RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 471
OP 482
DO 10.1124/jpet.115.225466
VO 354
IS 3
A1 Bonaventure, Pascal
A1 Shelton, Jonathan
A1 Yun, Sujin
A1 Nepomuceno, Diane
A1 Sutton, Steven
A1 Aluisio, Leah
A1 Fraser, Ian
A1 Lord, Brian
A1 Shoblock, James
A1 Welty, Natalie
A1 Chaplan, Sandra R.
A1 Aguilar, Zuleima
A1 Halter, Robin
A1 Ndifor, Anthony
A1 Koudriakova, Tatiana
A1 Rizzolio, Michele
A1 Letavic, Michael
A1 Carruthers, Nicholas I.
A1 Lovenberg, Timothy
A1 Dugovic, Christine
YR 2015
UL http://jpet.aspetjournals.org/content/354/3/471.abstract
AB 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.