A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors

Cyclo-oxygenase (COX) enzymes are the targets for non-steroidal anti-inflam matory drugs (NSAIDs). These drugs demonstrate a variety of inhibitory mech anisms, which include simple competitive, as well as slow binding and irrev ersible inhibition. In general, most NSAIDs inhibit COX-1 and -2 by similar mechanisms. A unique class of diarylheterocyclic inhibitors has been devel oped that is highly selective for COX-2 by virtue of distinct inhibitory me chanisms for each isoenzyme. Several of these inhibitors, with varying sele ctivity, have been utilized to probe the mechanisms of COX inhibition. Resu lts from analysis of both steady-state and time-dependent inhibition were c ompared. A generalized mechanism for inhibition, consisting of three sequen tial reversible steps, can account for the various types of kinetic behavio ur observed with these inhibitors.