Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.

中文翻译：

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发现，合成，选择性调制和DMPK表征5-氮杂螺[2.4]庚烷作为有效的食欲素受体拮抗剂。

从orexin 1受体选择性拮抗剂4，4-二取代哌啶系列开始，发现了一种新型的有效的5-azaspiro [2.4]庚烷双重orexin 1和orexin 2受体拮抗剂。本文公开了该系列的SAR和药代动力学优化。铅化合物15在大鼠中表现出针对orexin 1和orexin 2受体的有效活性，以及​​低的细胞色素P450抑制潜能，良好的脑渗透性和口服生物利用度。