title: Discovery of diazepane amide DORAs and 2-SORAs enabled by exploration of isosteric quinazoline replacements.
abstract: Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 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, 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, 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, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gilbert
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, 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, 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, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, 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, 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, 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, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Donghui
authors.initials: D
authors.lastname: Cui
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, PO Box 4, 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, 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, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011743:Pyrimidines; D011799:Quinazolines
keywords: Antagonists; Isostere; Orexin; Quinazoline; Sleep