Abstract

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