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

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

  • ACS Med Chem Lett. 2018 Jan 19;9(2):125-130. doi: 10.1021/acsmedchemlett.7b00481.
Matthew F Sammons 1,  Sujay V Kharade 2,  Kevin J Filipski 1,  Markus Boehm 1,  Aaron C Smith 3,  Andre Shavnya 3,  Dilinie P Fernando 3,  Matthew S Dowling 3,  Philip A Carpino 1,  Neil A Castle 4,  Shannon G Zellmer 4,  Brett M Antonio 4,  James R Gosset 1,  Anthony Carlo 3,  Jerod S Denton 2
Affiliations

Affiliations

  • 1 Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts 02139, United States.
  • 2 Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 3 Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States.
  • 4 Neusentis, Pfizer Worldwide Research & Development, Durham, North Carolina 27703, United States.
PMID: 29456800 DOI: 10.1021/acsmedchemlett.7b00481
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.

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