Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure

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• 作者：Haifeng Tang ; Yuping Zhu ; Nardos Teumelsan ; Shawn P. Walsh ; Aurash Shahripour ; Birgit T. Priest ; Andrew M. Swensen ; John P. Felix ; Richard M. Brochu ; Timothy Bailey ; Brande Thomas-Fowlkes ; Lee-Yuh Pai ; Caryn Hampton ; Aaron Corona ; Melba Hernandez ; Joseph Metzger ; Michael Forrest ; Xiaoyan Zhou ; Karen Owens ; Vincent Tong ; Emma Parmee ; Sophie Roy ; Gregory J. Kaczorowski ; Lihu Yang ; Magdalena Alonso-Galicia ; Maria L. Garcia ; Alexander Pasternak
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：7
• 期：7
• 页码：697-701
• 全文大小：317K
• 年卷期：0
• ISSN：1948-5875

文摘

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.