title: Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat.
abstract: Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. 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: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.forename: Swati P
authors.initials: SP
authors.lastname: Mercer
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: C Meacham
authors.initials: CM
authors.lastname: Harrell
authors.forename: Duane R
authors.initials: DR
authors.lastname: Reiss
authors.forename: Scott M
authors.initials: SM
authors.lastname: Doran
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Anderson
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
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: D000473:Alkanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055808:Drug Discovery; D004569:Electroencephalography; D006993:Hypnotics and Sedatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
chemical_list: D000473:Alkanes; D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; D006993:Hypnotics and Sedatives; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C017573:nonane