N-(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.
A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-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.
Department of Medicinal Chemistry, MethylGene Inc, Montréal, QC, Canada.
Michael
M
Mannion
Stéphane
S
Raeppel
Stephen
S
Claridge
Nancy
N
Zhou
Oscar
O
Saavedra
Ljubomir
L
Isakovic
Lijie
L
Zhan
Frédéric
F
Gaudette
Franck
F
Raeppel
Robert
R
Déziel
Normand
N
Beaulieu
Hannah
H
Nguyen
Ian
I
Chute
Carole
C
Beaulieu
Isabelle
I
Dupont
Marie-France
MF
Robert
Sylvain
S
Lefebvre
Marja
M
Dubay
Jubrail
J
Rahil
James
J
Wang
Hélène
H
Ste-Croix
A
A
Robert Macleod
Jeffrey M
JM
Besterman
Arkadii
A
Vaisburg
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases