A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for G signaling to measure agonistic activation of the orexin receptor type 2 (OXR). These compounds were synthesized in 4–9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OXR coupled G signaling. Our results also indicate that agonistic activity was stereospecific at both the benzylic and homobenzylic stereogenic centra. We identified methoxyethoxy-substituted pyrido-fused dihydroimidazolimine analog containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC of 339 nM and a maximal response (E) of 96 % in this assay. In vivo pharmacokinetic analysis indicated good brain exposure for several analogs. Our combined results provide important information towards a structurally novel class of orexin receptor agonists distinct from current chemotypes.

中文翻译：

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基于芳烃或吡啶稠合 1,3-二氢-2H-咪唑-2-亚胺的新型食欲素受体激动剂

设计了一类结构新颖的苯并或吡啶并稠合 1,3-二氢-2-咪唑-2-亚胺，并在肌醇磷酸积累测定中进行评估，以检测 G 信号传导，以测量 2 型食欲素受体 (OXR) 的激动活性。这些化合物是用容易获得的起始材料通过 4-9 个步骤合成的。苄基中心含有立体甲基或环丙基取代基以及正确配置的烷基醚、烷氧基烷基醚、氰基烷基醚或 α-羟基乙酰胺基取代的同型苄基侧链的类似物被认为是 OXR 偶联 G 信号传导的最有效激活剂。我们的结果还表明，苯甲基和同型苯甲基立体中心的激动活性都是立体特异性的。我们发现，含有立体异构苯甲基的甲氧基乙氧基取代的吡啶并稠合二氢咪唑亚胺类似物是最有效的激动剂，在该测定中记录了 339 nM 的 EC 值和 96% 的最大响应 (E)。体内药代动力学分析表明几种类似物具有良好的脑暴露效果。我们的综合结果为与当前化学类型不同的结构新颖的一类食欲素受体激动剂提供了重要信息。