From Indomethacin to a Selective Cox-2 Inhibitor

Abstract

It has been known since the early 1970’s that nonsteroidal antiinflammatory drugs (NSAIDs) exert their antinflammatory effects through the blocking of the synthesis of prostaglandins (PGs) by inhibiting cyclooxygenäse (COX).¹ Cyclooxygenase was believed to be a single enzyme present constitutively in many tissues. It is believed to be involved in the maintenance of essential physiological function such as platelet aggregation, cytoprotection in the stomach and maintenance of normal kidney function. While inhibiting the production of proinflammatory prostaglandins at the inflammatory sites, NSAIDs also reduce the cytoprotective PGs in the gastrointestinal (GI) tract, leading to mechanism-based GI toxicity.² The recent discovery of an inducible isoform of cyclooxygenase (COX-2) that is associated primarily with inflammation^3–5 has led to the hypothesis that NSAID-in-duced toxicity in the GI tract may be caused by the inhibition of the beneficial constitutive isoform of cyclooxygenase (COX-1) in these tissues, while the antiinflammatory effect of NSAIDs is due to the inhibition of the inducible isoform (COX-2) at the inflammation site. A selective COX-2 inhibitor has the potential therefore to be an effective antiinflammatory drug with reduced GI toxicity compared to current NSAIDs.