SYNTHESIS AND BIOLOGICAL EVALUATION OF THE 1,5-DIARYLPYRAZOLE CLASS OF CYCLOOXYGENASE-2 INHIBITORS - IDENTIFICATION OF RIFLUOROMETHYL)-1H-PYRAZOL-1-YL]BENZENESULFONAMIDE (SC-58635, CELECOXIB)

A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (C OX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early stru ctural lead (1f, SC-236) exhibited an unacceptably long plasma half-li fe, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identificat ion of ii ifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the t reatment of rheumatoid arthritis and osteoarthritis.