Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors

Robert M Borzilleri; Zhen-Wei Cai; Christopher Ellis; Joseph Fargnoli; Aberra Fura; Tracy Gerhardt; Bindu Goyal; John T Hunt; Steven Mortillo; Ligang Qian; John Tokarski; Viral Vyas; Barri Wautlet; Xioping Zheng; Rajeev S Bhide

doi:10.1016/j.bmcl.2004.12.079

Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors

Bioorg Med Chem Lett. 2005 Mar 1;15(5):1429-33. doi: 10.1016/j.bmcl.2004.12.079.

Authors

Robert M Borzilleri¹, Zhen-Wei Cai, Christopher Ellis, Joseph Fargnoli, Aberra Fura, Tracy Gerhardt, Bindu Goyal, John T Hunt, Steven Mortillo, Ligang Qian, John Tokarski, Viral Vyas, Barri Wautlet, Xioping Zheng, Rajeev S Bhide

Affiliation

¹ Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.

PMID: 15713401
DOI: 10.1016/j.bmcl.2004.12.079

Abstract

A versatile synthesis of the suitably functionalized pyrrolo[2,1-f][1,2,4]triazine nucleus is described. SAR at the C-5 and C-6 positions of the 4-(3-hydroxy-4-methylphenylamino)pyrrolo[2,1-f][1,2,4]triazine template led to compounds with good in vitro potency against VEGFR-2 kinase. Glucuronidation of the phenol group is mitigated by incorporation of a basic amino group on the C-6 side chain of the pyrrolotriazine nucleus.

MeSH terms

Animals
Cell Survival / drug effects
Endothelium, Vascular / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Mice
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Protein Binding
Structure-Activity Relationship
Triazines / chemical synthesis*
Triazines / chemistry
Triazines / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

Enzyme Inhibitors
Triazines
Vascular Endothelial Growth Factor Receptor-2