Abstract
c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of π-π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Cycle / drug effects
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cytochrome P-450 Enzyme System / metabolism*
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Drug Design*
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Female
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Hepatocyte Growth Factor / metabolism
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Humans
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Mice
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Mice, Nude
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Microsomes, Liver / drug effects
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Models, Molecular
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Molecular Structure
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Neoplasms / drug therapy*
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Neoplasms / pathology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Signal Transduction / drug effects
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Tissue Distribution
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Xenograft Model Antitumor Assays
Substances
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Protein Kinase Inhibitors
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Pyridines
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Hepatocyte Growth Factor
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Cytochrome P-450 Enzyme System
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Proto-Oncogene Proteins c-met