Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5562-7. doi: 10.1016/j.bmcl.2011.06.086. Epub 2011 Jun 30.


The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Orexin Receptors
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism
  • Sleep Wake Disorders / drug therapy*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Orexin Receptors
  • Piperidines
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • piperidine