2,4-Diamino-quinazolines as inhibitors of β-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer

被引：62

作者：

Chen, Zecheng ^{[1
]}

Venkatesan, Aranapakam M. ^{[1
]}

Dehnhardt, Christoph M. ^{[1
]}

Dos Santos, Osvaldo ^{[1
]}

Delos Santos, Efren ^{[1
]}

Ayral-Kaloustian, Semiramis ^{[1
]}

Chen, Lei ^{[2
]}

Geng, Yi ^{[2
]}

Arndt, Kim T. ^{[2
]}

Lucas, Judy ^{[2
]}

Chaudhary, Inder ^{[3
]}

Mansour, Tarek S. ^{[1
]}

机构：

[1] Wyeth Res, Chem Sci, Pearl River, NY 10965 USA

[2] Wyeth Res, Oncol, Pearl River, NY 10965 USA

[3] Wyeth Res, Drug Metab, Pearl River, NY 10965 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 17期

关键词：

beta-Catenin/Tcf-4; pathway; Inhibitors; 2,4-Diamino-quinazoline; WNT; AXIN2; APC;

D O I：

10.1016/j.bmcl.2009.07.070

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis and SAR of a series of 2,4-diamino-quinazoline derivatives as beta-catenin/Tcf-4 inhibitors are described. This series was developed by modifying the initial lead 1, which was identified by screening of our compound library and found to inhibit the beta-catenin/Tcf-4 pathway. Replacement of the biphenyl moiety in compound 1 with the N-phenylpiperidine-4-carboxamide chain as in 2, resulted in a number of new analogues, which are potent inhibitors of the beta-catenin/Tcf-4 pathway. Compound such as 16k exhibited good cellular potency, solubility, metabolic stability and oral bioavailability. (C) 2009 Elsevier Ltd. All rights reserved.

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收藏

页码：4980 / 4983

页数：4

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