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.