title: Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia.
abstract: Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. Electronic address: anthony_roecker@merck.com.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. Electronic address: treger@gtweed.com.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Reger
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: M Christa
authors.initials: MC
authors.lastname: Mattern
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Swati P
authors.initials: SP
authors.lastname: Mercer
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bergman
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Schreier
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Rowena V
authors.initials: RV
authors.lastname: Cube
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Dansu
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: C Meacham
authors.initials: CM
authors.lastname: Harrell
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.affiliation: Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Cabalu
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Donghui
authors.initials: D
authors.lastname: Cui
authors.affiliation: Department of Basic Pharmaceutical Sciences, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: Stellabott
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Young
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000068796:Orexin Receptor Antagonists; D011725:Pyridines; D013844:Thiazoles; C000596387:MK-3697
keywords: 2-SORA; Antagonists; Insomnia; Neurotransmitters; Orexin receptors