Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders, stress and anxiety disorders, addiction or eating disorders. It consists of two G protein‐coupled receptors, the orexin 1 and orexin 2 receptors, and two neuropeptides with agonistic effects, the orexin A and orexin B peptides. Herein we describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology‐based pharmacokinetic and pharmacodynamic modelling>^[1] and finally led to the selection of daridorexant, currently in phase 3 clinical trials for the treatment of insomnia disorders.

中文翻译：

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寻求治疗失眠症的最佳双食欲素受体拮抗剂（daridorexant）。

自 1998 年被发现以来，食欲素系统一直是研究界感兴趣的潜在治疗靶点，用于治疗睡眠/觉醒障碍、压力和焦虑障碍、成瘾或饮食障碍。它由两种 G 蛋白偶联受体（orexin 1 和orexin 2 受体）和两种具有激动作用的神经肽（orexin A 和orexin B 肽）组成。在此，我们描述了我们的努力，导致确定一组有前途的双食欲素受体拮抗剂 (DORA)，随后通过基于生理学的药代动力学和药效学建模> ^[1]并最终选择了目前处于 3 期临床的 daridorexant治疗失眠障碍的试验。