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

• Published in: The Journal of pharmacology and experimental therapeutics 1999-08, Vol.290 (2), p.551
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - metabolism; Animals; Arachidonate 15-Lipoxygenase - metabolism; Arachidonic Acid - metabolism; Arthritis, Experimental - blood; Arthritis, Experimental - metabolism; Blood Platelets - drug effects; Blood Platelets - enzymology; Cell Line; COS Cells; Cricetinae; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Digestive System - drug effects; Dogs; Edema - chemically induced; Edema - prevention & control; Female; Humans; Hyperalgesia - chemically induced; Hyperalgesia - prevention & control; In Vitro Techniques; Isoenzymes - metabolism; Lactones - pharmacology; Leukotriene B4 - biosynthesis; Male; Membrane Proteins; Microsomes - drug effects; Microsomes - enzymology; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Rats, Inbred Lew; Saimiri; Sulfones
• ISSN: 0022-3565; 1521-0103

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 PGE 2 in human osteosarcoma cells (IC 50 = 26 ± 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC 50 = 18 ± 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC 50 > 50 μM in U937 cells and IC 50 > 15 μM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC 50 = 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 (IC 50 = 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 PGE 2 synthesis with an IC 50 value of 0.53 ± 0.02 μM compared with an IC 50 value of 18.8 ± 0.9 μM for the inhibition of COX-1-derived thromboxane B 2 synthesis after blood coagulation. Using the ratio of the COX-1 IC 50 values over the COX-2 IC 50 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 (ID 50 = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID 50 = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID 50 = 0.24 mg/kg), and adjuvant-induced arthritis (ID 50 = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a 51 Cr 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 i