2. Academic Validation
  3. Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia

Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia

  • J Med Chem. 2013 Oct 10;56(19):7590-607. doi: 10.1021/jm4007627.
Claudia Betschart 1,  Samuel Hintermann,  Dirk Behnke,  Simona Cotesta,  Markus Fendt,  Christine E Gee,  Laura H Jacobson,  Grit Laue,  Silvio Ofner,  Vinod Chaudhari,  Sangamesh Badiger,  Chetan Pandit,  Juergen Wagner,  Daniel Hoyer
Affiliations

Affiliation

  • 1 Global Discovery Chemistry, ‡Neuroscience, and §Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
PMID: 23964859 DOI: 10.1021/jm4007627
Abstract

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, 1 (SB-649868), or suvorexant have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials in volunteers and primary insomnia patients. The relative contribution of antagonism of OX1R and OX2R for sleep induction is still a matter of debate. We therefore initiated a drug discovery project with the aim of creating both OX2R selective antagonists and DORAs. Here we report that the OX2R selective antagonist 26 induced sleep in mice primarily by increasing NREM sleep, whereas the DORA suvorexant induced sleep largely by increasing REM sleep. Thus, OX2R selective antagonists may also be beneficial for the treatment of insomnia.

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