2,3-diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors

Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-positi on and a phenyl ring in the 2-position are selective inhibitors of cyclooxy genase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically impr oved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-d ifluorophenyl derivative 7 (L1776,967) and the 3-pyridyl derivative 13 (L-7 84,506) are particularly interesting as potential antiinflammatory agents w ith reduced side-effect profiles. Both exhibit good oral bioavailability an d are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonst eroidal antiflammatory drugs.