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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Discovery of Dual Orexin Receptor Antagonists (DORAs) for the Treatment of Insomnia

Author(s): Paul J. Coleman, Christopher D. Cox and Anthony J. Roecker

Volume 11, Issue 6, 2011

Page: [696 - 725] Pages: 30

DOI: 10.2174/1568026611109060696

Price: $65


Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptor antagonists promote sleep in animals and humans. Indeed, small molecule orexin receptor antagonists have demonstrated clinical proof-of-concept in the treatment of primary insomnia. This review describes optimization of orexin receptor antagonists across diverse structural classes with a focus on how molecules were designed to optimize potency, physicochemical properties, pharmacokinetics, brain penetration, and in vivo activity.

Keywords: Brain penetration, diazepane, g-protein coupled receptor, insomnia, neuropeptide, orexin, sleep, proof-of-concept, physicochemical properties, rapid eye movement (REM) sleep, prepro-orexin, sleep-wake cycle, DORA, cataplexy, high-throughput screen, dimethoxy-THIQ region

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