Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: Part 2, optimization for blood pressure reduction in spontaneously hypertensive rats

被引：21

作者：

Ginn, John D. ^{[1
]}

Bosanac, Todd ^{[1
]}

Chen, Rhonda ^{[2
]}

Cywin, Charles ^{[1
]}

Hickey, Eugene ^{[1
]}

Kashem, Mohammed ^{[1
]}

Kerr, Steven ^{[2
]}

Kugler, Stanley ^{[2
]}

Li, Xiang ^{[1
]}

Prokopowicz, Anthony, III ^{[1
]}

Schlyer, Sabine ^{[1
]}

Smith, James D. ^{[2
]}

Turner, Michael R. ^{[1
]}

Wu, Frank ^{[1
]}

Young, Erick R. R. ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Dept Med Chem, Ridgefield, CT 06877 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Dept Cardiometab Dis, Ridgefield, CT 06877 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 17期

关键词：

Rho-kinase inhibitors; LIGHT-CHAIN PHOSPHORYLATION; FOCAL ADHESIONS; STRESS FIBERS; CHEMOTAXIS;

D O I：

10.1016/j.bmcl.2010.07.014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Phenylglycine substituted isoquinolones 1 and 2 have previously been described as potent dual ROCK1/ROCK2 inhibitors. Here we describe the further SAR of this series to improve metabolic stability and rat oral exposure. Piperidine analog 20 which demonstrates sustained blood pressure normalization in an SHR blood pressure reduction model was identified through this effort. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5153 / 5156

页数：4

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