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

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.

SUBMITTER: Tang H

PROVIDER: S-EPMC4025819 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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

Tang Haifeng H Walsh Shawn P SP Yan Yan Y de Jesus Reynalda K RK Shahripour Aurash A Teumelsan Nardos N Zhu Yuping Y Ha Sookhee S Owens Karen A KA Thomas-Fowlkes Brande S BS Felix John P JP Liu Jessica J Kohler Martin M Priest Birgit T BT Bailey Timothy T Brochu Richard R Alonso-Galicia Magdalena M Kaczorowski Gregory J GJ Roy Sophie S Yang Lihu L Mills Sander G SG Garcia Maria L ML Pasternak Alexander A

ACS medicinal chemistry letters 20120328 5

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 activit ...[more]

PMID: 24900480

Dataset Information

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

Publications

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

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