RT Journal Article SR Electronic T1 Rofecoxib [Vioxx, MK-0966; 4-(4′-Methylsulfonylphenyl)-3-phenyl-2-(5H)-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 FD American Society for Pharmacology and Experimental Therapeutics SP 551 OP 560 VO 290 IS 2 A1 C.-C. Chan A1 S. Boyce A1 C. Brideau A1 S. Charleson A1 W. Cromlish A1 D. Ethier A1 J. Evans A1 A. W. Ford-Hutchinson A1 M. J. Forrest A1 J. Y. Gauthier A1 R. Gordon A1 M. Gresser A1 J. Guay A1 S. Kargman A1 B. Kennedy A1 Y. Leblanc A1 S. Leger A1 J. Mancini A1 G. P. O’Neill A1 M. Ouellet A1 D. Patrick A1 M. D. Percival A1 H. Perrier A1 P. Prasit A1 I. Rodger A1 P. Tagari A1 M. Therien A1 P. Vickers A1 D. Visco A1 Z. Wang A1 J. Webb A1 E. Wong A1 L.-J. Xu A1 R. N. Young A1 R. Zamboni A1 D. Riendeau YR 1999 UL http://jpet.aspetjournals.org/content/290/2/551.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics