Discovery of novel pyrrolo-pyridine/pyrimidine derivatives bearing pyridazinone moiety as c-Met kinase inhibitors

作者：Wang, Lin Xiao; Liu, Xiaobo; Xu, Shan; Tang, Qidong; Duan, Yongli; Xiao, Zhen; Zhi, Jia; Jiang, Liwen; Zheng, Pengwu^*; Zhu, Wufu^*

来源：European Journal of Medicinal Chemistry, 2017, 141: 538-551.

DOI：10.1016/j.ejmech.2017.10.027

• Pyrrolo[2,3-b]pyridines
• Pyrrolo[2,3-d]pyrimidines
• Pyridazinone
• c -Met
• Antitumor activity
• Docking study

In continue to our previous research, eight series of pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine derivatives bearing pyridazinone moiety were designed, synthesized, and the in vitro antitumor activity was evaluated against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). Some selected compounds (22f, 22g, 26c and 26e) were evaluated for the activity against c-Met kinase, and according to the results of kinase inhibitory activity, the compound 22g was further evaluated for other four tyrosine kinases (Flt-3, VEGFR-2, c-Kit and EGFR) to test the enzyme-based selectivity. The most promising compound 22g showed excellent activity than lead compound Foretinib against A549, HepG2, MCF-7 and PC-3 cell lines, with the IC50 values of 2.19 +/- 0.45 mu M,132 +/- 0.26 mu M, 6.27 +/- 1.04 mu M and 4.63 +/- 0.83 mu M. The structure activity relationships (SARs) and docking studies indicated that the pyrrolo[2,3-b]pyridine derivatives bearing 4-oxo-pyridazinone moiety was superior to the pyrrolo[2,3-d]pyrimidine derivatives bearing 6-oxo-pyridazinone moiety. What's more, the target compounds modified with X and Y (X = H, Y = H) were favorable to the activity. And electron drawing groups (EWGs) of 4-Cl-3CF(3) on the aryl group show the best activity.

• 出版日期2017-12-1
• 单位江西科技师范大学