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Bioorg Med Chem Lett. 2010 Apr 15;20(8):2648-53. doi: 10.1016/j.bmcl.2010.02.031. Epub 2010 Feb 11.

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.

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  • 1Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA.


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.

Copyright 2010 Elsevier Ltd. All rights reserved.

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