Development of potent and selective small-molecule human Urotensin-II antagonists

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• 作者：John J. McAtee ; Jason W. Dodson ; Sarah E. Dowdell ; Gerald R. Girard ; Krista B. Goodman ; Mark A. Hilfiker ; Clark A. Sehon ; Deyou Sha ; Gren Z. Wang ; Ning Wang ; Andrew Q. Viet ; Daohua Zhang ; Nambi V. Aiy
• 关键词：Urotensin ; Antagonist ; hU-II ; U-II ; hUT ; GPR14
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 June 2008
• 卷：18
• 期：12
• 页码：3500-3503
• 文件大小：178 K

摘要

This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.