Tracing the origins of COX-2 inhibitors' structures.

Abstract

This review traces the origins of the chemical structure of the cyclooxygenase inhibitors celecoxib and rofecoxib. Early results from the search for non-steroid estrogens led to the triaryl-ethylenes such as chlortrianisene. A congener that incorporated a water-solubilizing basic ether grouping unexpectedly led to an estrogen antagonist and eventually the drug clomiphene. Elaboration of the structure gave the widely used drug used to treat breast cancer tamoxifen. Cyclized analogues such as nafoxidine showed equivalent activity but were not pursued. Later elaboration of those structures gave the now-marketed drug raloxifene. An indole analogue, indoxole, (2,3-dianisylindole) surprisingly showed anti-inflammatory activity. An analogue program designed to reduce photosensitivity from that compound eventually led to the discovery that the indole ring could be replaced by a simple thiazole, This resulted in the experimental cyclooxygenase inhibitor itazagrel. This compound incorporates many of the structural features found in celecoxib.