期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 3, 期 5, 页码 367-372出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml3000066
关键词
hypertension; heart failure; ROMK; K(ir)1.1; KCNJ1; diuretics; potassium channel; inward rectifier; K-ir; hERG; high-throughput screening (HTS)
The renal outer medullary potassium channel (ROMK or K(ir)1.1) 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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