini, J.; O'Neill, G. P.; Ouellet, M.; Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.; Therien, M.; Vikers, P.; Wong, E.; Xu, L.-J.; Young, R. N.; Zamboni, R.; Boyce, S.; Rupiniak, N.; Forrest, M.; Visco, D.; Patrick, D. The Discovery of Rofecoxib, [MK966, VIOXX, 4-(4′ -Methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an Orally Active Cyclooxygenase-2 Inhibitor. Bioorg. Med. Chem. Lett. 1999, 9, 1773-1778.
21. (b) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Gogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K. Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene Sulfonamide (SC-58635, Celecoxib). J. Med. Chem. 1997, 40, 1347-1365.
22. (c) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, Valdecoxib: A Potent and Selective Inhibitor of COX-2. J. Med. Chem. 2000, 43, 775-777.
23. (d) Friesen, R. W.; Brideau, C.; Chan, C. C.; Charleson, S.; Deschênes, D.; Dubé, D.; Ethier, D.; Fortin, R.; Gauthier, J. Y.; Girard, Y. Gordon, R.; Greig, G. M.; Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L. J.; Young, R. N. 2-Pyridnyl-3-(4-methylsulfonyl)phenylpyridines: Selective and Orally Active Cyclooxygenase-2 Inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 2777-2782.
24. (e) Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai, D.-W.; Paluki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.; DiMichele, L. ; Dormer, P.; Reider, P. J. A Practical Synthesis of a COX-2 Specific Inhibitor. J. Org. Chem. 2000, 65, 8415-8420.
25. Geba, G. P.; Weaver, A. L.; Polis, A. B.; Dixon, M. E.; Schnitzer, T. J. Efficacy of Rofecoxib, Celecoxib, and Acetaminophen in Osteoarthritis of the Knee: a Randomized Trial. JAMA 2002, 287, 64-71.
26. Whelton, A.; Fort, J. G.; Puma, J. A.; Normandin, D.; Bello, A. E.; Verburg, K. M. Cyclooxygenase-2-Specific Inhibitors and Cardiorenal Function: A Randomized, Controlled Trial of Celecoxib and Rofecoxib in Older Hypertensive Osteoarthritis Patients. Am. J. Ther. 2001, 8, 85-95.
27. Shin, S. S.; Noh, M.-S.; Byun, Y. J.; Choi, J. K.; Kim, J. Y.; Lim, K. M.; Ha, J.-Y.; Kim, J. K.; Lee, C. H.; Chung, S. 2,2-Dimethyl-4,5-diaryl-3(2H)furanone Derivatives as Selective Cyclooxygenase-2 Inhibitors. Bioorg. Med. Chem. Lett. 2001, 11, 165-168.
28. (a) Prasit, P.; Riendeau, D. Selective Cyclooxygenase-2 Inhibitors. Ann. Rep. Med. Chem. 1997, 32, 211-220.
29. (b) Leval, X. D.; Julémont, F.; Delarge, J.; Sanna, V.; Pirotte, B.; Dogné, J.-M. Advances in the Field of COX-2 Inhibition. Expert Opin. Ther. Patents 2002, 12, 969-989.
30. (a) Tang, C.; Shou, M.; Rushmore, T. H.; Mei, Q.; Sandhu, P.; Woolf, E. J.; Rose, M. J.; Gelmann, A.; Greenberg, H. E.; De Lepeleire, I.; Hecken, A. V. ; De Schepper, P. J.; Ebel, D. L.; Schwartz, J. I.; Rodrigues, A. D. In-vitro Metabolism of Celecoxib, a Cyclooxygenase-2 Inhibitor, by Allelic Variant Forms of Human Liver Microsomal Cytochrome P450 2C9: Correlation with CYP2C9 Genotype and in-vivo Pharmacokinetics. Pharmacogenetics 2001, 11, 223-235.
