Profile of JTE-522 as a human cyclooxygenase-2 inhibitor

Inhibitory activity and the mechanism of action of JTE-522 (4-(4-cyclohexyl -2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide), a novel selective cycloo xygenase (COX)-2 inhibitor, on human COX-1 and COX-2 were investigated and compared with those of reference compounds. In an enzyme assay, JTE-522 inh ibited yeast-expressed human recombinant COX-2 with an IC50 value of 0.085 mu M. In contrast, JTE-522 did not inhibit human COX-1 prepared from human platelets at concentrations up to 100 mu M. In a cell-based assay, JTE-522 diminished lipopolysaccharide-induced prostaglandin E-2 production in human peripheral blood mononuclear cells (COX-2) (IC50 value = 15.1 nM). On the other hand, JTE-522 was less potent at inhibiting calcium ionophore-induced thromboxane Bz production in washed human platelets (COX-1) (IC50 value = 6210 nM). JTE-522 showed highly selective inhibition of human COX-2, and it s activity was more selective than that of other COX-2 inhibitors (NS-398 a nd SC-58635). Human recombinant COX-2 activity was attenuated by JTE-522 in a dose-dependent and time-dependent manner. In contrast, the inhibitory ac tivity of JTE-522 on human COX-1 was not affected by preincubation time. CO X-2 inhibition by JTE-522 could not be recovered by gel filtration. These r esults indicate that JTE-522 is a highly selective, time-dependent and irre versible inhibitor of human COX-2.