A series of substituted-isoxazole derivatives was prepared as candidate farnesoid X receptor (FXR) antagonists, based on our previously proposed ligand superfamily concept. Structure-activity relationship studies indicated that the shape and the structural bulkiness of the substituent at the 5-position of the isoxazole ring affected FXR-antagonistic activity. Compounds 15 g (5-substituent: 2-naphthyl) and 15 h (5-substituent: 4-biphenyl) were identified as potent antagonists with higher selectivity for FXR over progesterone receptor than the naturally occurring FXR antagonist GS. The 5-substituent is also a critical determinant of the characteristic corepressor recruitment profile of this class of FXR antagonists, though distinct mechanisms appear to be involved: 15 h stabilizes the corepressor-nuclear receptor interaction, while 15 g inhibits coactivator recruitment.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmc.2007.01.046 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Hyodeoxycholic acid inhibits colorectal cancer proliferation through the FXR/EREG/EGFR axis.
Front Cell Dev Biol
January 2025
Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Background: The high morbidity and mortality rates of colorectal cancer (CRC) have been a public health concern globally, and the search for additional therapeutic options is imminent. Hyodeoxycholic acid (HDCA) has been receiving attention in recent years and has demonstrated potent efficacy in several diseases. Nonetheless, the antitumor effects and molecular pathways of HDCA in CRC remain largely unexplored.
View Article and Find Full Text PDFThe histamine pathway is a target to treat hepatic experimental erythropoietic protoporphyria.
Cell Mol Gastroenterol Hepatol
January 2025
Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA. Electronic address:
Background & Aims: Erythropoietic protoporphyria (EPP) is caused by mutations in ferrochelatase which inserts iron into protoporphyrin-IX (PP-IX) to generate heme. EPP is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. Despite available drugs that address photosensitivity, treatment of EPP-related liver disease remains an unmet need.
View Article and Find Full Text PDFDuodenal-jejunal bypass ameliorates MASLD in rats by regulating gut microbiota and bile acid metabolism through FXR pathways.
Hepatol Commun
February 2025
Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Background: Although bariatric and metabolic surgical methods, including duodenal-jejunal bypass (DJB), were shown to improve metabolic dysfunction-associated steatotic liver disease (MASLD) in clinical trials and experimental rodent models, their underlying mechanisms remain unclear. The present study therefore evaluated the therapeutic effects and mechanisms of action of DJB in rats with MASLD.
Methods: Rats with MASLD were randomly assigned to undergo DJB or sham surgery.
Citrobacter rodentium promotes brain cognitive dysfunction of type 2 diabetes mice by activating FXR mediated gut barrier damage.
Metab Brain Dis
January 2025
The Second Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, 541199, Guangxi, China.
Type 2 diabetes (T2D) is an important risk factor for brain cognitive impairment, but the specific mechanism is still unclear. The imbalance of gut microbiota under pathological conditions (such as an increase in pathogenic bacteria) may be involved in the occurrence of various diseases. The purpose of this study is to investigate the effect of increased abundance of gut Citrobacter rodentium on cognitive function in T2D mice.
View Article and Find Full Text PDFAssessing the efficacy of farnesoid X receptor agonists in the management of metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis: Efficacy of Farnesoid X Receptor Agonists in Metabolic Dysfunction-associated Steatotic Liver Disease: Systematic Review and Meta-analysis.
Clin Res Hepatol Gastroenterol
January 2025
School of Medicine, Wayne State University, Detroit, MI, USA.
Background And Aims: Several randomized clinical trials have been conducted assessing the potential efficacy of Farnesoid X receptor (FXR) agonists in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). A comprehensive review and analysis were needed to evaluate the findings of these trials. Hence, this systematic review and meta-analysis aim to study the association between FXR agonists and hepatic outcomes in patients with MASLD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!