Key result
A novel series of 3-sulfamoylbenzamide ROMK inhibitors, including compound (-)-16, demonstrated potent in vitro inhibition of human ROMK with species selectivity and insensitivity to the N171D mutation.
The discovery of 3-sulfamoylbenzamides as ROMK inhibitors reveals a novel binding mode that is highly selective for human over rat ROMK and insensitive to the N171D mutation.
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Expands selective ROMK inhibitor options; leaves open in vivo efficacy and clinical translation.
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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Sammons et al. (2018) conducted a letter in Hypertension and edema (target conditions). 3-sulfamoylbenzamides (e.g., compound (-)-16) was evaluated on In vitro ROMK inhibition (IC50). A novel series of 3-sulfamoylbenzamide ROMK inhibitors, including compound (-)-16, demonstrated potent in vitro inhibition of human ROMK with species selectivity and insensitivity to the N171D mutation.
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