Huang Wanqiu, Cao Zhijun, Wang Wenxin, Yang Zhongcheng, Jiao Shixuan, Chen Ya, Chen Siliang, Zhang Luyong, Li Zheng
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Bioorg Chem. 2024 Feb;143:107071. doi: 10.1016/j.bioorg.2023.107071. Epub 2024 Jan 4.
Farnesoid X receptor (FXR) was considered as a promising drug target in the treatment of cholestasis, drug-induced liver injury, and non-alcoholic steatohepatitis (NASH). However, the existing FXR agonists have shown different degrees of side effects in clinical trials without clear interpretation. MET-409 in clinical phase Ⅲ, has been proven significantly fewer side effects than that of other FXR agonists. This may be due to the completely different structure of FEX and other non-steroidal FXR agonists. Herein, the structure-based drug design was carried out based on FEX, and the more active FXR agonist LH10 (FEX EC = 0,3 μM; LH10 EC = 0.14 μM)) was screened out by the comprehensive SAR studies. Furthermore, LH10 exhibited robust hepatoprotective activity on the ANIT-induced cholestatic model and APAP-induced acute liver injury model, which was even better than positive control OCA. In the nonalcoholic steatohepatitis (NASH) model, LH10 significantly improved the pathological characteristics of NASH by regulating several major pathways including lipid metabolism, inflammation, oxidative stress, and fibrosis. With the above attractive results, LH10 is worthy of further evaluation as a novel agent for the treatment of liver disorders.
法尼酯X受体（FXR）被认为是治疗胆汁淤积、药物性肝损伤和非酒精性脂肪性肝炎（NASH）的一个有前景的药物靶点。然而，现有的FXR激动剂在临床试验中已显示出不同程度的副作用，且尚无明确解释。处于Ⅲ期临床的MET-409已被证明副作用明显少于其他FXR激动剂。这可能是由于FEX与其他非甾体FXR激动剂的结构完全不同。在此，基于FEX进行了基于结构的药物设计，并通过全面的构效关系研究筛选出了活性更高的FXR激动剂LH10（FEX EC = 0.3 μM；LH10 EC = 0.14 μM）。此外，LH10在ANIT诱导的胆汁淤积模型和APAP诱导的急性肝损伤模型上表现出强大的肝保护活性，甚至优于阳性对照奥贝胆酸（OCA）。在非酒精性脂肪性肝炎（NASH）模型中，LH10通过调节包括脂质代谢、炎症、氧化应激和纤维化在内的几个主要途径，显著改善了NASH的病理特征。鉴于上述引人注目的结果，LH10作为一种治疗肝脏疾病的新型药物值得进一步评估。
