Jpn. J. Pharmacol. 78 (3), 365-371 (1998)


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

Korekiyo Wakitani, Toyomichi Nanayama, Michiko Masaki and Mutsuyoshi Matsushita


Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco, Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan

Abstract: Inhibitory activity and the mechanism of action of JTE-522 (4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide), 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.

Keywords: Cyclooxygenase, Cyclooxygenase-1, Cyclooxygenase-2, JTE-522, Non-steroidal anti-inflammatory drug (NSAID)


Copyrightę The Japanese Pharmacological Society 1998

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