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.

DOI: 10.1016/j.bmc.2015.04.083

Cite this paper

@article{Hu2015DesignSA, title={Design, synthesis, and biological activity of phenyl-pyrazole derivatives as BCR-ABL kinase inhibitors.}, author={Liming Hu and Yuyan Zheng and Zhipeng Li and Yujie Wang and Yongjuan Lv and Xuemei Qin and Chengchu Zeng}, journal={Bioorganic & medicinal chemistry}, year={2015}, volume={23 13}, pages={3147-52} }