The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX₁) and orexin-2 (OX₂) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure–activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.

中文翻译：

---

（1 R，2 S）-2-{[（（2,4-二甲基嘧啶-5-基）氧基]甲基} -2-（3-氟苯基）-N-（5-氟吡啶-2-基）环丙烷甲酰胺的发现（E2006）：高效有效的口服Orexin受体拮抗剂

Orexin / hypocretin受体是G蛋白偶联受体的一个家族，由orexin-1（OX ₁）和orexin-2（OX ₂）受体亚型组成。食欲素受体在整个中枢神经系统中表达，并参与睡眠/觉醒周期的调节。由于这些受体的调节构成了与睡眠和清醒控制相关的疾病（如失眠）的新型治疗的有希望的靶标，因此，orexin受体拮抗剂的开发已成为药物发现研究中的重要重点。在这里，我们报告了新型orexin受体拮抗剂的设计，合成，表征和结构-活性关系（SAR）。对先前开发的化合物的核心结构进行了各种修改（-）-5（铅分子）产生具有改进的化学和药理学特征的化合物。研究提供了潜在的治疗剂，（1 R，2 S）-2-{[（（2,4-二甲基嘧啶-5-基）氧基]甲基} -2-（3-氟苯基）-N-（5-氟吡啶） -2-基）环丙烷甲酰胺（E2006），一种口服活性，有效的食欲素拮抗剂。通过使用睡眠参数测量，在体内研究中在小鼠中证明了该功效。