Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation

被引：14

作者：

Walsh, Shawn P. ^{[1
]}

Shahripour, Aurash ^{[1
]}

Tang, Haifeng ^{[1
]}

Teumelsan, Nardos ^{[1
]}

Frie, Jessica ^{[1
]}

Zhu, Yuping ^{[1
]}

Priest, Birgit T. ^{[2
]}

Swensen, Andrew M. ^{[2
]}

Liu, Jessica ^{[2
]}

Margulis, Michael ^{[2
]}

Visconti, Richard ^{[2
]}

Weinglass, Adam ^{[2
]}

Felix, John P. ^{[2
]}

Brochu, Richard M. ^{[2
]}

Bailey, Timothy ^{[2
]}

Thomas-Fowlkes, Brande ^{[2
]}

Alonso-Galicia, Magdalena ^{[3
]}

Zhou, Xiaoyan ^{[3
]}

Pai, Lee-Yuh ^{[3
]}

Corona, Aaron ^{[3
]}

Hampton, Caryn ^{[3
]}

Hernandez, Melba ^{[3
]}

Bentley, Ross ^{[3
]}

Chen, Jing ^{[3
]}

Shah, Kashmira ^{[3
]}

Metzger, Joseph ^{[3
]}

Forrest, Michael ^{[3
]}

Owens, Karen ^{[4
]}

Tong, Vincent ^{[4
]}

Ha, Sookhee ^{[5
]}

Roy, Sophie ^{[3
]}

Kaczorowski, Gregory J. ^{[2
]}

Yang, Lihu ^{[1
]}

Parmee, Emma ^{[1
]}

Garcia, Maria L. ^{[2
]}

Sullivan, Kathleen ^{[3
]}

Pasternak, Alexander ^{[1
]}

机构：

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

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

[3] Merck Res Labs, Dept Cardiometab Dis, Kenilworth, NJ 07033 USA

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

[5] Merck Res Labs, Dept Chem Modeling & Informat, Kenilworth, NJ 07033 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 07期

关键词：

ROMK; hypertension; heart failure; diuresis; natriuresis; POTASSIUM CHANNEL; BLOOD-PRESSURE; DIURETICS; CLONING; KIR1.1;

D O I：

10.1021/ml500440u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.

引用

页码：747 / 752

页数：6

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