非酒精性脂肪性肝炎（NASH）以肝细胞脂质过度沉积（脂肪变性）引发的肝脏炎症为主要特征，其发病率已超过乙型肝炎成为第一大类慢性肝病。目前仍没有直接治疗NASH的一线药物。因此，抗NASH创新药物研究意义重大。研究证明肝细胞脂肪变性诱导的线粒体氧化应激是NASH发病关键。申请人前期发现，化合物R17可促进肝细胞有氧代谢，降低脂质累积，抑制线粒体氧化应激，下调炎症因子水平，类似结果在肥胖小鼠模型上得到验证。为此，申请人提出通过促进能量代谢抑制脂质异位累积及其介导的线粒体氧化应激，保护肝细胞活性，进而从源头阻断脂质毒性，实现抗NASH的研究新策略。本项目拟设计合成新型R17类似物，并科学构建抗NASH评价体系，全面评价化合物活性并总结构效关系，深入研究代表性化合物的体内外抗NASH能力和分子作用机制，发现抗NASH先导化合物。为发展NASH治疗新策略和发现抗NASH新药提供理论和和实验依据。

Non-alcoholic steatohepathtitis (NASH) is characterized by inflammation induced by lipid ectopic accumulation (steatosis) in hepatocyte, its incidence has exceeded that of hepatitis B as the first leader of chronic liver disease. Currently there are still no approved drugs for NASH treatment. Hence, research and development of innovative anti-NASH drugs are very important. Studies have shown that mitochondrial oxidative stress caused by steatosis plays a pivotal role for NASH development. Our previous studies have found that hit compound R17 increased aerobic metabolism, reduced the triglyceride levels in hepatocytes, inhibited mitochondrial oxidative stress, decreased the levels of inflammatory factors. Similar results were verified in the obese mouse model. Thus the applicant propose a new strategy of anti-NASH drugs research based on promoting energy metabolism, inhibiting lipid ectopic accumulation and its mediated mitochondrial oxidative stress, protected hepatocytes viability beyond lipitoxicity from the starting. In this research, on the basis of our previous research results, we will design and synthesize a series of novel analogues of R17, reasonably construct the anti-NASH evaluation system, evaluate the activities of synthesized compounds and summarize the structure-activity relationship, identify the lead compounds, and further deeply study the molecular mechanism of lead compounds against NASH in vivo and in vitro. This project might provide a useful theoretical and experimental basis for the establishment of new therapy strategy and the development of new anti-NASH drugs.