Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: Synthesis and SAR studies

被引：42

作者：

Lin, Xiaodong ^{[1
]}

Murray, Jeremy M. ^{[1
]}

Rico, Alice C. ^{[1
]}

Wang, Michael X. ^{[1
]}

Chu, Daniel T. ^{[1
]}

Zhou, Yasheen ^{[1
]}

Del Rosario, Merci ^{[1
]}

Kaufman, Susan ^{[1
]}

Ma, Sylvia ^{[1
]}

Fang, Eric ^{[1
]}

Crawford, Kenneth ^{[1
]}

Jefferson, A. B. ^{[1
]}

机构：

[1] Chiron Corp, Biopharma Res, Small Mol Drug Discovery, Emeryville, CA 94608 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 16期

关键词：

protein kinase B/AKT; kinase inhibitor; substituted pyrimidine; cancer;

D O I：

10.1016/j.bmcl.2006.05.092

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC50 values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：4163 / 4168

页数：6

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