Profile of JTE-522 as a Human Cyclooxygenase-2 Inhibitor

Abstract

Inhibitory activity and the mechanism of action of JTE-522 (4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamid e), a novel selective cyclooxygenase (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 inhibited yeast-expressed human recombinant COX-2 with an IC50 value of 0.085 microM. In contrast, JTE-522 did not inhibit human COX-1 prepared from human platelets at concentrations up to 100 microM. In a cell-based assay, JTE-522 diminished lipopolysaccharide-induced prostaglandin E2 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 B2 production in washed human platelets (COX-1) (IC50 value = 6210 nM). JTE-522 showed highly selective inhibition of human COX-2, and its activity was more selective than that of other COX-2 inhibitors (NS-398 and SC-58635). Human recombinant COX-2 activity was attenuated by JTE-522 in a dose-dependent and time-dependent manner. In contrast, the inhibitory activity of JTE-522 on human COX-1 was not affected by preincubation time. COX-2 inhibition by JTE-522 could not be recovered by gel filtration. These results indicate that JTE-522 is a highly selective, time-dependent and irreversible inhibitor of human COX-2.

Differential expression of cyclooxygenase-2 (COX-2) in human bile duct epithelial cells and bile duct neoplasm

“…Nonselective inhibitors showed suppressive effects only at very high concentration. JTE-522 has been reported to possess the selective inhibitory effects of COX-2, 67,81 and to inhibit colon cancer cell growth by inducing apoptosis or reducing the expression of MMPs. 80 These data do suggest that COX-2 protein does effect, at least in part, the proliferation program of BDC.…”

Recruitment of a Prostaglandin E Receptor Subtype, EP3-Expressing Bone Marrow Cells Is Crucial in Wound-Induced Angiogenesis

“…Aspirin was kindly provided by Merck (Rahway, NJ), NS-398 46 was obtained from Cayman Chemical (Ann Arbor, MI), and JTE-522 47 was kindly supplied by Japan Tobacco (Tokyo, Japan). EP receptor selective agonists, ONO-DI-004, ONO-AEI-257, ONO-AE-248, and ONO-AEI-329, 39 were kindly supplied from Ono Pharmaceutical Co., Osaka, Japan.…”

“…A COX-2 selective inhibitor, NS-398 46 or JTE522, 47 was suspended in 5% gum Arabic at a concentration of 6 mg/ml and was orally administered (0.05 ml/10 g body weight, 30 mg/kg, twice a day) to the WT mice. For vehicle control mice, distilled water with 5% gum Arabic was administered orally (0.05 ml/10 g body weight, twice a day).…”

COX-2/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

“…(Tokyo, Japan). JTE-522 (4-[4-cyclohexyl-2-methyloxazol-5-yl]-2-fluorobenzenesulfonamide) (Wakitani et al, 1998) was donated by Japan Tobacco Inc. (Tokyo, Japan). The hemoglobin assay kit was obtained from Wako Pure Chemical Industries Ltd. (Osaka, Japan).…”