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.
Mannion
Michael
M
Department of Medicinal Chemistry, MethylGene Inc, Montréal, QC, Canada.
Raeppel
Stéphane
S
Claridge
Stephen
S
Zhou
Nancy
N
Saavedra
Oscar
O
Isakovic
Ljubomir
L
Zhan
Lijie
L
Gaudette
Frédéric
F
Raeppel
Franck
F
Déziel
Robert
R
Beaulieu
Normand
N
Nguyen
Hannah
H
Chute
Ian
I
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 M
JM
Vaisburg
Arkadii
A
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