新型FXR激动剂的优化合成、构效关系及其抗非酒精性脂肪肝病活性研究

Nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in developed countries and rich regions of China and the incidence seems to be rising as the obesity epidemic continues. Currently, no recommended conventional medicines are used in clinic. Farnesoid X receptor (FXR), as a potential drug target for NAFLD, plays key roles in the development and progression of NAFLD by the regulation of glucose and lipid metabolism. Accordingly, the development of potent agonists of FXR would be an important step in further the treatment of NAFLD. Herein, we described a novel phenylpropionic acid derivative sklb-14-312 with potential FXR activation (EC50=4.91μM). The sklb-14-312 could reduce the weight of body and fat, and improve fat deposition in the liver tissue of NAFLD. Therefore, in this study, we will focus on these planned works as follow: To design novel small-molecule sklb-14-312 derivatives on the basis of previous study; To synthesize related derivatives which first selected by virtual assessment of docking score, drug-likeness, pharmacokinetics and toxicity, and to finish FXR assay and further obtain drug leds; To summarize clear structure-activity relationship, and then to guide chemical modification and to get drug candidate; To evaluate candidate 's pharmacological activities in animal models of NAFLD, as well as to accomplish studies of pharmacokinetics and toxicity. In summary, these researches are aim to achieve one potent and safe FXR agonist as drug candidate for the treatment of NAFLD.

非酒精性脂肪肝（NAFLD）的发病率逐年上升，成为发达国家和我国富裕地区慢性肝病的重要病因。目前临床治疗NAFLD的药物尚不完善，而法尼酯X受体（FXR）与NAFLD发生和发展密切相关，因而开展靶向FXR的激动剂研究具有重要意义。前期研究发现的FXR激动剂sklb-14-132是结构新颖的肉桂酸衍生物（EC50=4.91μM），其在NAFLD模型中降低体重与脂肪重量，调节肝脏甘油三酯和胆固醇，缓解肝脏脂肪沉积，展示了潜在治疗效果，因此对其进行深入的药物化学研究具有重要价值。故本课题将优化sklb-14-132分子结构，构建新颖的衍生物库；通过虚拟筛选，对优选目标小分子进行化学合成与FXR活性筛选，获得先导化合物；探讨构-效关系，指导结构修饰，发现高效的候选分子，进而完成其在动物模型中药效学及药代、初步安全性评价，为靶向FXR的小分子激动剂在NAFLD防治研究与应用提供新的思路和依据。

非酒精性脂肪肝（NAFLD）的发病率逐年上升，成为发达国家和我国富裕地区慢性肝病的重要病因。目前临床治疗NAFLD的药物尚不完善，而法尼酯X受体（FXR）与NAFLD发生和发展密切相关，因而开展靶向FXR的激动剂研究具有重要意义。本项目在前期工作基础上进行结构优化，合成了150多个化合物，并进行了FXR活性测试。其中化合物B4具有较高的FXR活性，EC50为3.4μM，并进一步进行体内活性评价。治疗8周后，检测空腹血糖、口服葡萄糖耐量和胰岛素耐量，测定ALT、AST、TG、TC、LDL、HDL等的含量，取肝脏称重，计算肝指数，并对肝脏做HE染色，实验结果表明化合物B4在不影响摄食量的情况下，可以明显降低肥胖小鼠体重、脂肪量、空腹血糖、转氨酶和空腹血清胰岛素，提高胰岛素敏感性，改善血脂指标和口服葡萄糖耐量，且对NAFLD具有一定的治疗效果。