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J Med Chem ; 64(11): 7691-7701, 2021 06 10.
Article in English | MEDLINE | ID: mdl-34038119

ABSTRACT

A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.


Subject(s)
Natriuretic Agents/chemistry , Potassium Channel Blockers/chemistry , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Action Potentials/drug effects , Animals , Benzofurans/chemistry , Blood Pressure/drug effects , Diuretics/chemistry , Diuretics/metabolism , Diuretics/pharmacology , Dogs , Half-Life , Haplorhini , Humans , Male , Natriuretic Agents/metabolism , Natriuretic Agents/pharmacology , Piperazines/chemistry , Potassium/urine , Potassium Channel Blockers/metabolism , Potassium Channel Blockers/pharmacology , Potassium Channels, Inwardly Rectifying/metabolism , Rats , Rats, Inbred SHR
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