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. Issue 23 (1st December 2016)

• Record Type: Journal Article
• Authors: Hu, Liming; Cao, Tingting; Lv, Yongjuan; Ding, Yiming; Yang, Leifu; Zhang, Qiang; Guo, Mingzhou
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 23(2016)
• Page Start: 5830
• Page End: 5835
• Publication Date: 2016-12-01
• Subjects: BCR–ABL inhibitors -- Bioactivity -- Molecular docking -- Chronic myeloid leukemia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.10.007
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of 4-((pyrazolo[1, 5- a ]pyrimidin-6-yl)-1 H -pyrazol-1-yl)phenyl-3-benzamide derivatives and 4-((imidazo[1, 2- b ]pyridazin-3-yl)-1 H -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 compounds16a strongly suppressed BCR–ABL1 kinase with IC50 value of 8.5 nM. The tested compounds16a and16i 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.