Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase

被引：161

作者：

Cheney, I. Wayne ^{[1
]}

Yan, Shunqi ^{[1
]}

Appleby, Todd ^{[1
]}

Walker, Hell ^{[1
]}

Vo, Todd ^{[1
]}

Yao, Nanhua ^{[1
]}

Hamatake, Robert ^{[1
]}

Hong, Zhi ^{[1
]}

Wu, Jim Z. ^{[1
]}

机构：

[1] Valeant Pharmaceut R&D, Costa Mesa, CA 92626 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 06期

关键词：

Pim-1; kinase; Pim-1 kinase inhibitors; pyridone; fused-ring pyridone; X-ray complex structure; Pim;

D O I：

10.1016/j.bmcl.2006.12.086

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC50 = 50 nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R-1 phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor. (c) 2007 Elsevier Ltd. All rights reserved.

引用

收藏

页码：1679 / 1683

页数：5

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