Orexin Receptor Antagonists: Historical Perspectives and Future Opportunities

Author(s):

Stephen P. Andrews, Sarah J. Aves, John A. Christopher and Rebecca Nonoo   Pages 3438 - 3469 ( 32 )

Abstract:

The orexin receptors OX₁ and OX₂ play important roles in the regulation of sleep-wake cycles, feeding, reward and energy homeostasis. Since these G protein-coupled receptors were deorphanised in 1998, more than 200 patents containing orexin receptor antagonists have been filed and, in 2014, suvorexant (Belsomra®) became the first of these compounds to receive approval from the FDA. Suvorexant is a dual orexin receptor antagonist (DORA) which is available for the treatment of insomnia. This review provides a historical perspective on the discovery and development of DORAs as well as selective OX₁ receptor antagonists (1-SORAs) and selective OX₂ receptor antagonists (2-SORAs). 2-SORAs are under clinical evaluation for their ability to modulate sleep, and 1-SORAs have shown promise for the treatment of addiction in pre-clinical animal models. Detailed medicinal chemistry case studies are presented and future opportunities for orexin receptor antagonists are considered.

Keywords:

Antagonist, DORA, Insomnia, Orexin, Sleep, SORA, Suvorexant.

Affiliation:

Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK.

Graphical Abstract:

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