title: Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.
abstract: In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.
authors.affiliation: Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: jason_skudlarek@merck.com.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Skudlarek
authors.affiliation: Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Christina N
authors.initials: CN
authors.lastname: DiMarco
authors.affiliation: Department of Chemical Capabilities & Screening, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.affiliation: Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.affiliation: Department of In Vitro Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.affiliation: Department of In Vitro Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pausch
authors.affiliation: Department of In Vitro Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: O'Brien
authors.affiliation: Department of Drug Metabolism, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Cabalu
authors.affiliation: Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Brunner
authors.affiliation: Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.affiliation: Discovery Pharmaceutical Sciences, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Wuelfing
authors.affiliation: Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.affiliation: Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.affiliation: Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Savitz
authors.affiliation: Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Harrell
authors.affiliation: Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Novira Therapeutics, Inc., a part of Janssen Pharmaceuticals, Doylestown, PA 18902, USA(1).
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.affiliation: Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D004569:Electroencephalography; D004576:Electromyography; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000068797:Orexins / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D000068796:Orexin Receptor Antagonists; D000068797:Orexins
keywords: Antagonist; GPCR; Insomnia; Orexin; Sleep