title: Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia.
abstract: Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA. chris_cox@merck.com
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Breslin
authors.forename: David B
authors.initials: DB
authors.lastname: Whitman
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: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.forename: Swati P
authors.initials: SP
authors.lastname: Mercer
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.forename: Duane R
authors.initials: DR
authors.lastname: Reiss
authors.forename: C Meacham
authors.initials: CM
authors.lastname: Harrell
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Murphy
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.forename: Scott M
authors.initials: SM
authors.lastname: Doran
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Anderson
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.forename: Shane
authors.initials: S
authors.lastname: Roller
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Cabalu
authors.forename: Donghui
authors.initials: D
authors.lastname: Cui
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Steven D
authors.initials: SD
authors.lastname: Young
authors.forename: Ken S
authors.initials: KS
authors.lastname: Koblan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D064446:Orexin Receptors; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000235:genetics; D012890:Sleep / Q000187:drug effects; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013686:Telemetry; D014230:Triazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014851:Wakefulness / Q000187:drug effects
chemical_list: D001381:Azepines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014230:Triazoles; C551624:suvorexant