Hepagene Therapeutics, Inc., 218 Xinghu Street, Suzhou 215123, China.
J Med Chem. 2023 Jul 27;66(14):9363-9375. doi: 10.1021/acs.jmedchem.3c00456. Epub 2023 Jul 9.
The farnesoid X receptor (FXR) is a ligand-activated nuclear receptor. Activation of FXR significantly impacts the expressions of the pivotal genes involved in bile acid metabolism, inflammation, fibrosis, and homeostasis of lipid and glucose, leading to considerable interests in developing FXR agonists for the treatment of nonalcoholic steatohepatitis (NASH) or other FXR-relevant diseases. Herein, we describe the design, optimization, and characterization of a series of -methylene-piperazinyl derivatives as the nonbile acid FXR agonists. Particularly, compound (), a potent full FXR agonist, shows high selectivity, favorable ADME and pharmacokinetics profile, along with favorable activities demonstrated in both rodent PD model and HFD-CCl model and is currently in clinical development in patients with NASH in phase II.
法尼醇 X 受体 (FXR) 是一种配体激活的核受体。FXR 的激活显著影响参与胆汁酸代谢、炎症、纤维化和脂质及葡萄糖内稳态的关键基因的表达，这使得开发 FXR 激动剂用于治疗非酒精性脂肪性肝炎 (NASH) 或其他与 FXR 相关的疾病具有重要意义。在此，我们描述了一系列亚甲基哌嗪基衍生物作为非胆汁酸 FXR 激动剂的设计、优化和表征。特别是，化合物 ()，一种有效的全 FXR 激动剂，表现出高选择性、良好的 ADME 和药代动力学特性，以及在啮齿动物 PD 模型和 HFD-CCl 模型中均显示出良好的活性，目前正处于 NASH 患者的 II 期临床开发阶段。
