title: Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant.
abstract: Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Izzat T
authors.initials: IT
authors.lastname: Raheem
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Breslin
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bruno
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Cabalu
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Donghui
authors.initials: D
authors.lastname: Cui
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Garson
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: C Meacham
authors.initials: CM
authors.lastname: Harrell
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Stump
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Williams
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D004987:Ethers; C573816:MK-6096; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D010880:Piperidines; D011743:Pyrimidines; C032727:piperidine
keywords: Active wake; Delta sleep; Dual orexin receptor antagonist (DORA); Filorexant; REM sleep; Selective orexin receptor antagonist (SORA)