Preclinical pharmacological profiles of vornorexant, a novel potent dual orexin receptor antagonist.

Dual orexin receptor antagonists are known to inhibit the orexinergic signaling pathway, leading to promotion of sleep. Here, we report the pharmacological profiles of [(2S)-2-{[3-(5-Fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (vornorexant), also known as ORN0829. In in vitro assays, vornorexant exhibited a high affinity for OX₁ and OX₂ receptors, without any meaningful affinity for other receptors, transporters or ion channels, exerting receptor antagonist activity. Vornorexant had pharmacokinetic profiles with a relatively rapid absorption and short half-life, rapidly occupied the OX₁ and OX₂ receptors in the brain of rats after oral administration and rapidly dissociated from these receptors depending on the plasma concentration. In rats, daily oral administration of vornorexant just before the dark phase reduced the sleep onset latency and prolonged sleep time, and no tolerance developed up to 14 days. Vornorexant also reduced the sleep onset latency and prolonged sleep time in rats that had developed tolerance after daily treatment with the GABA_A receptor modulator, zolpidem. In addition, vornorexant also enhanced the sleep-promoting effects of zolpidem in rats. Moreover, vornorexant did not impair motor coordination in monotherapy and combination with ethanol in rats. These results indicate that vornorexant has desirable profiles with a rapid sleep onset latency and a short half-life, thereby a lowered risk of next-morning residual activity. Vornorexant could be a promising alternative therapeutic option to GABA_A receptor modulators for the treatment of insomnia. SIGNIFICANCE STATEMENT: Vornorexant is a novel and potent dual orexin receptor antagonist that was demonstrated to exert sleep-promoting effects by occupying the OX₁ and OX₂ receptors in the brain of rats. Moreover, vornorexant promoted sleep even after switching treatment from zolpidem or when administered in combination with zolpidem in rats. These results suggest that vornorexant possesses properties that are desirable for insomnia drugs.