COX-2 Enzyme and its Inhibitors

P.   M.   Sivakumar; Mukesh      Doble

Abstract

Cyclooxygenases (COX) are involved in the biosynthesis of prostaglandins from arachidonic acid (AA). At least three cyclooxygenase enzymes were believed to be present and the first two are constitutive (COX-1) and inducible (COX-2) in nature, while little information is available about the third enzyme. Classical NSAIDs are in use for a very long time which are known to inhibit both the COX enzymes and, they are used in treating inflammatory, thrombosis and analgesia. Inhibition of both the isoforms leads to side effects, while selective inhibition of COX-2, leads to therapeutically beneficial effect. Structurally different group of compounds called coxibs have been synthesized with increased selectivity towards COX-2 enzyme and as expected have reduced gastrointestinal toxicity. Further studies showed that selective COX-2 inhibitors could be useful in the treatment of colon cancer, angiogenesis, and Alzheimers disease. Recently due to their cardiovascular risk, COX-2 inhibitors namely rofecoxib and valdecoxib have been withdrawn from the market while the mechanism behind this side effect is unknown. Till now aspirin is the only NSAID with cardiovascular safety and is known to inhibit COX-1, which is absent with drugs like naproxen. So a detailed mechanistic understanding of the inhibition of COX-1 and COX-2 is imperative for better drug design with minimal side effect. In this review various structures that have been synthesized and natural products that have been tested towards COX -2 activity are discussed in detail. Also attempts are made to integrate structural requirements for coxibs and their interaction with the active site of both COX-1 and COX-2 enzymes.

Keywords: COX-2, NSAIDs, prostaglandins, inflammation, arachidonic acid