Discovery of a novel and potent dual orexin 1/2 receptor antagonist, lemborexant (E2006), for the treatment of sleep disorders

Abstract

The orexin receptors, two distinct G-protein coupled receptors (OX1R, OX2R) widely expressed in the brain, play a central role in the regulation of sleep and wakefulness. OX1R and OX2R exert their functions through the binding of endogenous neuropeptides orexin-A (hypocretin-1) and orexin-B (hypocretin-2) which are produced in the hypothalamus. Due to the therapeutic potential of modulating these receptors, it has been an active research area for the treatment of disorders associated with sleep/awake state control. Our original investigational drug, lemborexant, is a novel and potent dual orexin receptor antagonist derived from a unique tri-substituted cyclopropane chemical series, and the submission of the NDA and J-NDA for insomnia disorder treatment were achieved in Dec 2018 and Mar 2019, respectively. Moreover, a clinical trial for ISWRD (Irregular Sleep-Wake Rhythm Disorder) in Alzheimer dementia subjects is also ongoing. The drug discovery of lemborexant was already reported in the August 2018 issue, however, in this article we would like to elaborate on different details for the occasion of the Breakthrough Award, Division of Medicinal Chemistry, PSJ.