TY - JOUR T1 - Rofecoxib [Vioxx, MK-0966; 4-(4′-Methylsulfonylphenyl)-3-phenyl-2-(5<em>H</em>)-furanone]: A Potent and Orally Active Cyclooxygenase-2 Inhibitor. Pharmacological and Biochemical Profiles JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 551 LP - 560 VL - 290 IS - 2 AU - C.-C. Chan AU - S. Boyce AU - C. Brideau AU - S. Charleson AU - W. Cromlish AU - D. Ethier AU - J. Evans AU - A. W. Ford-Hutchinson AU - M. J. Forrest AU - J. Y. Gauthier AU - R. Gordon AU - M. Gresser AU - J. Guay AU - S. Kargman AU - B. Kennedy AU - Y. Leblanc AU - S. Leger AU - J. Mancini AU - G. P. O’Neill AU - M. Ouellet AU - D. Patrick AU - M. D. Percival AU - H. Perrier AU - P. Prasit AU - I. Rodger AU - P. Tagari AU - M. Therien AU - P. Vickers AU - D. Visco AU - Z. Wang AU - J. Webb AU - E. Wong AU - L.-J. Xu AU - R. N. Young AU - R. Zamboni AU - D. Riendeau Y1 - 1999/08/01 UR - http://jpet.aspetjournals.org/content/290/2/551.abstract N2 - 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 &gt; 50 μM in U937 cells and IC50 &gt; 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. The American Society for Pharmacology and Experimental Therapeutics ER -