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

被引：22

作者：

Tang, Haifeng ^{[1
]}

Zhu, Yuping ^{[1
]}

Teumelsan, Nardos ^{[1
]}

Walsh, Shawn P. ^{[1
]}

Shahripour, Aurash ^{[1
]}

Priest, Birgit T. ^{[2
]}

Swensen, Andrew M. ^{[2
]}

Felix, John P. ^{[2
]}

Brochu, Richard M. ^{[2
]}

Bailey, Timothy ^{[2
]}

Thomas-Fowlkes, Brande ^{[2
]}

Pai, Lee-Yuh ^{[3
]}

Hampton, Caryn ^{[3
]}

Corona, Aaron ^{[3
]}

Hernandez, Melba ^{[3
]}

Metzger, Joseph ^{[3
]}

Forrest, Michael ^{[3
]}

Zhou, Xiaoyan ^{[4
]}

Owens, Karen ^{[5
]}

Tong, Vincent ^{[5
]}

Parmee, Emma ^{[1
]}

Roy, Sophie ^{[4
]}

Kaczorowski, Gregory J. ^{[2
]}

Yang, Lihu ^{[1
]}

Alonso-Galicia, Magdalena ^{[4
]}

Garcia, Maria L. ^{[2
]}

Pasternak, Alexander ^{[1
]}

机构：

[1] Merck Res Labs, Dept Discovery Chem, Kenilworth, NJ 07033 USA

[2] Merck Res Labs, Dept Ion Channels, Kenilworth, NJ 07033 USA

[3] Merck Res Labs, Dept In Vivo Pharmacol, Kenilworth, NJ 07033 USA

[4] Merck Res Labs, Dept Cardiorenal, Kenilworth, NJ 07033 USA

[5] Merck Res Labs, Dept Pharmacokinet Pharmacodynam & Drug Metab, Kenilworth, NJ 07033 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 07期

关键词：

ROMK; diuretics; natriuresis; hypertension; heart failure; MK-7145; POTASSIUM CHANNEL; MEDICINAL CHEMISTRY; BLOOD-PRESSURE; CLONING; MICE;

D O I：

10.1021/acsmedchemlett.6b00122

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：697 / 701

页数：5

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