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Research ArticleArticle

Rofecoxib [Vioxx, MK-0966; 4-(4′-Methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: A Potent and Orally Active Cyclooxygenase-2 Inhibitor. Pharmacological and Biochemical Profiles

C.-C. Chan, S. Boyce, C. Brideau, S. Charleson, W. Cromlish, D. Ethier, J. Evans, A. W. Ford-Hutchinson, M. J. Forrest, J. Y. Gauthier, R. Gordon, M. Gresser, J. Guay, S. Kargman, B. Kennedy, Y. Leblanc, S. Leger, J. Mancini, G. P. O’Neill, M. Ouellet, D. Patrick, M. D. Percival, H. Perrier, P. Prasit, I. Rodger, P. Tagari, M. Therien, P. Vickers, D. Visco, Z. Wang, J. Webb, E. Wong, L.-J. Xu, R. N. Young, R. Zamboni and D. Riendeau
Journal of Pharmacology and Experimental Therapeutics August 1999, 290 (2) 551-560;
C.-C. Chan
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S. Boyce
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C. Brideau
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S. Charleson
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W. Cromlish
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D. Ethier
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J. Evans
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A. W. Ford-Hutchinson
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M. J. Forrest
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J. Y. Gauthier
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R. Gordon
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M. Gresser
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B. Kennedy
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Y. Leblanc
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J. Mancini
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Abstract

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4′-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE2 in human osteosarcoma cells (IC50 = 26 ± 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC50 = 18 ± 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC50 > 50 μM in U937 cells and IC50 > 15 μM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC50 = 0.34 μM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC50 = 26 μM at 0.1 μM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE2 synthesis with an IC50 value of 0.53 ± 0.02 μM compared with an IC50 value of 18.8 ± 0.9 μM for the inhibition of COX-1-derived thromboxane B2synthesis after blood coagulation. Using the ratio of the COX-1 IC50 values over the COX-2 IC50 values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID50 = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID50 = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID50 = 0.24 mg/kg), and adjuvant-induced arthritis (ID50 = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a 51Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.

Footnotes

  • Send reprint requests to: Dr. Chi-Chung Chan, Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire, Dorval, Quebec, Canada H9R 4P8. E-mail: chi_chung_chan{at}merck.com

  • Abbreviations:
    COX
    cyclooxygenase
    HBSS
    Hanks’ balanced salt solution
    NSAID
    nonsteroidal anti-inflammatory drug
    CHO
    Chinese hamster ovary
    TMPD
    N,N,N′,N′-tetramethyl-p-phenylenediamine
    AIA
    adjuvant-induced arthritis
    PG
    prostaglandin
    TBX
    thromboxane
    12-HETE
    12-hydroeicosatetraenoic acid
    PMN
    polymorphonuclear
    LTB
    leukotriene B
    DMSO
    dimethyl sulfoxide
    LPS
    lipopolysaccharide
    • Received December 22, 1998.
    • Accepted February 22, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 2
1 Aug 1999
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Research ArticleArticle

Rofecoxib [Vioxx, MK-0966; 4-(4′-Methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: A Potent and Orally Active Cyclooxygenase-2 Inhibitor. Pharmacological and Biochemical Profiles

C.-C. Chan, S. Boyce, C. Brideau, S. Charleson, W. Cromlish, D. Ethier, J. Evans, A. W. Ford-Hutchinson, M. J. Forrest, J. Y. Gauthier, R. Gordon, M. Gresser, J. Guay, S. Kargman, B. Kennedy, Y. Leblanc, S. Leger, J. Mancini, G. P. O’Neill, M. Ouellet, D. Patrick, M. D. Percival, H. Perrier, P. Prasit, I. Rodger, P. Tagari, M. Therien, P. Vickers, D. Visco, Z. Wang, J. Webb, E. Wong, L.-J. Xu, R. N. Young, R. Zamboni and D. Riendeau
Journal of Pharmacology and Experimental Therapeutics August 1, 1999, 290 (2) 551-560;

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Research ArticleArticle

Rofecoxib [Vioxx, MK-0966; 4-(4′-Methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: A Potent and Orally Active Cyclooxygenase-2 Inhibitor. Pharmacological and Biochemical Profiles

C.-C. Chan, S. Boyce, C. Brideau, S. Charleson, W. Cromlish, D. Ethier, J. Evans, A. W. Ford-Hutchinson, M. J. Forrest, J. Y. Gauthier, R. Gordon, M. Gresser, J. Guay, S. Kargman, B. Kennedy, Y. Leblanc, S. Leger, J. Mancini, G. P. O’Neill, M. Ouellet, D. Patrick, M. D. Percival, H. Perrier, P. Prasit, I. Rodger, P. Tagari, M. Therien, P. Vickers, D. Visco, Z. Wang, J. Webb, E. Wong, L.-J. Xu, R. N. Young, R. Zamboni and D. Riendeau
Journal of Pharmacology and Experimental Therapeutics August 1, 1999, 290 (2) 551-560;
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