Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles 14a–d, 15a–d, 17a, 17b, 18a–d, 19a, and 19b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 2-[3-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-pyrazol-1-yl]-N-phenylethanethioamide (18a) inhibited ALK5 phosphorylation with an IC50 value of 0.013 μM and showed 80% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.

Graphical abstractA series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles was prepared and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of 16 novel compounds was prepared and chemically characterized. ► The compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. ► Compound 18a exhibited highly potent ALK5 inhibitory activity.