NOVEL 1,2-DIARYLCYCLOPENTENES ARE SELECTIVE, POTENT, AND ORALLY-ACTIVE CYCLOOXYGENASE INHIBITORS

1,2-Diarylcyclopentenes have been shown to be very potent inhibitors of the inducible form of cyclooxygenase (COX-2) with inhibition (IC50) in the low nanomolar range and selectivity ratios as great as four orders of magnitude. In vivo testing in the rat carrageenan-induced paw edema model has established that 1,2-diarylcyclopentenes are orally active antiinflammatory agents with inhibition as high as 39% at 10 mpk. 1,2-Diarylcyclopentene sulfonamide inhibitors 2 were also found to be very potent COX-2 inhibitors, although a concomitant increase in COX-1 activity rendered these analogs less selective overall. Geminal substitution at the 4-position of 1,2-diarylcyclopentenes 1 and 2 produced methyl sulfone inhibitors 3 and sulfonamide inhibitors 4, respectively, which were also less selective due to increased COX-1 activity. Dehydration of 3 and 4a provided novel planar cyclopentadiene methyl sulfone inhibitors 5 and sulfonamide inhibitor 6a, respectively, which were found to be even less selective.