title: Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties.
abstract: Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. Electronic address: skuduk@noviratherapeutics.com.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Skudlarek
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Christina N
authors.initials: CN
authors.lastname: DiMarco
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Pausch
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: O'Brien
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Cabalu
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Brunner
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Savitz
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Harrell
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D004285:Dogs; D006207:Half-Life; D051379:Mice; D000068796:Orexin Receptor Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D064446:Orexin Receptors / Q000737:chemistry* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry; D051381:Rats; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy / Q000662:veterinary; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C573816:MK-6096; C000605130:MK-8133; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D010880:Piperidines; D011743:Pyrimidines; D014230:Triazoles
keywords: Antagonist; GPCR; Insomnia; Orexin; Sleep