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Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors.

ABSTRACT: Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4, this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors.

SUBMITTER: Sammons MF

PROVIDER: S-EPMC5807870 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors.

Sammons Matthew F MF Kharade Sujay V SV Filipski Kevin J KJ Boehm Markus M Smith Aaron C AC Shavnya Andre A Fernando Dilinie P DP Dowling Matthew S MS Carpino Philip A PA Castle Neil A NA Zellmer Shannon G SG Antonio Brett M BM Gosset James R JR Carlo Anthony A Denton Jerod S JS

ACS medicinal chemistry letters 20180119 2

Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit <b>4</b>, this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-m ...[more]

PMID: 29456800

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