The in vitro and in vivo study of a pyrazole derivative, J-1063, as a novel anti-liver fibrosis agent: Synthesis, biological evaluation, and mechanistic analysis

被引：13
|
作者：
Zheng, Guang-Hao [1 ,2 ]
Liu, Jian [1 ,2 ]
Guo, Fang Yan [1 ,2 ]
Zhang, Zhi-Hong [1 ,2 ]
Jiang, Yin-Jing [1 ,2 ]
Lin, Yong-Ce [1 ,2 ]
Lan, Xiao-Qi [1 ,2 ,3 ]
Ren, Jie [1 ,2 ]
Wu, Yan-Ling [1 ,2 ]
Nan, Ji-Xing [1 ,2 ,3 ,4 ]
Jin, Cheng Hua [1 ,2 ,3 ,4 ]
Lian, Li-Hua [1 ,2 ,3 ,4 ]
机构：
[1] Yanbian Univ, Key Lab Tradit Chinese Korean Med Res Yanbian Univ, Coll Pharm, Yanji 133002, Jilin, Peoples R China
[2] Yanbian Univ, Coll Pharm, Key Lab Nat Med Changbai Mt, Minist Educ, Yanji 133002, Jilin, Peoples R China
[3] Yanbian Univ, Coll Integrat Sci, Interdisciplinary Biol Funct Mol, Yanji 133002, Jilin, Peoples R China
[4] Yanbian Univ, Coll Pharm, Yanji 133002, Peoples R China
来源：
BIOORGANIC CHEMISTRY | 2022年 / 122卷
基金：
美国国家科学基金会;
关键词：
Pyrazole derivative; Liver fibrosis; Inflammation; TGF-beta; Smad; GROWTH-FACTOR; INFLAMMASOME ACTIVATION; MACROPHAGES; HOMEOSTASIS; DISEASES; CELLS;
D O I：
10.1016/j.bioorg.2022.105715
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：
In the present study, we completed the synthesis of a pyrazole derivative J-1063 and evaluated the kinase inhibitory activity of J-1063 activin receptor-like kinase 5 (ALK5) and p38 alpha mitogen-activated protein (MAP) in the enzymatic assay. We evaluated anti-fibrotic effects of J-1063 on TGF-beta-induced hepatic stellate cells acti-vation and TAA induced mice liver fibrosis. J-1063 showed much prior anti-fibrotic effects than those with LY2157299. Our data revealed that J-1063 exerted anti-fibrotic activity by inhibiting TGF-beta R1 (ALK5), which is likely related to the inhibition of TGF-beta-Smad signaling and NLRP3 inflammasome activation. The results suggest that J-1063 might be potential candidates for further anti-liver fibrosis drug development.
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页数：14
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