Novel Terphenyls as Selective Cyclooxygenase-2 Inhibitors and Orally Active Anti-inflammatory Agents

A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. The sulfonamide analogs <BO>17</BO> and <BO>21</BO> were found to be much more potent COX-2 inhibitors and orally active anti-inflammatory agents than the corresponding methyl sulfone analogs <BO>16</BO> and <BO>20</BO>, respectively, albeit with some decrease in COX-2 selectivity. Structure−activity relationship studies have determined that incorporation of two fluorine atoms in the central phenyl group, as in <BO>20</BO> and <BO>21</BO>, is extremely advantageous 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-difluorobenzenesulfonamide series are <BO>21a</BO>−<BO>c</BO>,<BO>k</BO>,<BO>l</BO>,<BO>n</BO> (COX-2, IC<INF>50</INF> = 0.002−0.004 μM), in which all have in vitro COX-1/COX-2 selectivity >1000. In addition, sulfonamides <BO>21a</BO>,<BO>b</BO>,<BO>d</BO>,<BO>g</BO>,<BO>j</BO>,<BO>m</BO>,<BO>n</BO>,<BO>q</BO> were shown to have greatly enhanced oral activity with more than 90% inhibition of prostaglandin E<INF>2</INF> production in the air pouch model of inflammation. Furthermore, sulfonamide <BO>21b</BO> was found to be very active in the rat adjuvant-induced arthritis model (ED<INF>50</INF> = 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED<INF>50</INF> = 38.7 mg/kg) with no indication of gastrointestinal toxicity in rats at doses as high as 200 mg/kg.