Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic

• Published in: Journal of medicinal chemistry 2021-06, Vol.64 (11), p.7691-7701
• Main Authors: Jiang, Jinlong, Ding, Fa-Xiang, Zhou, Xiaoyan, Bateman, Thomas J, Dong, Shuzhi, Gu, Xin, Keh deJesus, Reynalda, Pio, Barbara, Tang, Haifeng, Chobanian, Harry R, Levorse, Dorothy, Hu, Mengwei, Thomas-Fowlkes, Brande, Margulis, Michael, Koehler, Martin, Weinglass, Adam, Gibson, Jack, Houle, Kevin, Yudkovitz, Joel, Hampton, Caryn, Pai, Lee-Yuh, Samuel, Koppara, Cutarelli, Timothy, Sullivan, Kathleen, Parmee, Emma R, Davies, Ian, Pasternak, Alexander
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00406

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.