Mechanism of inhibition of novel COX-2 inhibitors.

Rome and Lands (1975) demonstrated that certain nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified by indomethacin, displayed time dependent inhibition of cyclooxygenase (COX) and that this type of time dependent inhibition is consistent with a two step model. The first step in this model represents the association of enzyme and inhibitor to form a rapidly reversible complex. The second step represents formation of an extremely tight, non-covalent complex that is only slowly reversible. With the recognition of distinct isoforms, it has also been established that COX-2 selective inhibitors are time dependent inhibitors of COX-2, but not of COX-1. This difference in mechanism of inhibition of COX-1 and COX-2 is the basis for their selectivity (Copeland et al., 1994). Time dependence of COX-2 selective inhibitors has been correlated to the presence of a side pocket present in the active site of COX-2 but not COX-1 (Gierse et al., 1996).