Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors

Recent studies from our laboratory have shown that derivatization of the ca rboxylate moiety in substrate analogue inhibitors, such as 5,8,11,14-eicosa tetraynoic acid, and in nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin and meclofenamic acid, results in the generation of potent and selective cyclooxygenase-2 (COX-2) inhibitors (Kalgutkar et al. Proc. N atl. Acad. Sci. U.S.A. 2000, 97, 925-930). This paper summarizes details of the structure-activity studies involved in the transformation of the aryla cetic acid NSAID, indomethacin, into a COX-2-selective inhibitor. Many of t he structurally di diverse indomethacin esters and amides inhibited purifie d human COX-2 with IC50 values in the low-nanomolar range but did not inhib it ovine COX-1 activity at concentrations as high as 66 mu M. Primary and s econdary amide analogues of indomethacin tt ere more potent as COX-2 inhibi tors than the corresponding tertiary amides. Replacement of the 4-chloroben zoyl group in indomethacin esters or amides with the 4-bromohenzyl function ality or hydrogen afforded inactive compounds. Likewise, exchanging the 2-m ethyl group on the indole ring in the ester and amide series with a hydroge n also generated inactive compounds. Inhibition kinetics revealed that indo methacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Conversion of indomet hacin into ester and amide derivatives provides a facile strategy for gener ating highly selective COX-2 inhibitors and eliminating the gastrointestina l side effects of the parent compound.