Design, synthesis and FXR partial agonistic activity of anthranilic acid derivatives bearing aryloxy moiety as therapeutic agents for metabolic dysfunction-associated steatohepatitis.

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-03 DOI:10.1016/j.bioorg.2024.107940
Cong Chen, Xianghui Zhou, Wa Cheng, Xin Li, Bing Zhang, Jiaojiao Tu, Jieyun Meng, Yanfen Peng, Xiaoqun Duan, Qiming Yu, Xiangduan Tan
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引用次数: 0

Abstract

Farnesoid X receptor (FXR) is considered a promising therapeutic target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Increasing evidence suggests that targeting FXR with full agonists may lead to side effects. FXR partial agonists, which moderately activate FXR signaling, are emerging as a feasible approach to mitigate side effects and address MASH. Herein, a series of novel anthranilic acid derivatives bearing aryloxy moiety were designed and synthesized using a hybrid strategy from the previously identified FXR partial agonists DM175 and AIV-25. Particularly, compound 26 exhibited potent FXR partial agonistic activity in a dual-luciferase reporter gene assay with an EC50 value of 0.09 ± 0.02 µM (75.13 % maximum efficacy relative to OCA). In the MASH mice model, compound 26 significantly ameliorated the pathological features of the liver, including steatosis, inflammation, and fibrosis. In addition, compound 26 displayed high selectivity, good oral bioavailability, high liver distribution, as well as an acceptable safety profile. Molecular simulation studies showed that compound 26 fitted well with the binding site of FXR. Collectively, these findings demonstrated that compound 26 might serve as a promising candidate targeting FXR for MASH treatment.

含芳基氧基的蒽酸衍生物的设计、合成和 FXR 部分激动活性,作为代谢功能障碍相关性脂肪性肝炎的治疗药物。
法尼类固醇 X 受体(FXR)被认为是治疗代谢功能障碍相关性脂肪性肝炎(MASH)的一个很有前景的治疗靶点。越来越多的证据表明,使用完全激动剂靶向 FXR 可能会导致副作用。适度激活 FXR 信号的 FXR 部分激动剂正成为减轻副作用和治疗 MASH 的可行方法。在此,研究人员采用混合策略,从先前鉴定的 FXR 部分激动剂 DM175 和 AIV-25 中设计并合成了一系列新型芳氧基蒽酸衍生物。特别是化合物 26 在双荧光素酶报告基因试验中表现出了强效的 FXR 部分激动活性,EC50 值为 0.09 ± 0.02 µM(相对于 OCA 的最大效力为 75.13%)。在 MASH 小鼠模型中,化合物 26 能显著改善肝脏的病理特征,包括脂肪变性、炎症和纤维化。此外,化合物 26 还具有高选择性、良好的口服生物利用度、高肝分布性以及可接受的安全性。分子模拟研究表明,化合物 26 与 FXR 的结合部位非常吻合。总之,这些研究结果表明,化合物 26 可作为靶向 FXR 的候选药物用于 MASH 治疗。
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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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