Abstract
The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
MeSH terms
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Animals
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Cell Proliferation / drug effects
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Drug Design
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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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Models, Molecular
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Molecular Structure
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Phosphorylation / drug effects
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / pathology
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Protein Kinase Inhibitors / chemistry
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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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Quinolines / chemistry
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Quinolines / pharmacokinetics
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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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Tissue Distribution
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Triazoles / chemistry
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Triazoles / pharmacokinetics
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Triazoles / pharmacology*
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Xenograft Model Antitumor Assays
Substances
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5-(8-fluoro-3-(1-(3-(2-methoxyethoxy)quinolin-6-yl)ethyl)(1,2,4)triazolo(4,3-a)pyridin-6-yl)-3-methylisoxazole
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Protein Kinase Inhibitors
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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