具有肝靶向作用的Autotaxin变构抑制剂的发现与抗纤维化研究

肝纤维化是以细胞外基质过度积聚为特征的创伤修复反应，可导致器官衰竭和肝功能的丧失，最终发展为肝硬化和肝癌。预防或逆转纤维化已成为新型肝脏特异性药物临床试验的主要终点，但目前还没有直接治疗肝纤维化的特效药物。近年来，ATX已被确证为肝纤维化关键血浆标志物之一，选择性抑制ATX，可显著减少致纤维化因子LPA的产生，有效减缓纤维化的进程。本项目拟在前期研究基础上，采用骨架重构及拓扑结构多样性开发技术，开展基于结构的变构ATX抑制剂设计与合成，通过多水平药理活性评价其生物活性，总结构效关系。采用在肝部特异性代谢的磷酸酯前药实现化合物肝部选择性，并对化合物进行药代及毒理试验评价；建立纤维化微组织模型，实现化合物抗纤维化潜力高通量筛选；构建CCl4等多种小鼠肝纤维化模型，系统评价优选化合物的体内抗纤维化效果，阐明化合物的抗纤维化机制，为肝纤维化治疗药物开发提供全新思路。

Liver fibrosis is a wound repair response characterized by excessive accumulation of extracellular matrix, which can lead to loss of liver function and organ failure, and eventually develop into liver cirrhosis and hepatic cell cancer. Prevention or reversal of fibrosis has become the main end point of clinical trials of new liver-targeted drugs, but there is no specific therapy for direct treatment of liver fibrosis. In recent years, ATX has been confirmed as one of the key plasma markers of liver fibrosis. Selective inhibition of ATX can significantly reduce the production of fibrogenic factor LPA and effectively slow down the process of liver fibrosis. On the basis of previous research, this project plans to conduct structure-based design and synthesis of allosteric ATX inhibitors by using skeleton reconstruction and topological diversity development technology. The biological activities are evaluated by multi-level pharmacological assays, and the structure-activity relationships will be summarized. Liver specifically metabolized phosphate prodrugs is involved to realize the liver selectivity of the compounds, and the druggable properties of the compounds were evaluated by pharmacokinetic and toxicological experiments. The fibrotic microstructure model is established to realize the high throughput screening of the antifibrotic potential of the compounds. To systematically evaluate the anti-fibrosis effect of the optimized compounds in vivo, several mouse liver fibrosis models such as CCl4-induced model will be constructed and the anti-fibrosis mechanism of the compounds will be clarified which is going to provide a new idea for the development of liver fibrosis therapeutic drugs.