Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1375147 | Bioorganic & Medicinal Chemistry Letters | 2010 | 6 Pages |
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.
Graphical abstractIsosteric replacement of one of the 3,5-ethylene-bridged morpholines in triazine mTOR inhibitors led to significant improvements in human microsomal stability, resulting in a compound that selectively suppressed mTOR biomarkers in vivo and possessed excellent efficacy in a murine xenograft model.Figure optionsDownload full-size imageDownload as PowerPoint slide