Design,synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors  

作　　者：Dandan Liu Huan Ge Fangling Xu Yufang Xu Wenjun Liu Honglin Li Lili Zhu Yanyan Diao Zhenjiang Zhao 

机构地区：[1]Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China [2]Research and Development Department,Jiangzhong Pharmaceutical Co.,Ltd.,Nanchang 330096,China

出　　处：《Chinese Chemical Letters》2022年第6期2969-2974,共6页中国化学快报（英文版）

基　　金：the National Key Research and Development Program(No.2016YFA0502304);the National Natural Science Foundation of China(No.81825020);the Shanghai Committee of Science and Technology(No.20S11901000);the Fundamental Research Funds for the Central Universities;sponsored by the National Program for Special Supports of Eminent Professionals;the National Program for Support of Top-Notch Young Professionals。

摘　　要：The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic.In this paper,a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design,synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib.Among them,21 b exhibited high inhibitory activity against JAK2 with an IC_(50)of 9 nmol/L,moreover,it showed 276-and 184-fold selectivity over JAK1 and JAK3,respectively.Besides,21 b had a significant antiproliferative activity against HEL cells,and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway.These results indicated that2-aminopyridine compound 21 b had the potential to be developed as a selective JAK2 inhibitor for further study.

关 键 词：JAK2 SELECTIVITY INHIBITORS Cancer Structure-activity relationships 

分 类 号：R914[医药卫生—药物化学] TQ463.5[医药卫生—药学]