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Orexin Receptor Antagonists: Historical Perspectives and Future Opportunities

[ Vol. 16 , Issue. 29 ]


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


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.


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


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

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