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.

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.

• Authors: Réjean Ruel, Carl Thibeault, Alexandre L'Heureux, Alain Martel, Zhen-Wei Cai, Donna Wei, Ligang Qian, Joel C Barrish, Arvind Mathur, Celia D'Arienzo, John T Hunt, Amrita Kamath, Punit Marathe, Yueping Zhang, George Derbin, Barri Wautlet, Steven Mortillo, Robert Jeyaseelan Sr, Benjamin Henley, Ravindra Tejwani, Rajeev S Bhide, George L Trainor, Joseph Fargnoli, Louis J Lombardo
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 9 Pg. 2985-9 (May 01 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18395443 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Angiogenesis Inhibitors (chemical synthesis, 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, pharmacology)
• Structure-Activity Relationship
• Triazines (chemical synthesis, pharmacology)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)
• Xenograft Model Antitumor Assays