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

Dae Kee Kim, Yeon Im Lee, Yeon Woo Lee, Purushottam M. Dewang, Yhun Yhong Sheen, Yeo Woon Kim, Hyun Ju Park, Jakyung Yoo, Ho Soon Lee, Yong Kook Kim

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27 Scopus citations

Abstract

A series of 4(5)-(6-methylpyridin-2-yl)imidazoles 16-19 and -pyrazoles 22-29, 33, and 34 have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in cell-based luciferase reporter assays. The 6-quinolinyl imidazole analogs 16 and 18 inhibited ALK5 phosphorylation with IC50 values of 0.026 and 0.034 μM, respectively. In a luciferase reporter assay using HaCaT cells transiently transfected with p3TP-luc reporter construct, 18 displayed 66% inhibition at 0.05 μM, while competitor compounds 2 and 3 showed 44% inhibition. The binding mode of 18 generated by flexible docking studies with ALK5:18 complex shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions.

Original languageEnglish
Pages (from-to)4459-4467
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number12
DOIs
StatePublished - 15 Jun 2010

Keywords

  • ALK5 inhibitor
  • Cell-based luciferase reporter assays
  • TGF-β

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