Design, synthesis, and biological evaluation of novel 3-aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as vascular endothelial growth factor receptor (VEGF-R) inhibitors

J Med Chem. 2008 Jul 10;51(13):3814-24. doi: 10.1021/jm8001185. Epub 2008 Jun 5.

Abstract

In this study we report on the design, synthesis, and biological evaluation of pyrrole-2-one 2 to be a highly potent VEGF-R2/3 inhibitor with IC 50 of 31/37 nM. The novel 3,4-diaryl-2 H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1 H-pyrrole-2,5-dione (maleimide) VEGF-R2/3 inhibitor 1 indicating two H-bond ligand-protein interactions in the ATP pocket for the amide 2 but not for the isomer 3. Flexible synthetic routes to 3,4-diaryl-2 H-pyrrole-2-ones and structure-activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC 50 values) are presented. Accordingly to the in vitro data, compounds 1 and 2 were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas 3 was determined to be significantly less active. Hence, the pyrrole-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Drug Design*
  • Endothelial Cells / drug effects
  • Humans
  • Hydrogen / chemistry
  • Indoles / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • Receptors, Vascular Endothelial Growth Factor / chemistry
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Structure-Activity Relationship

Substances

  • Angiogenesis Inhibitors
  • Indoles
  • Protein Kinase Inhibitors
  • Pyrroles
  • Hydrogen
  • Receptors, Vascular Endothelial Growth Factor

Associated data

  • PDB/1Y6A