Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic
| Autor: | Xin Gu, Brande Thomas-Fowlkes, Dorothy Levorse, Harry R. Chobanian, Timothy Cutarelli, Alexander Pasternak, Adam B. Weinglass, Ian W. Davies, Martin Koehler, Michael Margulis, Fa-Xiang Ding, Joel B. Yudkovitz, Jinlong Jiang, Haifeng Tang, Lee-Yuh Pai, Barbara Pio, Shuzhi Dong, Mengwei Hu, Kathleen A. Sullivan, Jack Gibson, Thomas Bateman, Koppara Samuel, Xiaoyan Zhou, Caryn Hampton, Reynalda deJesus, Kevin Houle, Emma R. Parmee |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_treatment Diuresis Action Potentials Blood Pressure Pharmacology 01 natural sciences Piperazines Natriuresis Excretion 03 medical and health sciences Dogs Rats Inbred SHR Drug Discovery medicine Potassium Channel Blockers Animals Humans Dosing Potassium Channels Inwardly Rectifying Diuretics 030304 developmental biology Benzofurans 0303 health sciences Chemistry Furosemide Haplorhini medicine.disease 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Heart failure ROMK Potassium Molecular Medicine Natriuretic Agents Diuretic medicine.drug Half-Life |
| Zdroj: | Journal of medicinal chemistry. 64(11) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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