1 research outputs found
Discovery and in Vitro Optimization of 3‑Sulfamoylbenzamides as ROMK Inhibitors
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-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