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

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

Abstract

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.

Keywords: Diuresis; Heart failure; Hypertension; Natriuresis; ROMK.

MeSH terms

  • Animals
  • Benzofurans / chemistry*
  • Benzofurans / pharmacokinetics
  • Benzofurans / pharmacology*
  • Diuresis / drug effects
  • Drug Discovery
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Potassium Channels, Inwardly Rectifying / antagonists & inhibitors*
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacokinetics
  • Tetrazoles / pharmacology

Substances

  • Benzofurans
  • Ether-A-Go-Go Potassium Channels
  • KCNJ1 protein, human
  • Potassium Channels, Inwardly Rectifying
  • Tetrazoles
  • 1H-tetrazole