Exploration of the 5-bromopyrimidin-4(3H)-ones as potent inhibitors of PDE5

被引：11

作者：

Gong, Xudong ^{[1
]}

Wang, Guan ^{[2
]}

Ren, Jing ^{[2
]}

Liu, Zheng ^{[3
]}

Wang, Zhen ^{[2
]}

Chen, Tiantian ^{[2
]}

Yang, Xiaojun ^{[3
]}

Jiang, Xiangrui ^{[2
]}

Shen, Jingshan ^{[2
]}

Jiang, Hualiang ^{[2
]}

Aisa, Haji Akber ^{[1
]}

Xu, Yechun ^{[2
]}

Li, Jianfeng ^{[2
]}

机构：

[1] Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Xinjiang Indigenous Med Plants Resource U, Urumiqi 830011, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[3] Vitargeta Therapeut Inc, Plainsboro, NJ 08536 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 17期

基金：

中国国家自然科学基金; 国家高技术研究发展计划(863计划);

关键词：

PDE5; inhibitors; 5-Bromopyrimidin-4(3H)-ones; DRUG DEVELOPMENT; PHOSPHODIESTERASE-5; DESIGN;

D O I：

10.1016/j.bmcl.2013.06.062

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The substituents both at the 6-position of the 5-bromopyrimidinone ring and at the 5'-position of the phenyl ring of 5-bromopyrimidin-4(3H)-ones were explored. 5-Bromo-6-isopropyl-2-(2-propoxyphenyl)pyrimidin-4(3H)-one was identified as a new scaffold for potent PDE5 inhibitors. The crystal structures of PDE5/2e and PDE5/10a complexes provided a structural basis for the inhibition of 5-bromopyrimidinones to PDE5. In addition, it was also found that there is a great tolerance for the substitution at the 5'-position of the phenyl ring of 5-bormopyrimidinones and the resulted compound 13a has the highest inhibition activity to PDE5 (IC50, 1.7 nM). (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：4944 / 4947

页数：4

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