State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
J Med Chem. 2020 Nov 12;63(21):12748-12772. doi: 10.1021/acs.jmedchem.0c01065. Epub 2020 Oct 13.
Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.
法尼醇 X 受体（FXR）在胆汁酸稳态、炎症、纤维化以及脂质和葡萄糖代谢中发挥着关键作用，成为非酒精性脂肪性肝炎（NASH）或其他依赖 FXR 的疾病的有前途的治疗靶点。奥贝胆酸的 III 期临床试验结果表明，FXR 激动剂有望成为 NASH 和纤维化患者的一种干预手段，但这种源自胆汁酸的 FXR 激动剂会给患者带来严重的瘙痒和心血管疾病风险的增加。在此，我们报告了我们在发现一系列非胆汁酸 FXR 激动剂方面的努力，基于基于结构的药物设计和结构优化策略，设计和合成了 36 种化合物。特别是，化合物 是一种高效且选择性的 FXR 激动剂，具有良好的药代动力学特征、高肝分布和良好的 疗效，表明它是治疗 NASH 或其他依赖 FXR 的疾病的潜在候选药物。
