Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis

J Med Chem. 2008 Mar 27;51(6):1695-705. doi: 10.1021/jm701129j. Epub 2008 Feb 27.

Abstract

Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.

MeSH terms

  • Administration, Oral
  • Angiogenesis Inhibitors / administration & dosage*
  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Animals
  • Benzoxazines / administration & dosage*
  • Benzoxazines / chemical synthesis
  • Benzoxazines / chemistry
  • Biological Availability
  • Cell Line
  • Cell Proliferation / drug effects
  • Corneal Neovascularization / blood
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Female
  • Humans
  • Injections, Subcutaneous
  • Ligands
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Animal
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / blood supply*
  • Neovascularization, Pathologic / prevention & control*
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Benzoxazines
  • Ligands
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2