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

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-beta type I receptor kinase (ALK5) and p38 alpha 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-1 displayed the similar level of potency to that of 5 against both ALK5 (IC50 = 7.68-13.70 nM) and p38 alpha 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. (C) 2015 Elsevier Ltd. All rights reserved.