Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: exploration of diverse hinge-binding fragments

Bioorg Med Chem. 2015 Jul 1;23(13):3228-36. doi: 10.1016/j.bmc.2015.04.071. Epub 2015 May 1.

Abstract

VEGFR-2 plays an essential role in angiogenesis and is an important target for cancer therapy. A series of biphenyl-aryl ureas were synthesized and evaluated as novel VEGFR-2 inhibitors. The pyridine, methylamine carbonyl pyridine and pivaloyl amide pyridine were introduced as novel hinge binding fragment. The majority of title compounds displayed potent VEGFR-2 inhibition. In particular, L1, L9, W14 and W15 exhibited significant enzymatic inhibitory activity with IC50 values of 0.36nM, 0.22nM, 0.15nM and 0.14nM. Compounds L1, L9 and W15 displayed potent antiproliferative activity against A549 and SMMC-7721 cells. SAR study suggested that incorporation of 3-trifluoromethyl and methylamine carbonyl on terminal pyridine could improve VEGFR-2 inhibitory activity. Molecular docking illustrated that urea moiety formed two critical hydrogen bonds with the DFG residues of VEGFR-2. The results indicated that these biphenyl-aryl ureas could serve as promising lead compounds for further optimization.

Keywords: Biphenyl; Hinge region; Structural diversity; Urea; VEGFR-2 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Hydrogen Bonding
  • Kinetics
  • Molecular Docking Simulation
  • Phenylurea Compounds / chemical synthesis*
  • Phenylurea Compounds / pharmacology
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antineoplastic Agents
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2