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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jun 6

PMID 24900480

Citations 10

Authors

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

Affiliations

Soon will be listed here.

Abstract

The renal outer medullary potassium channel (ROMK or Kir1.1) 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-activity 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.

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