title: Design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as potent orexin receptor antagonists.
abstract: Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of orexin receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as orexin receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. paul_coleman@merck.com
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: John D
authors.initials: JD
authors.lastname: Schreier
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bogusky
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: C Meacham
authors.initials: CM
authors.lastname: Harrell
authors.forename: Duane R
authors.initials: DR
authors.lastname: Reiss
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D008958:Models, Molecular; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012893:Sleep Wake Disorders / Q000188:drug therapy
chemical_list: C545228:1,4-diazepane; D001381:Azepines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide