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.

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.

• Authors: Paul J Coleman, John D Schreier, Christopher D Cox, Michael J Breslin, David B Whitman, Michael J Bogusky, Georgia B McGaughey, Rodney A Bednar, Wei Lemaire, Scott M Doran, Steven V Fox, Susan L Garson, Anthony L Gotter, C Meacham Harrell, Duane R Reiss, Tamara D Cabalu, Donghui Cui, Thomayant Prueksaritanont, Joanne Stevens, Pamela L Tannenbaum, Richard G Ball, Joyce Stellabott, Steven D Young, George D Hartman, Christopher J Winrow, John J Renger
• Journal: ChemMedChem (ChemMedChem) Vol. 7 Issue 3 Pg. 415-24, 337 (Mar 05 2012) ISSN: 1860-7187 [Electronic] Germany
• PMID: 22307992 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• DORA-22
• Hypnotics and Sedatives
• Orexin Receptors
• Piperidines
• Pyridines
• Receptors, G-Protein-Coupled
• Receptors, Neuropeptide
• Triazoles

Topics

• Animals
• Brain (drug effects, metabolism)
• Dogs
• Drug Discovery
• Humans
• Hypnotics and Sedatives (chemical synthesis, pharmacokinetics, pharmacology)
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Orexin Receptors
• Piperidines (chemical synthesis, pharmacokinetics, pharmacology)
• Protein Binding
• Pyridines (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Receptors, G-Protein-Coupled (antagonists & inhibitors, metabolism)
• Receptors, Neuropeptide (antagonists & inhibitors, metabolism)
• Sleep
• Sleep Initiation and Maintenance Disorders (drug therapy, metabolism)
• Stereoisomerism
• Structure-Activity Relationship
• Triazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Wakefulness (drug effects)