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

作者：Hu, Liming^*; Zheng, Yuyan; Li, Zhipeng; Wang, Yujie; Lv, Yongjuan; Qin, Xuemei; Zeng, Chengchu

来源：Bioorganic & Medicinal Chemistry, 2015, 23(13): 3147-3152.

DOI：10.1016/j.bmc.2015.04.083

• BCR-ABL
• Tyrosine kinase inhibitor
• Phenyl-pyrazole
• Molecular docking

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 326.0 nM. Among them, seven compounds exhibited BCR-ABL1 kinase inhibitory activities with IC50 values less than 50 nM. Compound 7a displayed the most potent inhibitory activity to BCR-ABL kinase (IC50: 14.2 nM). 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.

• 出版日期2015-7-1
• 单位北京工业大学