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- Title
Discovery of a novel and orally active Farnesoid X receptor agonist for the protection of acetaminophen‐induced hepatotoxicity.
- Authors
Cai, Zongyu; Wang, Bin; Zhou, Zongtao; Zhao, Xin; Hu, Lijun; Ren, Qiang; Deng, Liming; Li, Zheng; Wang, Guangji
- Abstract
Acetaminophen (APAP) overdose is a leading cause of acute hepatic failure and liver transplantation, while the existing treatments are poorly effective. Therefore, it is necessary to develop effective therapeutic drugs for APAP‐induced hepatotoxicity. Farnesoid X receptor (FXR) is a potential target for the treatment of liver disease, and the activation of FXR protects mice against APAP‐induced hepatotoxicity. Compound 5, a glycine‐conjugated derivative of FXR agonist 4, was designed to extend the chemical space of existing FXR agonists. Molecular modeling study indicated that compound 5 formed hydrogen bond network with key residues of FXR. Moreover, compound 5 (10 mg/kg) revealed better protective effects against APAP‐induced hepatotoxicity than parent compound 4 (30 mg/kg). Further mechanical research indicated that compound 5 regulated the expressions of genes related to FXR and oxidative stress. These findings suggest that compound 5 is a promising FXR agonist suitable for further research, and it is the first time to verify that the glycine‐conjugated derivative five exerted better protective effects than its parent compound.
- Subjects
FARNESOID X receptor; HEPATOTOXICOLOGY; LIVER failure; LIVER diseases; THERAPEUTICS; LIVER transplantation
- Publication
Chemical Biology & Drug Design, 2022, Vol 99, Issue 3, p483
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.14014