Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.

中文翻译：

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发现双食欲素受体拮抗剂[（7 R）-4-（5-氯-1,3-苯并恶唑-2-基）-7-甲基-1,4-二氮杂-1-基] [5-甲基- 2-（2 H -1,2,3-三唑-2-基）苯基]甲酮（MK-4305）治疗失眠

尽管人们对大脑睡眠控制的生物学基础有了更多的了解，但近年来已发现很少有治疗失眠的新机制。一个显着的例外是通过设计orexin受体拮抗剂来抑制兴奋性神经肽orexins A和B。在本文中，我们描述了如何努力理解领先的HTS衍生的二氮杂环庚烷orexin受体拮抗剂中不良口服药代动力学的起源如何导致在二氮杂环庚烷核心上被7-甲基取代的化合物10的鉴定。虽然10它显示出良好的效能，改善的药代动力学和出色的体内功效，在微粒体温育中形成了反应性代谢产物。机械学假说与用于评估生物激活作用的体外测定法相结合，导致用氯苯并恶唑取代10的氟喹唑啉环，从而提供3（MK-4305），这是一种有效的双食欲素受体拮抗剂，目前正在III期临床试验中进行测试原发性失眠的治疗。