Development of Dihydropyridone Indazole Amides as Selective Rho-Kinase Inhibitors

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• 作者：Krista B. Goodman ; Haifeng Cui ; Sarah E. Dowdell ; Dimitri E. Gaitanopoulos ; Robert L. Ivy ; Clark A. Sehon ; Robert A. Stavenger ; Gren Z. Wang ; Andrew Q. Viet ; Weiwei Xu ; Guosen Ye ; Simon F. Semus ; Chri
• 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：6 - 9
• 全文大小：120K
• 年卷期：v.50,no.1(January 11, 2007)
• ISSN：1520-4804

文摘

Rho kinase (ROCK1) mediates vascular smooth musclecontraction and is a potential target for the treatment of hypertensionand related disorders. Indazole amide 3 was identified as a potent andselective ROCK1 inhibitor but possessed poor oral bioavailability.Optimization of this lead resulted in the discovery of a series ofdihydropyridones, exemplified by 13, with improved pharmacokineticparameters relative to the initial lead. Indazole substitution played acritical role in decreasing clearance and improving oral bioavailability.