含哌啶-4-基脲的促黑素细胞激素受体1（MCH-R1）拮抗剂的优化：减少与hERG相关的不良反应。
Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities.
作者信息
Berglund Susanne, Egner Bryan J, Gradén Henrik, Gradén Joakim, Morgan David G A, Inghardt Tord, Giordanetto Fabrizio
机构信息
Medicinal Chemistry, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83, Mölndal, Sweden.
出版信息
Bioorg Med Chem Lett. 2009 Aug 1;19(15):4274-9. doi: 10.1016/j.bmcl.2009.05.066. Epub 2009 May 27.
The discovery and optimization of piperidin-4-yl-urea derivatives as MCH-R1 antagonists is herein described. Previous work around the piperidin-4-yl-amides led to the discovery of potent MCH-R1 antagonists. However, high affinity towards the hERG potassium channel proved to be an issue. Different strategies to increase hERG selectivity were implemented and resulted in the identification of piperidin-4-yl-urea compounds as potent MCH-R1 antagonists with minimized hERG inhibition.
本文描述了哌啶-4-基脲衍生物作为MCH-R1拮抗剂的发现与优化。围绕哌啶-4-基酰胺的先前工作导致了强效MCH-R1拮抗剂的发现。然而，对hERG钾通道的高亲和力被证明是一个问题。实施了不同的提高hERG选择性的策略，结果鉴定出哌啶-4-基脲化合物是强效的MCH-R1拮抗剂，且对hERG的抑制作用最小。
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