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

ChemMedChem. 2012 Mar 5;7(3):415-24, 337. doi: 10.1002/cmdc.201200025. Epub 2012 Feb 3.


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.

MeSH terms

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


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