N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.
A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Raeppel
Stéphane
S
Department of Medicinal Chemistry, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1.
Claridge
Stephen
S
Saavedra
Oscar
O
Gaudette
Frédéric
F
Zhan
Lijie
L
Mannion
Michael
M
Zhou
Nancy
N
Raeppel
Franck
F
Granger
Marie-Claude
MC
Isakovic
Ljubomir
L
Déziel
Robert
R
Nguyen
Hannah
H
Beaulieu
Normand
N
Beaulieu
Carole
C
Dupont
Isabelle
I
Robert
Marie-France
MF
Lefebvre
Sylvain
S
Dubay
Marja
M
Rahil
Jubrail
J
Wang
James
J
Ste-Croix
Hélène
H
Robert Macleod
A
A
Besterman
Jeffrey
J
Vaisburg
Arkadii
A
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000008:administration & dosage*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000577:Amides; D048289:Imidazolidines; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2