文献类型：期刊文献

英文题名：Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2

作者：Wang, Wanqi[1];Diao, Yanyan[1];Li, Wenjie[1];Luo, Yating[1];Yang, Tingyuan[1];Zhao, Yuyu[1];Qi, TianTian[1];Xu, Fangling[1];Ma, Xiangyu[1];Ge, Huan[1];Liang, Yingfan[1];Zhao, Zhenjiang[1];Liang, Xin[1];Wang, Rui[1];Zhu, Lili[1];Li, Honglin[1];Xu, Yufang[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China

年份：2019

卷号：29

期号：12

起止页码：1507

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000466365200015)】；

基金：The research is supported in part by the National Key Research and Development Program (Grant 2016YFA0502304), the National Natural Science Foundation of China (grant 81825020), the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (No. 2018ZX09711002), the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under Grant No. U1501501. Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals.

语种：英文

外文关键词：JAK2; Rheumatoid arthritis; Crizotinib; Molecular docking

摘要：Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50, = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 121 were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.