Synthesis and biological evaluation of amino-conjugated bile acid derivatives against non-alcoholic steatohepatitis

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-24 DOI:10.1016/j.bmcl.2025.130210

Zhitao Wu , Mingge Zhang , Meng Kun Yan , Chenyue Li , Guoyu Pan , Lijiang Xuan

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Abstract

Non-alcoholic steatohepatitis (NASH) is emerging as a rapidly growing health concern. Bile acids (BAs) function as endocrine signaling molecules and exhibit therapeutic potential for NASH. To develop safer and more effective BA derivatives for NASH treatment, 25 amino acid-conjugated bile acid derivatives were designed and synthesized based on the pharmacological properties of the leading compound A17. The anti-lipid accumulation, anti-inflammatory and anti-fibrosis activities of these compounds were evaluated, and their structure-activity relationships were elucidated. Notably, compound C04 exhibited superior in vitro activity compared to obeticholic acid and demonstrated enhanced efficacy in improving both NASH and fibrosis in preclinical murine models via oral administration. These findings suggest that C04 is a promising candidate for NASH treatment and warrants further investigation.

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氨基共轭胆汁酸衍生物抗非酒精性脂肪性肝炎的合成及生物学评价。

非酒精性脂肪性肝炎（NASH）是一个迅速发展的健康问题。胆汁酸（BAs）作为内分泌信号分子，具有治疗NASH的潜力。为了开发更安全、更有效的胆汁酸衍生物，以先导化合物A17的药理特性为基础，设计合成了25种氨基酸缀合胆汁酸衍生物。评价了这些化合物的抗脂质积累、抗炎和抗纤维化活性，并阐明了它们的构效关系。值得注意的是，与奥比胆酸相比，化合物C04在体外表现出更好的活性，并且在临床前小鼠模型中通过口服改善NASH和纤维化的功效更强。这些发现表明，C04是NASH治疗的一个有希望的候选药物，值得进一步研究。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.