Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase

Maddeboina Krishnaiah, Cheng Hua Jin, Yhun Yhong Sheen, Dae Kee Kim

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC50 = 7.68-13.70 nM) and p38α MAP kinase (IC50 = 1240-3370 nM). Among them, 19j inhibited ALK5 with IC50 value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.

Original languageEnglish
Pages (from-to)5228-5231
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number22
DOIs
StatePublished - 15 Nov 2015

Keywords

  • ALK5 inhibitor
  • Cancer
  • Fibrosis
  • Kinase assay
  • TGF-β

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