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

• Published in: Chinese chemical letters Vol. 33; no. 6; pp. 2969 - 2974
• Main Authors: Liu, Dandan, Ge, Huan, Xu, Fangling, Xu, Yufang, Liu, Wenjun, Li, Honglin, Zhu, Lili, Diao, Yanyan, Zhao, Zhenjiang
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.06.2022; Research and Development Department,Jiangzhong Pharmaceutical Co.,Ltd.,Nanchang 330096,China; Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China%Research and Development Department,Jiangzhong Pharmaceutical Co.,Ltd.,Nanchang 330096,China%Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China
• Subjects: Cancer; Inhibitors; JAK2; Selectivity; Structure-activity relationships; Selectivity; Inhibitors; JAK2; Structure-activity relationships; Cancer
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2021.12.099

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, 21b exhibited high inhibitory activity against JAK2 with an IC50 of 9 nmol/L, moreover, it showed 276- and 184-fold selectivity over JAK1 and JAK3, respectively. Besides, 21b had a significant antiproliferative activity against HEL cells, and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway. These results indicated that 2-aminopyridine compound 21b had the potential to be developed as a selective JAK2 inhibitor for further study. Compound 21b exhibited high inhibitory activity against JAK2 and high selectivity over JAK1 and JAK3. It also showed significant antiproliferative activity against HEL cells, and inhibited the phosphorylation of JAK2 in the down-stream signaling pathway, indicating that it was expected to be developed as a selective JAK2 inhibitor. [Display omitted] .