AI Article Synopsis
- ROMK channels (Kir1.1) are being targeted for new diuretics that can help manage hypertension and heart failure.
- The first compound (MK-7145) showed promising results in animal studies, including effective diuresis and lower blood pressure, but had a short duration of action requiring multiple doses.
- A new compound (MK-8153) has been developed with a longer half-life, which may lead to steadier diuretic effects and improved patient tolerance.
Article 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, (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, 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 (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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| http://dx.doi.org/10.1021/acs.jmedchem.1c00406 | DOI Listing |
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First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor.
Clin Pharmacol Ther
December 2024
Bristol Myers Squibb Research & Early Development, Princeton, New Jersey, USA.
In patients with heart failure (HF) who respond inadequately to loop diuretic therapy, BMS-986308, an oral, selective, reversible renal outer medullary potassium channel (ROMK) inhibitor may represent an effective diuretic with a novel mechanism of action. We present data from the first-in-human study aimed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) following single ascending doses of BMS-986308 in healthy adult participants. Forty healthy participants, aged from 20 to 55 years, and body mass index (BMI) from 19.
View Article and Find Full Text PDFRole of calcineurin in regulating renal potassium (K) excretion: Mechanisms of calcineurin inhibitor-induced hyperkalemia.
Acta Physiol (Oxf)
August 2024
Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Calcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium-dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na and K transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting-related-receptor-with-A-type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2.
View Article and Find Full Text PDFDiscovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure.
J Med Chem
June 2024
Bristol Myers Squibb Research & Early Development, Princeton, New Jersey 08540, United States.
Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.
View Article and Find Full Text PDFImpaired distal renal potassium handling in streptozotocin-induced diabetic mice.
Am J Physiol Renal Physiol
July 2024
Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
Diabetes is closely associated with K disturbances during disease progression and treatment. However, it remains unclear whether K imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K intake on systemic K balance and renal K handling in streptozotocin (STZ)-induced diabetic mice.
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