咪唑烷酮衍生物作为强效PPARα/δ激动剂治疗胆汁淤积性肝病的设计、合成和生物学评价

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-01-15 DOI:10.1016/j.ejmech.2025.117284

Zhuoxin Fu, Xin Liu, Wenhui Yu, Yufan Kuang, Fengqin Wang, Zhiqiang Qian, Qinglong Xu, Liang Dai, Zhiqi Feng

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引用次数: 0

摘要

胆汁淤积性肝病（CLD）是一个日益严重的公共卫生问题，在临床实践中缺乏有效的治疗药物。过氧化物酶体增殖激活因子受体α/δ (PPARα/δ)被认为是CLD的潜在治疗靶点。本研究开发了一系列新型咪唑烷酮类PPARα/δ激动剂，优选化合物8表现出有效且平衡的激动活性。化合物8对其他相关核受体具有较高的选择性，可有效调节小鼠PPARα/δ靶基因的表达。值得注意的是，化合物8表现出良好的药代动力学特征和有效的体内抗cld作用。总的来说，化合物8有望开发一种抗cld药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Design, Synthesis, and Biological Evaluation of Imidazolidinone Derivatives as Potent PPARα/δ Agonists for the Treatment of Cholestatic Liver Diseases

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Design, Synthesis, and Biological Evaluation of Imidazolidinone Derivatives as Potent PPARα/δ Agonists for the Treatment of Cholestatic Liver Diseases

Cholestatic liver disease (CLD) represents a significant and growing public health concern, and there is a lack of effective therapeutic drug in clinical practice. Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for CLD. In this study, a series of novel imidazolidinone PPARα/δ agonists were developed, and the preferred compound 8 displayed potent and well-balanced agonistic activity. Compound 8 showed high selectivity over other related nuclear receptors and effectively regulated the PPARα/δ target genes expression in mice. Notably, compound 8 demonstrated good pharmacokinetic profiles and potent in vivo anti-CLD effects. Collectively, compound 8 holds promise for developing an anti-CLD agent.

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.