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)