31. (b) Nicoll-Griffith, D. A.; Yergey, J. A.; Trimble, L. A.; Silva, J. M.; Li, C.; Chauret, N.; Gauthier, J. Y.; Grimm, E.; Léger, S.; Roy, P.; Thérien, M.; Wang, Z.; Prasit, P.; Zamboni, R.; Young, R. N.; Brideau, C.; Chan, C.-C.; Mancini, J.; Riendeau, D. Synthesis, Characterization, and Activity of Metabolites Derived from the Cyclooxygenase-2 Inhibitor Rofecoxib (MK-0966, Vioxx). Bioorg. Med. Chem. Lett. 2000, 10, 2683-2686.
32. Joshi, A. S.; Raghavan, N.; Williams, R. M.; Takahashi, K.; Shingu, H.; King, S.-Y. P. Simultaneous Quantification of an Antiinflammatory Compound (DuP 697) and a Potential Metabolite (X6882) in Human Plasma and Urine by High-Performance Liquid Chromatography. J. Chromatogr. B: Biomed. Sci. Appl. 1994, 660, 143-150.
33. Parker, W.; Raphael, R. A.; Wilkinson, D. I. The Structure and Synthesis of Bullatenone. J. Chem. Soc. 1958, 3871-3875.
34. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. The Palladium-catalyzed Cross-coupling Reaction of Phenylboronic Acid with Haloarenes in the Presence of Bases. Synth. Commun. 1981, 11, 513-517.
35. (b) Hoshino, Y.; Miyaura, N.; Suzuki. A. Novel Synthesis of Isoflavones by the Palladium-catalyzed Cross-coupling Reaction of 3-Bromochromones with Arylboronic Acids of Its Esters. Bull. Chem. Soc. Jpn. 1988, 61, 3008-3010.
36. Herrmann, K.; Simchen, G. Synthese von Acylcyaniden (α-Oxonitrilen) mit Cyanotrimethylsilan. Synthesis 1979, 204-205.
37. Lee, K.-W.; Choi, Y. H.; Joo, Y. H.; Kim, J. K.; Shin, S. S.; Byun, Y. J.; Kim, Y.; Chung, S. A Facile One-Pot Synthesis of 4,5-Diaryl-2,2-dimethyl-3(2H)-furanones. Bioorg. Med. Chem. 2002, 10, 1137-1142.
38. (a) Kharasch, N.; Bruice, T. C. Derivatives of Sulfenic Acids. V. 1-Fluorenone Sulfur Compounds. J. Am. Chem. Soc. 1951, 73, 3240-3244.
39. (b) Vleeschauwer, M. D.; Gauthier, J. Y. Remarkably Mild and Simple Preparations of Sulfinates, Sulfonyl Chlorides and Sulfonamides from Thioanisoles. Synlett 1997, 375-377.
40. 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.
41. Brideau, C.; Kargman, S.; Liu, S.; Dallob, A. L.; Ehrich, E. W.; Rodger, I. W.; Chan, C.-C. A Human Whole Blood Assay for Clinical Evaluation of Biochemical Efficacy of Cyclooxygenase Inhibitors. Inflammation Res. 1996, 45, 68-74.
42. 50 = 1.5 μg/mL.
43. Kurumbail, R. G.; Stevens, A. M.; Gierse, J. K.; Mcdonald, J. J.; Stegeman, R. A.; Pak, J. Y.; Gildhaus, D.; Miyashiro, J. M.; Penning, T. D.; Seibert, K. Isakson, P. C.; Stallings, W. C. Structual Basis for Selective Inhibition of Cyclooxygenase-2 by Anti-inflammatory Agent. Nature 1996, 384, 644-648
44. Li, J. J.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Collins, J. T.; Garland, D. J.; Gregory, S. A.; Huang, H.-C.; Isakson, P. C.; Koboldt, C. M.; Logusch, E. W.; Norton, M. B.; Perkins, W. E.; Reinhard, E. J.; Seibert, K. ; Veenhuizen, A. W.; Zhang, Y.; Reitz, D. B. 1,2-Diarylcyclopentenes as Selective Cyclooxygenase-2 Inhibitors and Orally Active Anti-inflammatory Agents. J. Med. Chem. 1995, 38, 4570-4578.
