化学
立体中心
立体化学
乙醚
取代基
兴奋剂
受体
生物化学
对映选择合成
有机化学
催化作用
作者
Wentian Wang,Alok Ranjan,Wei Zhang,Qiren Liang,Karen S. MacMillan,Karen Chapman,Xiaoyu Wang,Preethi Chandrasekaran,Noelle S. Williams,Daniel M. Rosenbaum,Jef K. De Brabander
标识
DOI:10.1016/j.bmcl.2024.129624
摘要
A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for Gq signaling to measure agonistic activation of the orexin receptor type 2 (OX2R). 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 OX2R coupled Gq 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 63c containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC50 of 339 nM and a maximal response (Emax) 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.
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