Details

Autor(en) / Beteiligte

• Dou, Xiaodong
• Huo, Tongyu
• Liu, Yameng
• Pang, Zichen
• Su, Lingyu
• Zhao, Xinyi
• Peng, Xing
• Liu, Zhenming
• Zhang, Liangren
• Jiao, Ning

Titel

Discovery of novel and selective farnesoid X receptor antagonists through structure-based virtual screening, preliminary structure-activity relationship study, and biological evaluation

Ist Teil von

• European journal of medicinal chemistry, 2024-04, Vol.269, p.116323-116323, Article 116323

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Farnesoid X receptor (FXR) is a bile acids receptor and plays a crucial role in regulating bile acids, lipids, and glucose metabolism. Previous research suggests that inhibiting FXR activation can be beneficial in reducing cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, offering potential treatment options for metabolic syndrome with lipid disorders. Herein, we report p-acetylaminobenzene sulfonate derivatives as a novel scaffold of FXR antagonists by multistage screening. Among these derivatives, compound F44-A13 exhibited a half-maximal inhibitory concentration of 1.1 μM. Furthermore, compound F44-A13 demonstrated effective inhibition of FXR activation in cellular assays and exhibited high selectivity over eleven other nuclear receptors. Besides, compound F44-A13 significantly suppressed the regulation of FXR target genes Shp, Besp, and Cyp7a1, while reducing cholesterol levels in human hepatoma HepG2 cells. Pharmacological studies conducted on C57BL/6 mice further confirmed that compound F44-A13 had beneficial effects in reducing cholesterol, triglycerides, and LDL-C levels. These findings highlight that F44-A13 is a highly selective FXR antagonist that might serve as a useful molecule for further FXR studies as well as the development of FXR antagonists for the potential treatment of metabolic diseases with lipid disorders. [Display omitted] •A series of p-acetylaminobenzene sulfonate derivatives were identified as novel and selective antagonists of FXR.•Compound F44-A13 displayed an IC50 value of 1.1 μM, and high selectivity over eleven other nuclear receptors.•Compound F44-A13 strongly reversed the regulation of FXR target genes and reduced the cholesterol levels in HepG2 cells.•Compound F44-A13 exhibited beneficial effects on reducing cholesterol, triglycerides, and LDL-C levels in C57BL/6 mice.•The structure-activity relationship of p-acetylaminobenzene sulfonate derivatives was investigated by molecular simulation.