NOVEL TERPHENYLS AS SELECTIVE CYCLOOXYGENASE-2 INHIBITORS AND ORALLY-ACTIVE ANTIINFLAMMATORY AGENTS

A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhi bitors. The sulfonamide analogs 17 and 21 were found to be much more p otent COX-2 inhibitors and orally active anti-inflammatory agents than the corresponding methyl sulfone analogs 16 and 20, respectively, alb eit with some decrease in COX-2 selectivity. Structure-activity relati onship studies have determined that incorporation of two fluorine atom s in the central phenyl group, as in 20 and 21, is extremely advantage ous for both in vitro COX-2 potency and selectivity as well as in vivo activity. Several noticeable examples in the 1,2-diaryl-4,5-difluorob enzenesulfonamide series are 21a-c,k,l,n (COX-2, IC50 = 0.002-0.004 mu M), in which all have in vitro COX-1/COX-2 selectivity >1000. In addi tion, sulfonamides 21a,b,d,g,j,m,n,q were shown to have greatly enhanc ed oral activity with more than 90% inhibition of prostaglandin E(2) p roduction in the air pouch model of inflammation. Furthermore, sulfona mide 21b was found to be very active in the rat adjuvant-induced arthr itis model (ED(50) = 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED(50) = 38.7 mg/kg) with no indication of gastrointestinal tox icity in rats at doses as high as 200 mg/kg.