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Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

Swati P Mercer1, Anthony J Roecker, Susan Garson

  • 1Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.

Bioorganic & Medicinal Chemistry Letters
|November 13, 2013
PubMed

Insights

Researchers developed new selective orexin-2 receptor antagonists (2-SORAs) for insomnia treatment. A novel compound showed significant sleep promotion in rats, offering a potential new therapeutic avenue.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • The orexin system is a key target for insomnia treatment.
  • Selective orexin-2 receptor antagonists (2-SORAs) are needed for further research.
  • Previous development was limited by a lack of suitable small molecule probes.

Purpose of the Study:

  • To discover and optimize novel, orally bioavailable, and selective orexin-2 receptor antagonists.
  • To identify potent small molecule probes for studying the orexin system.

Main Methods:

  • Medicinal chemistry optimization of 2,5-diarylnicotinamides.
  • In vivo testing of lead compounds in EEG telemetrized rats.

Main Results:

  • A novel series of 2,5-diarylnicotinamides were identified as potent orexin-2 receptor antagonists.
  • Compounds demonstrated oral bioavailability.
  • One compound promoted sleep in rats.

Conclusions:

  • The discovered 2,5-diarylnicotinamides are promising candidates for selective orexin-2 receptor antagonism.
  • These compounds can serve as valuable tools for further research into the orexin system and sleep.
  • This work advances the development of novel insomnia therapeutics.
Keywords:
HypocretinInsomniaOrexin receptor antagonistsRat sleep EEGSelective orexin-2 receptor antagonists

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