Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists

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• 作者：Roland Geyer ; Uwe Nordemann ; Andrea Strasser ; Hans-Joachim Wittmann ; Armin Buschauer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3452-3470
• 全文大小：969K
• 年卷期：0
• ISSN：1520-4804

文摘

2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H₄ receptor (hH₄R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hH_xR (x: 1–4) subtypes on Sf9 cell membranes (radioligand binding, [³⁵S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H₄R (HEK-293 cells). The most potent H₄R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H₄R agonist in this series (EC₅₀ 11 nM; H₄R vs H₃R, >100-fold selectivity; H₁R, H₂R, negligible activities), whereas the optical antipode proved to be an H₄R antagonist ([³⁵S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H₄R state by the enantiomers.