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The orexin system plays a pivotal role in regulating sleep and wakefulness, thus, orexin receptors (OX1 and OX2 receptors) have gained much attention as promising therapeutic targets for the treatment of insomnia. We synthesized a novel and potent dual orexin receptor antagonist (DORA), ORN0829 (investigation code name as TS-142), which was designed to have short-acting effects. Here we report pharmacological and pharmacokinetic profiles of ORN0829 in rats. Methods The antagonistic activities of ORN0829 were assessed using calcium mobilization assays. Ala-orexin A-induced [Ca2+]i response was measured with CHO-K1 cells stably expressing human/rat orexin receptor. Rats implanted the EEG/EMG electrodes were orally administrated ORN0829 at doses of 1, 3 or 10 mg/kg at the dark onset and sleep-wake stages were inspected visually. In addition, pharmacokinetic profiles of ORN0829 were investigated in rats. Results ORN0829 inhibited Ala-orexin A-increased [Ca2+]i response with a Kb of 0.67/0.44 nmol/L (for human/rat OX1 receptor), and with a Kb of 0.84/0.80 nmol/L (for human/rat OX2 receptor), respectively, indicating that ORN0829 is a potent DORA with no species differences. ORN0829 dose-dependently increased total sleep time and reduced sleep onset latency at doses of 1, 3 and 10 mg/kg. Importantly, the ORN0829 levels in plasma and cerebrospinal fluid rapidly reached a maximum concentration, and decreased with an elimination half-life of less than 1 h. Conclusion The present study indicates that ORN0829 is a novel and potent DORA with sleep-promoting effects, and that it exhibits ideal pharmacokinetic profiles (rapid absorption and short half-life) in rats. A phase 2a study of TS-142 using patients with insomnia has been completed, which is presented in a separate poster. Support Taisho Pharmaceutical. Co., Ltd.

0004 TS-142: A Novel and Potent Dual Orexin Receptor Antagonist with Sleep-Promoting Effects in Rats