Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

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• 作者：Haifeng Tang ; Shawn P. Walsh ; Yan Yan ; Reynalda K. de Jesus ; Aurash Shahripour ; Nardos Teumelsan ; Yuping Zhu ; Sookhee Ha ; Karen A. Owens ; Brande S. Thomas-Fowlkes ; John P. Felix ; Jessica Liu ; Martin Kohler ; Birgit T. Priest ; Timothy Bailey ; Richard Brochu ; Magdalena Alonso-Galicia ; Gregory J. Kaczorowski ; Sophie Roy ; Lihu Yang ; Sander G. Mills ; Maria L. Garcia ; Alexander Pasternak
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：3
• 期：5
• 页码：367-372
• 全文大小：340K
• 年卷期：v.3,no.5(May 10, 2012)
• ISSN：1948-5875

文摘

The renal outer medullary potassium channel (ROMK or K_ir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure鈥揳ctivity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against other members of the inward rectifier family of potassium channels.

Keywords:

hypertension; heart failure; ROMK; K_ir1.1; KCNJ1; diuretics; potassium channel; inward rectifier; K_ir; hERG; high-throughput screening (HTS)