title: Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia.
abstract: 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.
authors.affiliation: Janssen Research & Development, LLC, San Diego, California Pbonave1@its.jnj.com CDugovic@its.jnj.com.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shelton
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Sujin
authors.initials: S
authors.lastname: Yun
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Diane
authors.initials: D
authors.lastname: Nepomuceno
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Steven
authors.initials: S
authors.lastname: Sutton
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Ian
authors.initials: I
authors.lastname: Fraser
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: James
authors.initials: J
authors.lastname: Shoblock
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Natalie
authors.initials: N
authors.lastname: Welty
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Zuleima
authors.initials: Z
authors.lastname: Aguilar
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Robin
authors.initials: R
authors.lastname: Halter
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ndifor
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Koudriakova
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Michele
authors.initials: M
authors.lastname: Rizzolio
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Letavic
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lovenberg
authors.affiliation: Janssen Research & Development, LLC, San Diego, California Pbonave1@its.jnj.com CDugovic@its.jnj.com.
authors.forename: Christine
authors.initials: C
authors.lastname: Dugovic
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000068796:Orexin Receptor Antagonists; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy* / Q000378:metabolism; D012894:Sleep Stages / Q000187:drug effects; D012895:Sleep, REM / Q000187:drug effects; D000077334:Zolpidem
chemical_list: D006993:Hypnotics and Sedatives; D000068796:Orexin Receptor Antagonists; D011725:Pyridines; D000077334:Zolpidem; D004298:Dopamine