Synthesis of novel diarylamino-1,3,5-triazine derivatives as FAK inhibitors with anti-angiogenic activity

A series of diarylamino-1,3,5-triazines as FAK inhibitors have been prepared and evaluated for in vitro enzymatic activity and anti-angiogenic activity on HUVEC cells. We report herein the synthesis of novel diarylamino-1,3,5-triazine derivatives as FAK (focal adhesion kinase) inhibitors and the eva...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-08, Vol.23 (16), p.4552-4556
Main Authors: Dao, Pascal, Jarray, Rafika, Le Coq, Johanne, Lietha, Daniel, Loukaci, Ali, Lepelletier, Yves, Hadj-Slimane, Réda, Garbay, Christiane, Raynaud, Françoise, Chen, Huixiong
Format: Article
Language:English
Subjects:
adhesion
Angiogenesis Inhibitors - chemical synthesis
Angiogenesis Inhibitors - chemistry
Angiogenesis Inhibitors - pharmacology
Anti-angiogenic activity
Cell Survival - drug effects
chemistry
Crystallography, X-Ray
Diarylamino-1,3,5-triazines
Endothelial cells
Endothelial Cells - drug effects
Enzyme Activation - drug effects
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
FAK inhibitors
Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors
Human Umbilical Vein Endothelial Cells
Humans
Molecular Structure
Morpholines - chemistry
Morpholines - pharmacology
Synthesis
Triazines - chemical synthesis
Triazines - chemistry
Triazines - pharmacology
viability
X-ray diffraction
X-ray structure
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Summary:A series of diarylamino-1,3,5-triazines as FAK inhibitors have been prepared and evaluated for in vitro enzymatic activity and anti-angiogenic activity on HUVEC cells. We report herein the synthesis of novel diarylamino-1,3,5-triazine derivatives as FAK (focal adhesion kinase) inhibitors and the evaluation of their anti-angiogenic activity on HUVEC cells. Generally, the effects of these compounds on endothelial cells could be correlated with their kinase inhibitory activity. The most efficient compounds displayed inhibition of viability against HUVEC cells in the micromolar range, as observed with TAE-226, which was designed by Novartis Pharma AG. X-ray crystallographic analysis of the co-crystal structure for compound 34 revealed that the mode of interaction with the FAK kinase domain is highly similar to that observed in the complex of TAE-226.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.06.038