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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 |
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| Authors: | Michael Mannion Stéphane Raeppel Stephen Claridge Nancy Zhou Oscar Saavedra Ljubomir Isakovic Lijie Zhan Frédéric Gaudette Franck Raeppel Robert Déziel Normand Beaulieu Hannah Nguyen Ian Chute Carole Beaulieu Isabelle Dupont Marie-France Robert Sylvain Lefebvre Marja Dubay Jubrail Rahil James Wang Arkadii Vaisburg |
| Institution: | 1. Department of Medicinal Chemistry, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1;2. Department of Cell Biology and Pharmacology, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1;3. Department of Lead Discovery, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1;4. Department of PK/Analytical Chemistry, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1 |
| Abstract: | 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 IC50 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. |
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