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Updated: May 23, 2025

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Discovery of a New Class of Orexin 2 Receptor Agonists as a Potential Treatment for Narcolepsy

Davide Pozzi1, Romain Siegrist1, Jens-Uwe Peters1

  • 1Idorsia Pharmaceuticals Limited, Hegenheimermattweg 91, Allschwil CH-4123, Switzerland.

Journal of Medicinal Chemistry
|May 5, 2025
PubMed

Insights

Researchers discovered new OX2 agonists that stabilize wakefulness and reduce cataplexy. These brain-penetrant, orally bioavailable compounds show promise for treating narcolepsy type 1 and other hypersomnolence disorders.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • The orexinergic system regulates wakefulness via OX1 and OX2 receptors.
  • Narcolepsy Type 1 (NT1) involves orexin neuron loss, causing excessive sleepiness and cataplexy.
  • Current NT1 treatments manage symptoms but not the underlying cause.

Purpose of the Study:

  • To discover and characterize novel small-molecule OX2 agonists.
  • To evaluate the efficacy of these agonists in preclinical models of narcolepsy.

Main Methods:

  • Discovery of brain-penetrant, orally bioavailable OX2 agonists with a phenylglycine-like scaffold.
  • Assessment of compound efficacy in a mouse model of NT1.
  • Evaluation of wakefulness-promoting effects in healthy dogs.

Main Results:

  • Two novel OX2 agonists were identified.
  • These compounds demonstrated the ability to stabilize wakefulness and reduce cataplexy in an NT1 mouse model.
  • Increased wakefulness duration was observed in healthy dogs treated with the compounds.

Conclusions:

  • The novel OX2 agonists show therapeutic potential for narcolepsy and other hypersomnolence disorders.
  • These findings represent a significant advancement in the search for effective narcolepsy treatments.

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