Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors

被引：10

作者：

Liang, Xuewu ^{[1
]}

Huang, Yongxue ^{[1
]}

Zang, Jie ^{[1
]}

Gao, Qianwen ^{[1
]}

Wang, Binghe ^{[2
]}

Xu, Wenfang ^{[1
]}

Zhang, Yingjie ^{[1
]}

机构：

[1] Shandong Univ, Sch Pharm, Dept Med Chem, Jinan 250012, Shandong, Peoples R China

[2] Georgia State Univ, Georgia Res Alliance Eminent Scholar Drug Discove, Dept Chem, Atlanta, GA 30303 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2016年 / 24卷 / 12期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

Inhibitors; JAKs; Kinase; 4-Aminopyrazole; JANUS KINASE; JAK/STAT PATHWAY; DISCOVERY;

D O I：

10.1016/j.bmc.2016.04.030

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10 mu M, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67 mu M, 0.098 mu M and 0.039 mu M, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：2660 / 2672

页数：13

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