1. Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties.
- Author
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Coleman PJ, Schreier JD, Cox CD, Breslin MJ, Whitman DB, Bogusky MJ, McGaughey GB, Bednar RA, Lemaire W, Doran SM, Fox SV, Garson SL, Gotter AL, Harrell CM, Reiss DR, Cabalu TD, Cui D, Prueksaritanont T, Stevens J, Tannenbaum PL, Ball RG, Stellabott J, Young SD, Hartman GD, Winrow CJ, and Renger JJ
- Subjects
- Animals, Brain drug effects, Brain metabolism, Dogs, Drug Discovery, Humans, Hypnotics and Sedatives pharmacokinetics, Hypnotics and Sedatives pharmacology, Magnetic Resonance Spectroscopy, Models, Molecular, Orexin Receptors, Piperidines pharmacokinetics, Piperidines pharmacology, Protein Binding, Pyridines pharmacokinetics, Pyridines pharmacology, Rats, Receptors, G-Protein-Coupled metabolism, Receptors, Neuropeptide metabolism, Sleep, Sleep Initiation and Maintenance Disorders metabolism, Stereoisomerism, Structure-Activity Relationship, Triazoles pharmacokinetics, Triazoles pharmacology, Wakefulness drug effects, Hypnotics and Sedatives chemical synthesis, Piperidines chemical synthesis, Pyridines chemical synthesis, Receptors, G-Protein-Coupled antagonists & inhibitors, Receptors, Neuropeptide antagonists & inhibitors, Sleep Initiation and Maintenance Disorders drug therapy, Triazoles chemical synthesis
- Abstract
Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexin 1 and orexin 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
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