2-Arylureidophenyl-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines as highly potent and selective ATP competitive mTOR inhibitors: Optimization of human microsomal stability

被引：23

作者：

Verheijen, Jeroen C. ^{[1
]}

Richard, David J. ^{[1
]}

Curran, Kevin ^{[1
]}

Kaplan, Joshua ^{[1
]}

Yu, Ker ^{[2
]}

Zask, Arie ^{[1
]}

机构：

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 08期

关键词：

mTOR; PI3K; Kinase inhibitors; Cancer; Oncology; Microsomes; MAMMALIAN TARGET; RAPAMYCIN MTOR; DISCOVERY; PATHWAY; RICTOR;

D O I：

10.1016/j.bmcl.2010.02.031

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Isosteric replacement of one of the 3,5-ethylene-bridged morpholines in 2-arylureidophenyl-4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines led to significant improvements in human microsomal stability. 3-R-Me-morpholine and tetrahydropyran were identified as preferred isosteres for the bridged morpholine. Combination of tetrahydropyran substitution with an N-Me-piperazinophenylureido group led to 27, that selectively suppressed mTOR biomarkers in vivo and possessed excellent efficacy in a murine xenograft model. (C) 2010 Elsevier Ltd. All rights reserved.

引用

收藏

页码：2648 / 2653

页数：6

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