Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia

J Med Chem. 2010 Jul 22;53(14):5320-32. doi: 10.1021/jm100541c.


Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.

MeSH terms

  • Animals
  • Azepines / chemical synthesis
  • Azepines / pharmacokinetics
  • Azepines / pharmacology*
  • Biological Availability
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dogs
  • Humans
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / metabolism
  • Orexin Receptors
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / genetics
  • Sleep / drug effects
  • Sleep Initiation and Maintenance Disorders / drug therapy
  • Stereoisomerism
  • Structure-Activity Relationship
  • Telemetry
  • Triazoles / chemical synthesis
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*
  • Wakefulness / drug effects


  • Azepines
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Triazoles
  • suvorexant