Abstract
A series of 2-aminopyridine-3-carboxamide derivatives against c-Met were designed and synthesized by employing bioisosteric replacement of heterocyclic moieties with the amide bond. The structure-activity relationship (SAR) at various positions of the scaffold was explored. In this study, a promising compound (S)-24o with a c-Met IC(50) of 0.022 μM was identified. The compound exhibited dose-dependent inhibition of the phosphorylation of c-Met as well as downstream signaling in EBC-1 cells. Furthermore, the interactive binding model of (S)-24o with c-Met was elucidated by virtue of a molecular modeling study.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / chemical synthesis
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Aminopyridines / chemistry
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Aminopyridines / pharmacology*
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Humans
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Models, Molecular
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Molecular Structure
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Niacinamide / analogs & derivatives*
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Niacinamide / chemical synthesis
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Niacinamide / chemistry
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Niacinamide / pharmacology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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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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Structure-Activity Relationship
Substances
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Aminopyridines
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Niacinamide
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Proto-Oncogene Proteins c-met