2-Heterosubstituted-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl pyridines as selective and orally active cyclooxygenase-2 inhibitors

A series of novel 2-alkoxy, 2-thioalkoxy and 2-amino-3-(4-methylsulfonyl)phenylpyridines has been synthesized and shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. Structure-activity relationship studies have demonstrated that central pyridine ring substituents play an important role in the COX-2 potency, selectivity vs the COX-1 enzyme, and oral activity. A series of novel 2-heterosubstituted pyridine is described as selective COX-2 inhibitors from which several potent and orally bioavailable analogs were found to be very active in rat models of inflammation, pyrexia, and pain.