Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
J Med Chem. 2021 Jul 8;64(13):9525-9536. doi: 10.1021/acs.jmedchem.1c00831. Epub 2021 Jun 24.
Non-alcoholic steatohepatitis (NASH) presents as an epidemic chronic liver disease that is closely associated with metabolic disorders and involves hepatic steatosis, inflammation, and fibrosis as key factors. Despite the enormous global prevalence of NASH, effective pharmacological interventions are lacking. Based on the hypothesis that the multifactorial condition NASH may benefit from combined multiple modes of action for enhanced therapeutic efficacy, we have previously developed dual FXR activators/sEH inhibitors (FXRa/sEHi) and observed remarkable antifibrotic effects upon their use in rodent NASH models. However, these first-generation FXRa/sEHi were characterized by moderate metabolic stability and short in vivo half-life. Aiming to overcome these pharmacokinetic drawbacks, we have systematically studied the structure-activity and structure-stability relationships of the chemotype and obtained second-generation FXRa/sEHi with improved pharmacokinetic parameters. With high plasma exposure, a half-life greater than 5 h, and similar dual potency on the intended targets, presents as a substantially optimized FXRa/sEHi for late-stage preclinical development.
非酒精性脂肪性肝炎（NASH）表现为一种流行的慢性肝脏疾病，与代谢紊乱密切相关，其关键因素包括肝脂肪变性、炎症和纤维化。尽管 NASH 在全球的患病率极高，但缺乏有效的药物干预措施。基于 NASH 这一多因素疾病可能受益于联合多种作用模式以增强治疗效果的假设，我们之前开发了双重 FXR 激动剂/可溶性环氧化物水解酶抑制剂（FXRa/sEHi），并在啮齿动物 NASH 模型中观察到它们具有显著的抗纤维化作用。然而，这些第一代 FXRa/sEHi 的代谢稳定性中等，体内半衰期短。为了克服这些药代动力学上的缺陷，我们系统地研究了该化学型的结构-活性和结构-稳定性关系，并获得了第二代具有改善的药代动力学参数的 FXRa/sEHi。具有高血浆暴露、半衰期大于 5 小时以及对预期靶点的双重效力相似，代表了一种经过大量优化的 FXRa/sEHi，可用于后期临床前开发。
