Rofecoxib (brand name: Vioxx, co-marketed by Monsanto and Merck) is a non-steroidal anti-inflammatory drug (NSAID) that was voluntarily withdrawn from the market in 2004 but is now tentatively used for treatment of osteoarthritis, rheumatoid arthritis, acute pain in adults, and primary dysmenorrhea, as well as acute treatment of migraine attacks with or without auras. It is a selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, rofecoxib exerts its effects by inhibiting the synthesis of prostaglandins involved in pain, fever and inflammation. COX-2 catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGE2) and PGE2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precusor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Rofecoxib inhibits COX-2 via noncompetitive negative allosteric modulation by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Similar to other COX-2 inhibitors, such as celecoxib (Celebrex) and valdecoxib, rofecoxib appears to exploit slight differences in the size of the COX-1 and -2 binding pockets to gain selectivity. COX-1 contains isoleucines at positions 434 and 523, whereas COX-2 has slightly smaller valines occupying these positions. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the adverse cardiovascular effects observed. Rofecoxib (like most "coxib" NSAIDs) is approximately ten times more selective for COX-2 than COX-1. Unlike celecoxib, rofecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. Like other NSAIDs, rofecoxib exhibits anti-inflammatory, analgesic, and antipyretic activity.

Rofecoxib Drug Action Pathway (New) References