Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia
Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia
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DOI：
10.1021/jm100541c
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发表时间：
2010-07-22
影响因子：
7.3
通讯作者：
Coleman, Paul J.
中科院分区：
文献类型：
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作者：
Cox, Christopher D.;Breslin, Michael J.;Coleman, Paul J.
尽管人们对大脑睡眠控制的生物学基础有了越来越多的了解，但近年来几乎没有发现治疗失眠的新机制。一个值得注意的例外是通过设计食欲素受体拮抗剂来抑制兴奋性神经肽食欲素A和B。在这里，我们描述了在HTS衍生的一种领先的地西平增食欲素受体拮抗剂中，为了了解口服药代动力学不良的原因，如何导致化合物10在地西平核心上进行了7-甲基取代。尽管10显示出良好的效力、改善的药代动力学和良好的体内疗效，但它在微粒体孵育中形成了反应性代谢物。一种机制假说，再加上一种评估生物活性的体外试验，导致用氯苯并恶唑取代了10个氟喹啉-唑啉环，以提供3(MK-4305)，这是一种有效的双增食欲素受体拮抗剂，目前正在进行治疗原发性失眠的第三阶段临床试验。
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 fluoroquina-zoline 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.