FXR/FASN双靶点化合物的设计、合成和抗肝纤维化活性研究

Nonalcoholic steatohepatitis (NASH) has gradually become the most severe one among nonalcoholic fatty liver diseases. However, the progress of the research and treatment on all aspects of NASH has been very slow. Comprehensive studies have disclosed that nicky derivative X receptor (FXR) which serves as a bile acid receptor has two major functions of both keeping control of the bile acid homeostasis and a regulatory effect of lipid and glucose metabolism. Herein, the FXR is novel drug target which has a lot of potential on the treatment of NASH.. Fatty acid synthase (FASN) is considered as the key enzyme of hepatic lipogenesis, and the inhibition of FASN expression or activity can significantly reduce the accumulation of liver fat. Studies have presented that FXR and FASN, that are two important drug targets, have a synergistic role in regulating fatty acid generation. So, in this project, we incorporated the bioactive pharmacophore of FASN inhibitor on our lead compound F4-14, and designed a kind of FXR/FASN compounds with novel core structures by taking advantage of bioisosteric replacement and skeleton migration. These designed and synthesized compounds provide a new idea for the research of NASH and the correlated mechanism of drug interaction.

非酒精性脂肪性肝炎（NASH）已经逐渐成为非酒精性脂肪性肝病里最严重的病变，但有关NASH各方面的研究和治疗进展较慢。研究发现，法尼基衍生物X受体（FXR）作为胆汁酸感受器，不但控制着体内胆汁酸稳态，而且对脂类及糖代谢也具有重要的调控作用，被认为是最具潜力的NASH治疗靶点。脂肪酸合成酶（FASN）是脂肪酸合成过程中的关键酶，抑制FASN的表达或活性可以显著的减少肝脏脂肪的聚积。有研究表明，FXR和FASN这两个重要的药物靶点存在着协同调控脂肪酸的生成，进而影响脂肪（甘油三酯）的聚积和肝纤维化的理论基础。因此，在本课题中，我们创新性的首次将我们发现的FXR激动活性的先导化合物F4-14的基本骨架与临床FASN抑制剂的药效团融合起来，进一步采用电子等排、骨架迁越等策略来设计并合成一类结构新颖的FXR/FASN双靶点目标化合物，用于NASH治疗的候选化合物的发现和其相关作用机制研究。

本课题以前期研究发现的优异化合物FL4-14为先导化合物，基于优势骨架，结合化合物蛋白晶体复合物结构分析，通过运用阻断药物代谢位点、生物电子等排、骨架跃迁、药效团拼合原理等设计结构新颖的化合物，并根据有效的合成方法合成衍生物，对其进行初步的药效学评价、药代动力学评价，以期得到活性更优、安全性更高、成药性更好、更具开发潜力的候选化合物。在执行期内，本项目共设计合成了55个化合物，其中有20个化合物在细胞水平的EC50值均低于10 nM，优于阳性药OCA及工具化合物GW4064，尤其化合物A55（EC50=0.06 nM）对FXR的激动活性要优于先导化合物FL4-14（EC50 = 5.80 nM）和临床化合物LY-2562175（EC50 = 4.10 nM）的激动活性；筛选出的候选化合物A15在CCl4诱导肝纤维化小鼠模型、高脂高果糖饮食加CCl4诱导NASH模型等两个动物模型中展现出良好的体内活性，具备强效的逆转NASH进程的作用，展现出良好的开发潜力；同时在DSS诱导的小鼠急性肠炎模型中，候选化合物A55表现出良好的体内肠炎治疗效果，拓展了该系列化合物适应症应用范围。受本课题资助，在Advanced Synthesis & Catalysis期刊发表文章1篇，培养硕士研究生2名。