Abstract
Starting from quinazoline 3a, we designed potent and selective ALK5 inhibitors over p38MAP kinase from a rational drug design approach based on co-crystal structures in the human ALK5 kinase domain. The quinazoline 3d exhibited also in vivo activity in an acute rat model of DMN-induced liver fibrosis when administered orally at 5mg/kg (bid).
MeSH terms
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Activin Receptors / antagonists & inhibitors*
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Activin Receptors / metabolism
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Animals
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Cell Line
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Crystallography, X-Ray
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Drug Design
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Humans
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Protein Binding
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemical synthesis*
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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 / metabolism
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Protein Structure, Tertiary
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Quinazolines / administration & dosage
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Quinazolines / chemical synthesis*
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Quinazolines / 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 / metabolism
Substances
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Protein Kinase Inhibitors
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Quinazolines
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Receptors, Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Activin Receptors
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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