PHARMACOLOGICAL PROFILE OF JTE-522, A NOVEL PROSTAGLANDIN-H SYNTHASE-2 INHIBITOR, IN RATS

Objective and Design: The antinociceptive, antipyretic, and anti-infla mmatory effects of JTE-522, a novel selective prostaglandin H synthase (PGHS)-2 inhibitor, were examined in rats. Materials: Sheep seminal v esicle PGHS-1 and placenta PGHS-2 were used for in vitro assay, while for in vivo experiments, male rats (4-8 weeks old) were used. Treatmen t: JTE-522 and reference compounds (0.01-100 mu M) were subjected to e nzyme assay. JTE-522 (0.3-30 mg/kg) and indomethacin (0.3-10 mg/kg) we re administered orally. Results: JTE-522 inhibited PGHS-2 (IC50: 0.64 mu M) without affecting PGHS-1 activity at 100 mu M. In rats with yeas t induced hyperalgesia, JTE-522 showed a dose-dependent antinociceptiv e effect (ED50: 4.4 mg/kg). In rats with yeast-induced pyrexia, JTE-52 2 significantly reversed the pyrexic response (ED50: 3.9 mg/kg). Orall y administered JTE-522 dose-dependently inhibited carrageenin-induced rat paw edema (ED30: 4.7 mg/kg). In rats with adjuvant-induced arthrit is, JTE-522 showed a significant inhibitory effect at daily doses of 0 .3-3 mg/kg. JTE-522 did not cause severe gastric lesions at oral doses up to 300 mg/kg. Conclusions: Our results indicate that the selective PGHS-2 inhibitor JTE-522 may represent a novel type of anti-inflammat ory drug without adverse effects on the gastrointestinal tract. JTE-52 2 may thus be a promising agent for treating both acute inflammatory d iseases and chronic inflammatory diseases such as rheumatoid arthritis .