Synthesis, biological evaluation and molecular modelling of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1 H -imidazoles as ALK5 inhibitors

摘要

A series of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles, 7a–c , 11a–h , and 16a–h has been synthesised and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Incorporation of a quinoxalin-6-yl moiety and a methylene linker at the 4- and 2-position of the imidazole ring, respectively, and a m-CONHsub2/sub substituent in the phenyl ring generated a highly potent and selective ALK5 inhibitor 11e . Docking model of ALK5 in complex with 11e showed that it fitted well in the ATP-binding pocket with favourable interactions.