Design, synthesis, and biological activity of 4-(imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-phenylben zamide derivatives as BCR-ABL kinase inhibitors

作者：Hua, Liming^*; Cao, Tingting; Lv, Yongjuan; Ding, Yiming; Yang, Leifu; Zhang, Qiang; Guo, Mingzhou

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(23): 5830-5835.

DOI：10.1016/j.bmcl.2016.10.007

• BCR-ABL inhibitors
• Bioactivity
• Molecular docking
• Chronic myeloid leukemia

A series of 4-((pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide derivatives and 4-((imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-)phenyl-3-benzamide derivatives were designed, synthesized as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. These new compounds were screened for BCR-ABL1 kinase inhibitory activity, and most of them appeared good inhibitory activity against BCR-ABL1 kinase. One of the most potent compounds 16a strongly suppressed BCR-ABL1 kinase with IC50 value of 8.5 nM. The tested compounds 16a and 16i showed strong inhibitory activities against K562 with IC50 value of less than 2 nM. Molecular docking studies indicated that these compounds fitted well with the active site of BCR-ABL1 protein. The results showed these inhibitors may serve as lead compounds for further developing new drugs targeted BCR-ABL kinase.

• 出版日期2016-12-1
• 单位北京工业大学; 中国人民解放军总医院