Abstract
Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.
MeSH terms
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Activin Receptors, Type I / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Fibronectins / biosynthesis
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Fibronectins / genetics
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases
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RNA, Messenger / biosynthesis
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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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Smad3 Protein
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Structure-Activity Relationship
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Trans-Activators / metabolism
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Tumor Cells, Cultured
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p38 Mitogen-Activated Protein Kinases
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Fibronectins
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Imidazoles
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RNA, Messenger
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Receptors, Transforming Growth Factor beta
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SMAD3 protein, human
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Smad3 Protein
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Trans-Activators
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human