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Bioorg Med Chem Lett. 2013 Nov 1;23(21):5829-32. doi: 10.1016/j.bmcl.2013.08.104. Epub 2013 Sep 6.

Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one.

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Department of Medicinal Chemistry, Rahway, NJ 07065, United States; Department of Ions Channels, Cardiovascular Disease, Rahway, NJ 07065, United States; Department of Drug Metabolism and Pharmacology, Rahway, NJ 07065, United States; Department of Merck Research Laboratories, Rahway, NJ 07065, United States. Electronic address:


A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents.


Diuresis; Heart failure; Hypertension; Natriuresis; ROMK

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