Synthesis and biological evaluation of pyrido[3′,2':4,5]furo [3,2-d]pyrimidine derivatives as novel PI3 kinase p110α inhibitors

被引：131

作者：

Hayakawa, Masahiko

Kaizawa, Hiroyuki

Moritomo, Hiroyuki

Koizumi, Tomonobu

Ohishi, Takahide

Yamano, Mayumi

Okada, Minoru

Ohta, Mitsuaki

Tsukamoto, Shin-ichi

Raynaud, Florence I.

Workman, Paul

Waterfield, Michael D.

Parker, Peter

机构：

[1] Astellas Pharma Inc, Drug Discovery Res, Tsukuba, Ibaraki 3002698, Japan

[2] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Sutton SN2 5NG, Surrey, England

[3] Ludwig Inst Canc Res, London W1W 7BS, England

[4] Canc Res UK London Res Inst, London WC2A 3PX, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 09期

关键词：

PI3; kinase; p110; alpha; inhibitor; anti-cancer agent;

D O I：

10.1016/j.bmcl.2007.02.032

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

4-Morpholin-4-ylpyrido[3 ',2 ':4,5]thieno[3,2-dlpyrimidine 2a was discovered in our chemical library as a novel pl Wa inhibitor with an IC50 of 1.4 mu M. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3 ',2 ':4,5]furo[3,2-dlpyrimidine derivative 10e was discovered as a p110 alpha inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110 beta. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：2438 / 2442

页数：5

共 31 条

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