title: Discovery and Optimization of 1-(4-chloro-3-(trifluoromethyl)- phenyl)-3-(2-(amino)pyridin-3-yl)ureas as Novel KDR Kinase Inhibitors.
abstract: Kinase insert Domain-containing Receptor (KDR) is one of the currently validated targets for anticancer drug discovery and development. Herein, a series of o-amino-arylurea derivatives have been synthesized and evaluated for their kinase inhibitory activity. The optimization on the basis of biological screening and molecular modeling resulted in obvious increase in KDR kinase inhibitory activity compared with the hit compound. Eventually, we identified a potent inhibitor 5a of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-((quinolin-4-ylmethyl) amino)pyridin-3-yl)urea scaffold against KDR (IC50 = 0.0689 µM), which can serve as good starting point for further KDR inhibitor optimization and development.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiao
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Pengfei
authors.initials: P
authors.lastname: Xu
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shangyan
authors.initials: S
authors.lastname: Yang
authors.forename: Danfeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Organic Chemistry, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, P.R. China. twf@cpu.edu.cn.
authors.forename: Weifang
authors.initials: W
authors.lastname: Tang
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D057075:Enzyme Assays; D062105:Molecular Docking Simulation; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: C000621030:1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-((quinolin-4-ylmethyl)amino)pyridin-3-yl)urea; D000631:Aminopyridines; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2