Virtual Screening and Synthesis of New Chemical Scaffolds as VEGFR-2 Kinase Inhibitors (original) (raw)

2012, Arzneimittelforschung

VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 kinase inhibitors. Similarity ensemble approach was used to reduce the chemical space of ZINC database to select a subset of compounds. A validated structure-based pharmacophore was developed and adopted to screen the selected subset. Initial hits mapped to the pharmacophore were filtered using docking and scoring. Selected compounds were synthesized and biologically tested. Compound 9 showed very good cytotoxicity profile against the NCI 60 cancer cell lines, while compound 8 showed reasonable inhibition of VEGFR-2 tyrosine kinase. . Choquette D,Teffera Y,Polverino A,Harmange J-C. Discovery of novel 1,2,3,4tetrahydroisoquinolines and 3,4-dihydroisoquinoline-1(2H)-ones as potent and selective inhibitors of KDR: Synthesis, SAR, and pharmacokinetic properties. Subtype 4. J Med Chem. 20 05 ; 48:2534 -2547. 25. Kakuta H,Zheng X,Oda H,Harada S,Sugimoto Y,Sasaki K, et al. Cyclooxygenase-1selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor. J Med Chem. 2008; 51:2400-2411. 26. Rode H B,Sprang T,Besch A,Loose J,Otto H H. Pseudosaccharin amine derivatives: synthesis and elastase inhibitory activity. Pharmazie. 2005; 60:723-731. 27. Romagnoli R,Baraldi P G,Remusat V,Carrion M D,Cara C L,Cruz-Lopez O, et al. Synthesis and biological evaluation of 2-amino-3-(3', 4', 5'-trimethoxy-phenylsulfonyl)-5aryl thiophenes as a new class of antitubulin agents. Med Chem. 2007; 3:507-512. 28. Dumas J,Smith R A,Lowinger T B. Recent developments in the discovery of protein kinase inhibitors from the urea class. Curr Opin Drug Discov Devel. 2004; 7:600-616. 29. Hu W-P,Chen Y-K,Yu H-S,Huang S-M,Tsai F-Y,Chang L-S, et al. Synthesis, and biological evaluation of 2-(4-aminophenyl)benzothiazole derivatives as photosensitizing agents.