化学
Janus激酶2
生物利用度
药理学
选择性
酪氨酸激酶2
细胞因子
基因亚型
贾纳斯激酶
细胞生长
化学合成
激酶
体外
受体
IC50型
生物化学
内科学
基因
生长因子
血小板源性生长因子受体
医学
催化作用
作者
Pengfei Xu,Pei Shen,Hai Wang,Lian Qin,Jie Ren,Qian Sun,Raoling Ge,Jinlei Bian,Yi Zhong,Zhiyu Li,JuBo Wang,Zhixia Qiu
标识
DOI:10.1016/j.ejmech.2021.113394
摘要
Herein, we describe the design, synthesis, and structure−activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs.
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