1 Synthesis and StructureActivity Relationships of 2 (Aryloxy)quinazoline Ureas as Novel, Potent, and Selective Vascular 3 Endothelial Growth Factor Receptor-2 Inhibitors

9 ABSTRACT: In our continuing search for medicinal agents to treat proliferative diseases, 10 quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial 11 growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) 12 tyrosine kinase inhibitors. A quantitative structureactiviey relationship analysis was 13 conducted to rationalize the structureactivity relationship and to predict how similar the 14 inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking 15 of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis 16 of new compounds. A series of N-(aromatic)-N'-{4-((6,7-dimethoxyquinazolin-4-yl)oxy)- 17 phenyl}urea were identified as potent and selective inhibitors of the tyrosine kinase activity 18 of VEGFR-2 (fetal liver kinase 1, kinase insert domain-containing receptor). An efficient 19 route was developed that enabled the synthesis of a wide variety of analogues with 20 substitution on several positions of the template. Substitution of diarylurea, competitive 21 with ATP, afforded several analogues with low nanomolar inhibition of enzymatic activity of VEGFR-2. In this paper, we describe 22 the synthesis, structureactivity relationships, and pharmacological characterization of the series.