FXR/TGR5双靶点激动剂的设计、优化及生物活性评价

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is a burgeoning health problem worldwide. However, current NAFLD treatment is limited and pharmacological options are insufficient. Activation or modulation of bile acid receptors, such as the farnesoid X receptor (FXR) and TGR5, appear to affect NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. Virtual screening approach was performed to identify dual agonists of FXR and TGR5 using the common feature pharmacophore models and molecular docking. Then, using the hit compounds, a series of novel derivatives were optimized, synthesized and structure-activity relationship studied to develop novel dual agonists of FXR and TGR5 with high potency and selectivity. Hopefully, our studies will pave a road towards discovering some novel, potent dual agonists of FXR and TGR5 with significant promise for the treatment of NAFLD/NASH.

非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)的发病率逐年升高，且目前缺乏有效的治疗手段，严重威胁人类健康。胆汁酸受体法尼酯X受体(FXR)和Takeda G蛋白偶联受体5(TGR5)可通过调节体内的胆汁酸影响NAFLD/NASH疾病的发生发展。本项目基于“一石二鸟”策略借助药效团模型和以受体为基础的双靶点联合筛选手段进行虚拟筛选，同时结合分子水平和细胞水平的活性测试，发现具有FXR/TGR5双靶点激动活性的先导化合物；在此基础上进行多轮结构优化与改造，总结构效关系，探索发现双靶点药物的结构优化方法，以期最终发现安全有效，具有开发前景的FXR/TGR5双靶点激动剂。本课题的顺利开展为NAFLD/NASH的治疗与预防提供一种可利用的手段，具有潜在的应用价值和广阔的市场前景。

胆汁酸受体FXR和TGR5可以与胆汁酸在多个层面相互作用，影响机体的胰岛素敏感性，参与脂质与糖的代谢，是代谢性疾病药物开发的重要靶标。本项目首先借助计算机辅助药物设计手段，以构建的FXR和TGR5的药效团模型为基础进行虚拟筛选，从而得到结构新颖、活性较优的FXR激动剂、TGR5激动剂及FXR/TGR5双靶点激动剂。接着以筛选得到的TGR5激动剂依托咪酯为苗头化合物，经结构优化及构效关系考察得到苄基咪唑酰胺类化合物，该类化合物具有较好的TGR5激动活性，且能够有效降低小鼠体内血糖水平。在苄基咪唑酰胺类化合物结构基础上，再经骨架跃迁设计得到3-苯氧基-2-甲酰胺类TGR5激动剂，该类化合物对TGR5的激动活性进一步提高，能够促进小鼠GLP-1的分泌。最后，为了降低系统性TGR5激动剂的副作用，设计开发了一类能够与肠黏蛋白结合的非体循环TGR5激动剂，该类分子显著降低了系统性TGR5激动剂胆囊肿大的副作用。其中，化合物F114在小鼠糖耐实验、胰岛素抵抗实验、长期药效（DIO和db/db小鼠）等体内实验中均显示出明显的降糖效果，且能有效改善胰岛素敏感性，具有不错的开发应用前景。