ABSTRACT
A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.
Subject(s)
Antineoplastic Agents/chemistry , Malonates/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Humans , Malonates/chemical synthesis , Malonates/pharmacokinetics , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokineticsABSTRACT
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.
Subject(s)
Amides/chemistry , Imidazolidines/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/administration & dosage , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amides/pharmacology , Animals , Cell Line, Tumor , HCT116 Cells , Humans , Imidazolidines/pharmacology , Mice , Protein Kinase Inhibitors/pharmacology , Rats , Vascular Endothelial Growth Factor Receptor-2/metabolism , Xenograft Model Antitumor Assays/methodsABSTRACT
A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC(50) values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Division/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Humans , Mice , Models, Chemical , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
[reaction: see text] AlMe(3) dramatically increases the diastereoselectivity of addition of vinyllithiums to alpha-chiral aldehydes but decreases that of methyllithium. Our results are explained in terms of an addition of the free vinyllithium on the Me(3)Al-aldehyde complex.
