The discovery of selective small molecule ROMK inhibitors provides tool compounds for in vivo pharmacological assessment as potential novel diuretics for hypertension and heart failure.
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Yields selective ROMK inhibitor tools for diuretic mechanism studies in hypertension and HF; clinical translation remains untested.
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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Tang et al. (2012) studied this question.
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