title: Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate.
abstract: The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (34), are described herein.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: Christine
authors.initials: C
authors.lastname: Dugovic
authors.forename: Tatiana
authors.initials: T
authors.lastname: Koudriakova
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.forename: Kiev S
authors.initials: KS
authors.lastname: Ly
authors.forename: Neelakandha S
authors.initials: NS
authors.lastname: Mani
authors.forename: Diane
authors.initials: D
authors.lastname: Nepomuceno
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pippel
authors.forename: Michele
authors.initials: M
authors.lastname: Rizzolio
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Shelton
authors.forename: Chandra R
authors.initials: CR
authors.lastname: Shah
authors.forename: Brock T
authors.initials: BT
authors.lastname: Shireman
authors.forename: Lana K
authors.initials: LK
authors.lastname: Young
authors.forename: Sujin
authors.initials: S
authors.lastname: Yun
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D004285:Dogs; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D011758:Pyrroles