2,4-二氨基喹唑啉作为β-连环蛋白/Tcf-4通路抑制剂：对结直肠癌的潜在治疗作用
2,4-Diamino-quinazolines as inhibitors of beta-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer.
作者信息
Chen Zecheng, Venkatesan Aranapakam M, Dehnhardt Christoph M, Dos Santos Osvaldo, Delos Santos Efren, Ayral-Kaloustian Semiramis, Chen Lei, Geng Yi, Arndt Kim T, Lucas Judy, Chaudhary Inder, Mansour Tarek S
机构信息
Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, USA.
出版信息
Bioorg Med Chem Lett. 2009 Sep 1;19(17):4980-3. doi: 10.1016/j.bmcl.2009.07.070. Epub 2009 Jul 17.
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.
描述了一系列作为β-连环蛋白/Tcf-4抑制剂的2,4-二氨基喹唑啉衍生物的合成及构效关系。该系列是通过修饰最初的先导化合物1开发而来，先导化合物1是通过筛选我们的化合物库鉴定出来的，发现其能抑制β-连环蛋白/Tcf-4信号通路。如化合物2那样，用N-苯基哌啶-4-甲酰胺链取代化合物1中的联苯部分，得到了许多新的类似物，它们是β-连环蛋白/Tcf-4信号通路的有效抑制剂。诸如化合物16k等化合物表现出良好的细胞活性、溶解性、代谢稳定性和口服生物利用度。
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