Abstract
Two series of nitrogenous heterocycle compounds--1,2,4-trisubstituted imidazoles and 1,3,5-trisubstituted pyrazoles have been synthesized and evaluated for their ALK5 inhibitory activity and cytotoxicity in TGFbeta-Smad2 assay and MTT assay, respectively. The ALK4/5/7 inhibitory activity of some compound was also evaluated in ALK4/5/7 autophosphorylation assays. Compounds 6c and 14c showed relatively potent ALK5 inhibition while weak cytotoxicity. At the same time, compounds 6c and 14c display relatively better ALK5 selectivity versus ALK4/ALK7 (nearly 10-fold) compared with SB431542, a well known ALK5 inhibitor. Compound 6g2 proved to be a moderately selective ALK4 inhibitor versus ALK5 and ALK7 (>10-fold). The binding mode of 14c generated by flexible docking study shows that 14c fits well into the site cavity of ALK5 by forming several tight interactions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzamides / pharmacology
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Binding Sites
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Cell Line
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Crystallography, X-Ray
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Dioxoles / pharmacology
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry*
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Imidazoles / toxicity
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Phosphorylation
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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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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / toxicity
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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
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Structure-Activity Relationship
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Benzamides
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Dioxoles
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Imidazoles
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Protein Kinase Inhibitors
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Pyrazoles
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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