Design, synthesis, and biological evaluation of novel 2-pyridinyl-[1,2,4]triazoles as inhibitors of transforming growth factor beta1 type 1 receptor.

A series of 2-pyridinyl-[1,2,4]triazoles have been synthesized and evaluated for their ALK5 inhibitory activity in the luciferase reporter assays. Compound 12b showed significant ALK5 inhibition (SBE-Luciferase, 73%; p3TP-Luciferase, 85%) at a concentration of 5 microM that is comparable to that of SB-431542 (SBE-Luciferase, 79%; p3TP-Luciferase, 88%), but weak p38 alpha MAP kinase inhibition (4%) at a concentration of 10 microM that is much lower than that of SB-431542 (54%). The binding mode of 12b generated by flexible docking studies revealed that the structure of 12b is a good fit into the (NPC-30345)-binding cavity of ALK5.