Abstract
A novel class of 4-pyridinoxy-2-anilinopyridine-based TGF-beta type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors is reported. The binding mode of this scaffold was successfully predicted by analyzing possible docked binding modes of literature inhibitors and novel synthetic ideas. Compounds such as 19 are potent ALK5 inhibitors with good physicochemical and pharmacokinetic properties and thus represent high quality leads for further optimization.
MeSH terms
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Animals
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Catalytic Domain
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Cell Line, Tumor
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Drug Discovery
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Humans
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Inhibitory Concentration 50
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Kinetics
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Male
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Models, Molecular
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism
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Pyridines / chemistry*
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Pyridines / metabolism
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Rats
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Receptors, Transforming Growth Factor beta / chemistry
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Receptors, Transforming Growth Factor beta / metabolism
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Structure-Activity Relationship
Substances
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Protein Kinase Inhibitors
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Pyridines
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Receptors, Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, rat