Discovery of Aminofurazan-azabenzimidazoles as Inhibitors of Rho-Kinase with High Kinase Selectivity and Antihypertensive Activity
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- 作者：Robert A. Stavenger ; Haifeng Cui ; Sarah E. Dowdell ; Robert G. Franz ; Dimitri E. Gaitanopoulos ; Krista B. Goodman ; Mark A. Hilfiker ; Robert L. Ivy ; Jack D. Leber ; Joseph P. Marino ; Jr. ; Hye-Ja Oh ; Andr
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：January 11, 2007
- 年：2007
- 卷：50
- 期：1
- 页码：2 - 5
- 全文大小：103K
- 年卷期：v.50,no.1(January 11, 2007)
- ISSN：1520-4804
文摘
The discovery, proposed binding mode, and optimizationof a novel class of Rho-kinase inhibitors are presented. Appropriatesubstitution on the 6-position of the azabenzimidazole core providedsubnanomolar enzyme potency in vitro while dramatically improvingselectivity over a panel of other kinases. Pharmacokinetic data wasobtained for the most potent and selective examples and one (6n) hasbeen shown to lower blood pressure in a rat model of hypertension.