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

Myoung-Soon Park, Hyun-Ju Park, Young Jae An, Joon Hun Choi, Geunyoung Cha, Hwa Jeong Lee, So-Jung Park, Purushottam M Dewang, Dae-Kee Kim

Journal of enzyme inhibition and medicinal chemistry 2020 Dec

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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-CONH2 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.

Citation

Myoung-Soon Park, Hyun-Ju Park, Young Jae An, Joon Hun Choi, Geunyoung Cha, Hwa Jeong Lee, So-Jung Park, Purushottam M Dewang, Dae-Kee Kim. Synthesis, biological evaluation and molecular modelling of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles as ALK5 inhibitors. Journal of enzyme inhibition and medicinal chemistry. 2020 Dec;35(1):702-712