Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity

被引：71
作者：
Stavenger, Robert A.
Cui, Haifeng
Dowdell, Sarah E.
Franz, Robert G.
Gaitanopoulos, Dimitri E.
Goodman, Krista B.
Hilfiker, Mark A.
Ivy, Robert L.
Leber, Jack D.
Marino, Joseph P., Jr.
Oh, Hye-Ja
Viet, Andrew Q.
Xu, Weiwei
Ye, Guosen
Zhang, Daohua
Zhao, Yongdong
Jolivette, Larry J.
Head, Martha S.
Semus, Simon F.
Elkins, Patricia A.
Kirkpatrick, Robert B.
Dul, Edward
Khandekar, Sanjay S.
Yi, Tracey
Jung, David K.
Wright, Lois L.
Smith, Gary K.
Behm, David J.
Doe, Christopher P.
Bentley, Ross
Chen, Zunxuan X.
Hu, Erding
Lee, Dennis
机构：
[1] GlaxoSmithKline Inc, Dept Med Chem, King Of Prussia, PA 19406 USA
[2] GlaxoSmithKline Inc, Dept Invest Biol Vasc Biol, King Of Prussia, PA 19406 USA
[3] GlaxoSmithKline Inc, Dept Drug Metab & Pharmacokinet, CVU CEDD, King Of Prussia, PA 19406 USA
[4] GlaxoSmithKline Inc, Dept Computat & Struct Sci, King Of Prussia, PA 19406 USA
[5] GlaxoSmithKline Inc, Dept Gene Express & Prot Biochem, King Of Prussia, PA 19406 USA
[6] GlaxoSmithKline Inc, Dept Assay Dev & Cpd Profiling & High Throughput, Res Triangle Pk, NC 27709 USA
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 01期
关键词：
D O I：
10.1021/jm060873p
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
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收藏
页码：2 / 5
页数：4
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