Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups.
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.
Gaudette
Frédéric
F
Department of Medicinal Chemistry, MethylGene Inc, 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1.
Raeppel
Stéphane
S
Nguyen
Hannah
H
Beaulieu
Normand
N
Beaulieu
Carole
C
Dupont
Isabelle
I
Macleod
A Robert
AR
Besterman
Jeffrey M
JM
Vaisburg
Arkadii
A
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D047428:Protein Kinase Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2