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
  • 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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