基于结构的新型ALK5抑制剂的设计、合成及其抗肝纤维化活性研究

转化生长因子-β1（TGF-β1）是提高肝纤维化最有效的细胞因子，通过促进细胞外基质（ECM）的产生及沉积，而引起肝纤维化，其中TGF-β1/Smad信号传导通路是促进ECM生成的重要途径。该通路的相关因子TGF-β1型受体激酶（ALK5）被认为是治疗肝纤维化的理想靶标，其抑制剂有望成为治疗肝纤维化的有效药物。.在前期工作中，发现了含3a和22c的2种化合物在体外对该激酶显示高活性、高选择性、低细胞毒性和较高的抗肝纤维化活性。本项目以3a和22c为先导化合物，利用结构设计的方法（生物电子等排替换、提高代谢稳定性和蛋白结合力等），对这2种化合物进行结构优化，设计了多种化合物，重点要解决目前肝纤维化药物存在的选择性差、毒性大等问题。通过该研究，分析化合物结构与肝纤维化活性的关系，力争提高活性、改善生物利用度和半衰期，以期发现临床前研究潜力的新型ALK5抑制剂，为研发抗肝纤维化药物奠定基础。

Transforming growth factor-β1 (TGF-β1) is the most effective cytokine to improve liver fibrosis, and causes liver fibrosis by promoting the production and deposition of extracellular matrix (ECM). TGF-β1/Smad signaling pathway regulating gene expression of ECM is an important way to promote the generation of ECM. Therefore, TGF-β type I receptor kinase (or activin receptor like kinase 5, ALK5) associated with this pathway is considered as an ideal target for the treatment of liver fibrosis, and its inhibitors are expected to be effective drugs in the treatment of liver fibrosis. . In the previous work, we found that two small-molecule inhibitors represented by compounds 3a and 22c showed high activity and selectivity to the kinase in vitro, and showed low cytotoxicity and high anti-hepatic fibrosis activity. In this project, 3a and 22c were used as lead compounds, and the structural design methods (such as bioisosteric replacement, improvement of metabolic stability and protein binding ability) were used to optimize the structure of these two compounds, and a variety of compounds were designed, focusing on solving the problems of poor selectivity and high toxicity of current hepatic fibrosis drugs. Through the study of this project, the relationship between compound structure and hepatic fibrosis activity was analyzed, so as to improve the activity, bioavailability and half-life, so as to find novel ALK5 inhibitors with preclinical research potential and lay a foundation for the development of anti-hepatic fibrosis drugs.