Potent, Selective and Orally Bioavailable Dihydropyrimidine Inhibitors of Rho Kinase (ROCK1) as Potential Therapeutic Agents for Cardiovascular Diseases

被引：64

作者：

Sehon, Clark A. ^{[1
]}

Wang, Gren Z. ^{[1
]}

Viet, Andrew Q. ^{[1
]}

Goodman, Krista B. ^{[1
]}

Dowdell, Sarah E. ^{[1
]}

Elkins, Patricia A. ^{[3
]}

Semus, Simon F. ^{[3
]}

Evans, Christopher ^{[2
]}

Jolivette, Larry J. ^{[2
]}

Kirkpatrick, Robert B. ^{[4
]}

Dul, Edward ^{[4
]}

Khandekar, Sanjay S. ^{[4
]}

Yi, Tracey ^{[4
]}

Wright, Lois L. ^{[5
]}

Srnith, Gary K. ^{[5
]}

Behm, David J. ^{[6
]}

Bentley, Ross ^{[7
]}

Doe, Christopher P. ^{[7
]}

Hu, Erding ^{[6
]}

Lee, Dennis ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Dept Med Chem, King Of Prussia, PA 19406 USA

[2] GlaxoSmithKline Inc, Dept Drug Metab & Pharmacokinet, King Of Prussia, PA 19406 USA

[3] GlaxoSmithKline Inc, CVU CEDD, Dept Computat & Struct Sci, King Of Prussia, PA 19406 USA

[4] GlaxoSmithKline Inc, Dept Gene Express & Prot Biochem, King Of Prussia, PA 19406 USA

[5] GlaxoSmithKline Inc, Dept Assay Dev & Compound Profiling, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline Inc, Dept Vasc Biol, King Of Prussia, PA 19406 USA

[7] GlaxoSmithKline Inc, Dept Investigat Biol, King Of Prussia, PA 19406 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 21期

关键词：

D O I：

10.1021/jm8005096

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK 1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused oil the optimization of dihydropyrimidine 2. which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.

引用

页码：6631 / 6634

页数：4

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