期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 8, 页码 2648-2653出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.02.031
关键词
mTOR; PI3K; Kinase inhibitors; Cancer; Oncology; Microsomes
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.
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