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

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• 作者：Liming Hu^a ; ^{huliming@bjut.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Tingting Cao^a ; Yongjuan Lv^a ; Yiming Ding^a ; Leifu Yang^b ; Qiang Zhang^b ; Mingzhou Guo^c
• 关键词：BCR&ndash ; ABL inhibitors ; Bioactivity ; Molecular docking ; Chronic myeloid leukemia
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：26
• 期：23
• 页码：5830-5835
• 全文大小：1007 K

文摘

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.