45. (b) Huang, H.-C.; Li, J. J.; Garland, D. J.; Chamberlain, T. S.; Reinhard, E. J.; Manning, R. E.; Seibert, K.; Koboldt, C. M.; Gregory, S. A.; Anderson, G. D.; Veenhuizen, A. W.; Zhang, Y.; Perkins, W. E.; Burton, E. G.; Cogburn, J. N.; Isakson, P. C.; Reitz, D. B. Diaryl-sprio[2,4]-heptenes as Orally Active, Highly Selective Cyclooxygenase-2 Inhibitors: Synthesis and Struture-activity Relationships. J. Med. Chem. 1996, 39, 253-266.
46. (c) Reitz, D. B.; Huang, H.-C.; Li, J. J.; Garland, D. J.; Manning, R. E.; Anderson, G. D.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Isakson, P. C. Selective Cyclooxygeanse-2 Inhibitors: Novel 4-Spiro 1,2-Diarylcyclopentenes Are Potent and Orally Active COX-2 Inhibitors. Bioorg. Med. Chem. Lett. 1995, 5, 867-872.
47. 1H NMR spectrum. The furan form was the major tautomer.
48. (a) Matsushita, M.; Masaki, M.; Yagi, Y.; Tanaka, T.; Wakitani, K. Pharmacological Profile of JTE-522, a Novel Prostaglandin H Synthase-2 Inhibitor, in Rats. Inflammation Res. 1997, 46, 461-466.
49. (b) JTE-522. Drugs of the Future 1998, 23, 598-601.
50. (c) Hashimoto, H.; Imamura, K.; Haruta, J.; Wakitani, K. 4-(4-Cycloalkyl/aryl-oxazol-5-yl)-benzenesulfonamides as Selective Cyclooxygenase-2 Inhibitors: Enhancement of the Selectivity by Introduction of a Fluorine Atom and Identification of a Potent, Highly Selective, and Orally Active COX-2 Inhibitor JTE-522. J. Med. Chem. 2002, 45, 1511-1517.
51. Even though only derivatives substituted with fluorine were described in Table 4 due to space limitation, derivatives substituted with a halogen other than fluorine may be found in the following patent. The trend observed in Table 4 was grossly maintained also with the derivatives substituted with chlorine and bromine. Shin, S. S.; Noh, M.-S.; Byun, Y. J.; Choi, J. K.; Kim, J. K.; Lim, K. M.; Kim, J. Y.; Choi, Y. H.; Ha, J.-Y.; Lee, K.-W.; Moh, J. H.; Jeong, Y. S.; Chung, S.; Joo, Y. H.; Lee, C. H.; Kang, S. H.; Park, Y.-H.; Yi, J. B. 4,5-Diaryl-3(2H)furanone Derivatives as Cyclooxygenase-2 Inhibitors. U.S. Patent 6, 492,-416, 2002.
52. (a) Lombardino, J. G. Nonsteroidal Antiinflammatory Drugs. In Chemistry and Pharmacology of Drugs; Lednicer, D. Ed.; John Wiley & Sons: New York, 1985; pp 116-129.
53. (b) Lombardino, J. G. Nonsteroidal Antiinfammatory Drugs. In Chemistry and Pharmacology of Drugs; Lednicer, D. Ed.; John Wiley & Sons: New York, 1985; pp 150-154.
54. 50's assessed by the therapeutic model using Lewis rats with those by the preventive model.
55. (b) For the AA data for rofecoxib, refer to Chan, C. C.; Boyce, S.; Brideau, C.; Charleson, S.; Cromlish, W.; Ethier, D.; Evans, J.; Ford-Hutchinson, A. W.; Forrest, M. J.; Gauthier, J. Y.; Gordon, R.; Gresser, M.; Guay, J.; Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.; O'Neill, G. P.; Ouellet, M.; Patrick, D.; Percival, M. D.; Perrier, H.; Prasit, P.; Rodger, I.; Tagari, P.; Therien, M.; Vickers, P.; Visco, D.; Wang, Z.; Webb, J.; Wong, E.; Xu, L.-J.; Young, R. N.; Zamboni, R. Riendeau, D. Rofecoxib [Vioxx, MK-0966; 4-(4′-Methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: A Potent and Orally Active Cyclooxygenase-2 Inhibitor. Pharmacological and Biochemical Profiles. J Pharmacol. Exp. Ther. 1999, 290, 551-560.
