Design, Synthesis, and Biological Evaluation of 3-[4-(2-Hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a Potent, Orally Active, Brain Penetrant Inhibitor of Phosphodiesterase 5 (PDE5)

被引：13

作者：

Hughes, Robert O. ^{[1
]}

Rogier, D. Joseph ^{[1
]}

Jacobsen, E. Jon ^{[1
]}

Walker, John K. ^{[1
]}

MacInnes, Alan ^{[1
]}

Bond, Brian R. ^{[1
]}

Zhang, Lena L. ^{[1
]}

Yu, Ying ^{[1
]}

Zheng, Yi ^{[1
]}

Rumsey, Jeanne M. ^{[1
]}

Walgren, Jennie L. ^{[1
]}

Curtiss, Sandra W. ^{[1
]}

Fobian, Yvette M. ^{[1
]}

Heasley, Steven E. ^{[1
]}

Cubbage, Jerry W. ^{[1
]}

Moon, Joseph B. ^{[1
]}

Brown, David L. ^{[1
]}

Acker, Brad A. ^{[1
]}

Maddux, Todd M. ^{[1
]}

Tollefson, Mike B. ^{[1
]}

Mischke, Brent V. ^{[1
]}

Owen, Dafydd R. ^{[2
]}

Freskos, John N. ^{[1
]}

Molyneaux, John M. ^{[1
]}

Benson, Alan G. ^{[1
]}

Blevis-Bal, Rhadika M. ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, St Louis, MO 63017 USA

[2] Pfizer Global Res & Dev, Sandwich CT13 9NJ, Kent, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 06期

关键词：

D O I：

10.1021/jm901781q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)- 1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.

引用

页码：2656 / 2660

页数：5

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