1,2-DIARYLCYCLOPENTENES AS SELECTIVE CYCLOOXYGENASE-2 INHIBITORS AND ORALLY-ACTIVE ANTIINFLAMMATORY AGENTS

A series of 1,2-diarylcyclopentene methyl sulfones and sulfonamides ha ve been shown to be remarkably potent and selective cyclooxygenase-2 ( COX-2) inhibitors. The methyl sulfone analogs 7 showed excellent COX-2 activity, with IC(50)s ranging from 0.003 (7f,n) to 0.87 (7o) mu(M. I n addition, most analogs of 7 showed no activity (IC50 > 100 mu M) aga inst the COX-1 enzyme. Replacement of the methyl sulfone moiety with a sulfonamide group gave a slightly more potent (typically 2-5-fold) bu t less selective COX-2 inhibitor, mainly due to an increase (20- > 100 -fold) in COX-1 activity. However, in vitro COX-1/COX-2 selectivity fo r the sulfonamides 8 could be increased in many cases by simply incorp orating a substituent at the 3-position of the phenyl group. Furthermo re, in vitro selectivity increased with the size and number of substit uents, as demonstrated in the selectivity trend of 8k (8000) > 8j (190 0) > 8i (500) > 8h (100). More importantly, the sulfonamide COX-2 inhi bitors showed greatly enhanced oral activity in the rat model of estab lished adjuvant-induced arthritis, with inhibition values of 79.0% (8a ), 81.5% (8c), and 83.0% (8g) at 1 mg/kg. On the basis of its overall biological profile, sulfonamide 8c was evaluated as a potential clinic al candidate, displaying an ED(50) of 22 mpk in the rat carrageenan-in duced paw edema model and an ED(50) of 0.16 mpk in the rat established adjuvant-induced arthritis model with no indication of gastrointestin al toxicity in rats and mice at 200 mpk. In addition, a preparative-sc ale synthetic route to sulfonamide 8c has been developed.