Design, synthesis, and biological activity of phenyl-pyrazole derivatives as BCR–ABL kinase inhibitors

Abstract

4-(Pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives have been proposed as new BCR–ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. In the present study, a series of 4-(pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives were synthesized and their activities against BCR–ABL1 kinase in vitro were evaluated by using Kinase-Glo assay. All new compounds showed from moderate to potent activities against wild-type (wt) BCR–ABL1 kinase with an IC50 range from 14.2 to 326.0nM. Among them, seven compounds exhibited BCR–ABL1 kinase inhibitory activities with IC50 values less than 50nM. Compound 7a displayed the most potent inhibitory activity to BCR–ABL kinase (IC50: 14.2nM). Docking simulation was performed for compounds 7a and 7i into the BCR–ABL kinase structure active site to determine the probable binding model. The preliminary structure–activity relationship was discussed. The interesting activities of these compounds may make them promising candidates as therapeutic agents for chronic myelogenous leukemia.