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

  • Bioorg Chem. 2022 May;122:105715. doi: 10.1016/j.bioorg.2022.105715.
Guang-Hao Zheng  1 ,  Jian Liu  1 ,  Fang Yan Guo  1 ,  Zhi-Hong Zhang  1 ,  Yin-Jing Jiang  1 ,  Yong-Ce Lin  1 ,  Xiao-Qi Lan  2 ,  Jie Ren  1 ,  Yan-Ling Wu  1 ,  Ji-Xing Nan  3 ,  Cheng Hua Jin  4 ,  Li-Hua Lian  5
Affiliations
  • 1. 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.
  • 2. 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.
  • 3. 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. Electronic address: [email protected].
  • 4. 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. Electronic address: [email protected].
  • 5. 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. Electronic address: [email protected].
PMID: 35279552 DOI: 10.1016/j.bioorg.2022.105715
Abstract

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.

Keywords
Inflammation; Liver fibrosis; Pyrazole derivative; Smad; TGF-β.
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