TY - JOUR T1 - Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 471 LP - 482 DO - 10.1124/jpet.115.225466 VL - 354 IS - 3 AU - Pascal Bonaventure AU - Jonathan Shelton AU - Sujin Yun AU - Diane Nepomuceno AU - Steven Sutton AU - Leah Aluisio AU - Ian Fraser AU - Brian Lord AU - James Shoblock AU - Natalie Welty AU - Sandra R. Chaplan AU - Zuleima Aguilar AU - Robin Halter AU - Anthony Ndifor AU - Tatiana Koudriakova AU - Michele Rizzolio AU - Michael Letavic AU - Nicholas I. Carruthers AU - Timothy Lovenberg AU - Christine Dugovic Y1 - 2015/09/01 UR - http://jpet.aspetjournals.org/content/354/3/471.abstract N2 - Dual orexin receptor antagonists have been shown to promote sleep in various species, including humans. Emerging research indicates that selective orexin-2 receptor (OX2R) antagonists may offer specificity and a more adequate sleep profile by preserving normal sleep architecture. Here, we characterized JNJ-42847922 ([5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone), a high-affinity/potent OX2R antagonist. JNJ-42847922 had an approximate 2-log selectivity ratio versus the human orexin-1 receptor. Ex vivo receptor binding studies demonstrated that JNJ-42847922 quickly occupied OX2R binding sites in the rat brain after oral administration and rapidly cleared from the brain. In rats, single oral administration of JNJ-42847922 (3–30 mg/kg) during the light phase dose dependently reduced the latency to non–rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, whereas REM sleep was minimally affected. The reduced sleep onset and increased sleep duration were maintained upon 7-day repeated dosing (30 mg/kg) with JNJ-42847922, then all sleep parameters returned to baseline levels following discontinuation. Although the compound promoted sleep in wild-type mice, it had no effect in OX2R knockout mice, consistent with a specific OX2R-mediated sleep response. JNJ-42847922 did not increase dopamine release in rat nucleus accumbens or produce place preference in mice after subchronic conditioning, indicating that the compound lacks intrinsic motivational properties in contrast to zolpidem. In a single ascending dose study conducted in healthy subjects, JNJ-42847922 increased somnolence and displayed a favorable pharmacokinetic and safety profile for a sedative/hypnotic, thus emerging as a promising candidate for further clinical development for the treatment of insomnia. ER -