56. (d) For the AA data for meloxicam, refer to Pairet, M.; Ryn, J. v.; Schierok, H.; Mauz, A.; Trummlitz, G.; Engelhardt, G. Differential Inhibition of Cyclooxygenases-1 and -2 by Meloxicam and Its 4′-Isomer. Inflammation Res. 1998, 47, 270-276.
57. (e) For the AA data for etoricoxib, see Drugs of the Future 2001, 26, 346-353.
58. (f) For the AA data for valdecoxib, refer to Drugs of the Future 2001, 26, 133-140.
59. Toxicokinetic studies also suggested no indication of drug accumulation upon repeat dose in male SD rats for compounds 1b, 1f, and 20b.
60. Lombardino, J. G. Nonsteroidal Antiinflammatory Drugs. In Chemistry and Pharmacology of Drugs; Lednicer, D., Ed.; John Wiley & Sons: New York, 1985; pp 219-230.
61. Riendeau, D.; Percival, M. D.; Boyce, S.; Brideau, C.; Charleson, S.; Cromlish, W.; Ethier, D.; Evans, E. J.; Falgueyret, J.-P.; Ford-Hutchinson, A. W.; Gordon, R.; Greig, G.; Gresser, M.; Guay, J.; Kargman, S.; Léger, S. ; Mancini, J. A.; O'Neil, G.; Ouellet, M.; Rodger, I. W.; Thérien, M.; Wang, Z.; Webb, J. K.; Wong, E.; Xu, L.; Young, R. N.; Zamboni, R.; Prasit, P.; Chan, C.-C. Biochemical and Pharmacological Profile of a Tetrasubstituted Furanone as a Highly Selective COX-2 Inhibitor. Brit. J. Pharmacol. 1997, 121, 105-117.
62. Futaki, N.; Yoshikawa, K.; Hamasaka, Y.; Arai, I.; Higuchi, S.; Iizuka, H.; Otomo, S. NS-398, a Novel Non-steroidal Anti-inflammatory Drug with Potent Analgesic and Antipyretic Effects, which Causes Minimal Stomach Lesions. Gen. Pharmacol. 1993, 24, 105-110.
63. (a) The observed % inhibitions against carrageenan-induced thermal hyperalgesia were (26 ± 10), (59 ± 21), and (118 ± 30) % for 0.1, 0.3, and 1.0 mg/kg 20b in the male SD rat by oral gavage, respectively. In case of indomethacin as the positive control, the observed % inhibitions were (18 ± 13) and (47 ± 30)% for 0.3 and 1.0 mg/kg, respectively. N = 8 per group.
64. (b) The oral analgesic activity of 20b was not directly compared with that of rofecoxib. Considering that rofecoxib has comparable lipophilicity to 20b as judged by calculated logP values (1.83 for rofecoxib and 2.38 for 20b by the Crippen's method on CS ChemDraw Ultra version 5.0), rofecoxib is a reasonable COX-2 inhibitor for comparison of analgesic activity with 20b, though.
65. Chung, S.; et al. Bioorg. Med. Chem. Lett., submitted. When sulfoxide analogue 21 (X = H, R = 3,5-difluoro; see Scheme 4 for structure) was orally administered to rats, the sulfoxide analogue was absorbed fast and subsequently in vivo transformed into methyl sulfone compound 1f according to pharmacokinetic studies. Repeat dose oral safety studies for both 21 and 1f indicated that rats were significantly more tolerant to 21 than to 1f at comparable systemic exposure level of 1f, suggesting that there should be a notable level of local gastrointestinal toxicity occurring during the drug absorption in the gastrointestinal tract. Thus, minimization of the time needed for GI drug influx could be important for further improvement of GI safety of COX-2 inhibitor of a given COX-2 selectivity.