Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China.
Bioorg Chem. 2022 May;122:105715. doi: 10.1016/j.bioorg.2022.105715. Epub 2022 Mar 3.
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 p38α mitogen-activated protein (MAP) in the enzymatic assay. We evaluated anti-fibrotic effects of J-1063 on TGF-β-induced hepatic stellate cells activation 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-βR1 (ALK5), which is likely related to the inhibition of TGF-β--Smad signaling and NLRP3 inflammasome activation. The results suggest that J-1063 might be potential candidates for further anti-liver fibrosis drug development.
在本研究中，我们完成了吡唑衍生物 J-1063 的合成，并在酶促测定中评估了 J-1063 对激活素受体样激酶 5 (ALK5) 和 p38α 丝裂原活化蛋白 (MAP) 的激酶抑制活性。我们评估了 J-1063 对 TGF-β 诱导的肝星状细胞激活和 TAA 诱导的小鼠肝纤维化的抗纤维化作用。J-1063 显示出比 LY2157299 更好的抗纤维化作用。我们的数据表明，J-1063 通过抑制 TGF-βR1（ALK5）发挥抗纤维化活性，这可能与抑制 TGF-β--Smad 信号和 NLRP3 炎性体激活有关。结果表明，J-1063 可能是进一步开发抗肝纤维化药物的潜在候选药物。
