Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups

Frédéric Gaudette; Stéphane Raeppel; Hannah Nguyen; Normand Beaulieu; Carole Beaulieu; Isabelle Dupont; A Robert Macleod; Jeffrey M Besterman; Arkadii Vaisburg

doi:10.1016/j.bmcl.2009.12.099

Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups

Bioorg Med Chem Lett. 2010 Feb 1;20(3):848-52. doi: 10.1016/j.bmcl.2009.12.099. Epub 2010 Jan 4.

Authors

Frédéric Gaudette¹, Stéphane Raeppel, Hannah Nguyen, Normand Beaulieu, Carole Beaulieu, Isabelle Dupont, A Robert Macleod, Jeffrey M Besterman, Arkadii Vaisburg

Affiliation

¹ Department of Medicinal Chemistry, MethylGene Inc, 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1.

PMID: 20071170
DOI: 10.1016/j.bmcl.2009.12.099

Abstract

A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere-a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymatic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these molecular entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme.

Publication types

Comparative Study

MeSH terms

Amides / chemistry*
Amides / pharmacology
Coculture Techniques
Endothelial Cells / drug effects
Endothelial Cells / enzymology
Fibroblasts / drug effects
Fibroblasts / enzymology
Humans
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
Receptors, Vascular Endothelial Growth Factor / metabolism
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Amides
Protein Kinase Inhibitors
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor Receptor-2