Abstract
Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.
MeSH terms
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Animals
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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Cells, Cultured
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Humans
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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Mice
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Mice, Nude
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Mink
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Structure, Tertiary
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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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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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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6-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo(1,2-b)pyrazol-3-yl)-1H-benzoimidazole
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Benzimidazoles
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Pyrazoles
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Pyrroles
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Receptors, Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Receptor, Transforming Growth Factor-beta Type I