Synthesis and structure-activity relationships of pyrazine-pyridine biheteroaryls as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors

J Med Chem. 2005 Jul 28;48(15):4892-909. doi: 10.1021/jm058205b.


There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Palladium-catalyzed C-C bond, C-N bond formation reactions were used to assemble various pyrazine-pyridine biheteroaryls as potent VEGFR-2 inhibitors. Among them, 4-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-ylamino}-butan-1-ol (39) and N-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-yl}-N',N'-dimethyl-ethane-1,2-diamine (41) exhibited the highest kinase selectivity against fibroblast growth factor receptor kinase, platelet-derived growth factor receptor kinase, and glycogen synthase kinase-3. All of these compounds showed good cellular potency to inhibit VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC) but with modest effects on the unstimulated growth of HUVEC. The low inhibition of these compounds to the growth of tumor cell lines, such as HeLa, HCT-116, and A375 further confirms that these VEGFR-2 inhibitors are not cytotoxic agents. The in vivo antitumor activity of 39 and 41 were demonstrated in the A375 human melanoma xenograft nude mice model. Molecular modeling (QSAR analysis) was conducted in an attempt to rationalize the observed structure-activity relationship.

MeSH terms

  • Aminopyridines / chemical synthesis*
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endothelium, Vascular / cytology
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Quantitative Structure-Activity Relationship
  • Umbilical Veins / cytology
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Xenograft Model Antitumor Assays


  • 4-(5-(6-(3-chlorophenylamino)pyrazin-2-yl)pyridin-3-ylamino)butan-1-ol
  • Aminopyridines
  • Antineoplastic Agents
  • N-(5-(6-(3-chlorophenylamino)pyrazin-2-yl)pyridin-3-yl)-N',N'-dimethylethane-1,2-diamine
  • Pyrazines
  • Pyridines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2