2. Academic Validation
  3. Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic

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

  • J Med Chem. 2021 Jun 10;64(11):7691-7701. doi: 10.1021/acs.jmedchem.1c00406.
Jinlong Jiang 1,  Fa-Xiang Ding 1,  Xiaoyan Zhou 2,  Thomas J Bateman 3,  Shuzhi Dong 1,  Xin Gu 1,  Reynalda Keh deJesus 1,  Barbara Pio 1,  Haifeng Tang 1,  Harry R Chobanian 2,  Dorothy Levorse 4,  Mengwei Hu 4,  Brande Thomas-Fowlkes 2,  Michael Margulis 2,  Martin Koehler 2,  Adam Weinglass 2,  Jack Gibson 2,  Kevin Houle 2,  Joel Yudkovitz 2,  Caryn Hampton 2,  Lee-Yuh Pai 2,  Koppara Samuel 3,  Timothy Cutarelli 5,  Kathleen Sullivan 2,  Emma R Parmee 1,  Ian Davies 1,  Alexander Pasternak 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 2 Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 3 Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 4 Discovery and Preclinical Sciences, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 5 Discovery Process Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
PMID: 34038119 DOI: 10.1021/acs.jmedchem.1c00406
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.

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