Abstract
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Discovery
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Hepatocyte Growth Factor / metabolism
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Humans
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Male
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Models, Molecular
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Phosphorylation
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / metabolism
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Pyridones / chemical synthesis*
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Pyridones / pharmacology
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Quinolines / chemical synthesis*
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Quinolines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Triazoles / chemical synthesis*
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Triazoles / pharmacology
Substances
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Antineoplastic Agents
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HGF protein, mouse
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Protein Kinase Inhibitors
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Pyridones
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Quinolines
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Triazoles
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met