Activation of the nuclear farnesoid X receptor (FXR) which acts as cellular bile acid sensor has been validated as therapeutic strategy to counter liver disorders such as non-alcoholic steatohepatitis by the clinical efficacy of obeticholic acid. FXR antagonism, in contrast, is less well studied and potent small molecule FXR antagonists are rare. Here we report the systematic optimization of a novel class of FXR antagonists towards low nanomolar potency. The most optimized compound antagonizes baseline and agonist induced FXR activity in a full length FXR reporter gene assay and represses intrinsic expression of FXR regulated genes in hepatoma cells. With this activity and a favorable toxicity-, stability- and selectivity-profile it appears suitable to further study FXR antagonism in vitro and in vivo.

通过奥贝胆酸的临床疗效，已验证了作为细胞胆汁酸传感器的核法呢素X受体（FXR）的激活是对抗肝脏疾病（例如非酒精性脂肪性肝炎）的治疗策略。相比之下，对FXR的拮抗作用研究较少，有效的小分子FXR拮抗剂也很少见。在这里，我们报告了针对低纳摩尔效能的一类新型FXR拮抗剂的系统优化。最优化的化合物可在全长FXR报告基因试验中拮抗基线和激动剂诱导的FXR活性，并抑制肝癌细胞中FXR调控基因的内在表达。具有这种活性和良好的毒性，稳定性和选择性特征，似乎适合进一步在体内和体外研究FXR拮抗作用。