Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor

Bioorg Med Chem Lett. 2008 May 1;18(9):2985-9. doi: 10.1016/j.bmcl.2008.03.057. Epub 2008 Mar 22.

Abstract

We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cell Line
  • Cytochrome P-450 CYP3A Inhibitors
  • Drug Design*
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Mice, Inbred BALB C
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • Triazines / chemical synthesis
  • Triazines / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo(2,3-b)pyridin-5-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-amine
  • Angiogenesis Inhibitors
  • Cytochrome P-450 CYP3A Inhibitors
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Pyrroles
  • Triazines
  • Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-2