Pharmacological profile of JTE-522, a novel prostaglandin H synthase-2 inhibitor, in rats

Abstract.

Objective and Design: The antinociceptive, antipyretic, and anti-inflammatory effects of JTE-522, a novel selective prostaglandin H synthase (PGHS)-2 inhibitor, were examined in rats.¶Materials: Sheep seminal vesicle 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.¶Treatment: JTE-522 and reference compounds (0.01–100 μM) were subjected to enzyme assay. JTE-522 (0.3–30 mg/kg) and indomethacin (0.3–10 mg/kg) were administered orally.¶Results: JTE-522 inhibited PGHS-2 (IC₅₀: 0.64 μM) without affecting PGHS-1 activity at 100 μM. In rats with yeast-induced hyperalgesia, JTE-522 showed a dose-dependent antinociceptive effect (ED₅₀: 4.4 mg/kg). In rats with yeast-induced pyrexia, JTE-522 significantly reversed the pyrexic response (ED₅₀: 3.9 mg/kg). Orally administered JTE-522 dose-dependently inhibited carrageenin-induced rat paw edema (ED₃₀: 4.7 mg/kg). In rats with adjuvant-induced arthritis, 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-inflammatory drug without adverse effects on the gastrointestinal tract. JTE-522 may thus be a promising agent for treating both acute inflammatory diseases and chronic inflammatory diseases such as rheumatoid arthritis.