Pharmacology of a selective cyclooxygenase-2 inhibitor, HN-56249: a novel compound exhibiting a marked preference for the human enzyme in intact cells

HN-56249 (3-(2,4-dichlorothiophenoxy)-4-methylsulfonylamino-benzenesulfonam ide), a highly selective cyclooxygenase (COX)-2 inhibitor, is the prototype of a novel series of COX inhibitors comprising bicyclic arylethersulfonami des; of this series HN-56249 is the most potent and selective human COX-2 i nhibitor. HN-56249 inhibited platelet aggregation as a measure of COX-1 activity only moderately (IC50 26.5+/-1.7 mu M). In LPS-stimulated monocytic cells the r elease of prostaglandin (PG) F-1 alpha as a measure of COX-2 was markedly i nhibited (IC50 0.027+/-0.001 CIM) Thus, HN-56249 showed an approximately 10 00-fold selectivity for COX-2 in intact cells. In whole blood assays HN-562 49 showed a potent inhibitory activity for COX-2 (IC50 0.78+/-0.37 mu M) on ly. COX-1 was only weakly inhibited (IC50 867+/-181 mu M). Hence, HN-56249 exhibited a greater than 1000-fold selectivity for whole blood COX-2. HN-56 249 surpassed the COX-2 selectivities of the COX-2 selective inhibitors 3-c yclohexyloxy-4-methylsulfonylamino-nitro-benzene (NS-398) and 6-(2,4-difluo rophenoxy)-5-methylsulfonylamino-1-indanone (flosulide) in the intact cell assays by eight- and threefold, respectively, and in the whole blood assays by approximately 40-fold. Following i.v. administration HN-56249 inhibited carrageenan-induced rat pa w oedema only moderately (ID50 26.2+/-5.7 mg/kg, mean +/- SEM), approximate ly tenfold less potent than indomethacin (ID50 2.1+/-0.2 mg/kg, mean +/- SE M). After oral administration HN-56249 reversed thermal hyperalgesia in the carrageenan-induced rat paw oedema test, however, some 30-fold less potent ly than diclofenac. Comparing the inhibitory potency of HN-56249 against hu man COX-2 with that against murine COX-2 in intact cells revealed a 300-fol d selectivity for the human enzyme. Similar effects were observed with othe r COX-2-selective arylethersulfonamides. In contrast, non-COX-2-selective a rylethersulfonamides, including a highly selective COX-1 inhibitor, inhibit ed human and murine COX-2 approximately equipotently. In conclusion, HN-56249 is a novel potent and highly selective COX-2 inhibi tor with a marked preference for the human COX-2 enzyme in vitro. Despite e xcellent bioavailability and the long plasma half-life of HN-56249, anti-in flammatory effects in rodents were only moderate. We suggest these differin g in vitro-in vivo effects observed could be due to significant inflammator y prostaglandin synthesis by COX-1, or to the genetic differences between h uman and rodent COX-2, or to both.