CYCLOOXYGENASE-2 INHIBITORS - SYNTHESIS AND PHARMACOLOGICAL ACTIVITIES OF 5-METHANESULFONAMIDO-1-INDANONE DERIVATIVES

The recent discovery of an alternative form cyclooxygenase (cyclooxyge nase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-in flammatory drugs with fewer side effects than existing nonsteroidal an ti-inflammatory drugs (NSAIDs). We have now identified fluorophenyl)th io]-5-methanesulfonamido-1-indanone (20) (L-745,337) as a potent, sele ctive, and orally active COX-2 inhibitor. The structure-activity relat ionships in this series have been extensively studied. Ortho- and para -substituted B-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave comp ounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 2 0 has an efficacy profile that is superior or comparable to that of th e nonselective COX inhibitor indomethacin in animal models of inflamma tion, pain, and fever and appears to be nonulcerogenic within the dosa ge ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, c ompound 20 is more potent in the rat paw edema assay, has a longer t(1 /2) in squirrel monkeys, and seems less ulcergenic than 2 in rats.