Acetaminophen misuse is a leading cause of acute liver failure and liver transplantation for which therapy is poorly effective. FXR ligands have shown effective in reducing liver injury in several experimental and clinical settings. In this Letter, we have elaborated on the structure of GW4064, the first nonsteroidal agonist for FXR, to identify novel isoxazoles endowed with FXR agonistic activity and improved ADME properties. The pharmacological characterization and molecular docking studies for the structure-activity rationalization allowed the identification of several FXR agonists with nanomolar potency in transactivation and SRC-1 recruitment assays. This characterization resulted in the identification of a potent FXR agonist, compound that was orally active, and rescued mice from acute liver failure caused by acetaminophen overdose in a FXR-dependent manner.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466548 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.8b00423 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Aberrant basement membrane production by HSCs in MASLD is attenuated by the bile acid analog INT-767.
Hepatol Commun
December 2024
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
Background: The farnesoid X receptor (FXR) is a leading therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis. INT-767, a potent FXR agonist, has shown promise in preclinical models. We aimed to define the mechanisms of INT-767 activity in experimental MASH and dissect cellular and molecular targets of FXR agonism in human disease.
View Article and Find Full Text PDFDesign, synthesis, and biological evaluation of novel highly potent FXR agonists bearing piperidine scaffold.
Eur J Med Chem
January 2025
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address:
Metabolic dysfunction-associated steatohepatitis (MASH) has become a serious threat to human health, which exhibited an increasing prevalence globally. Recently, the farnesoid X receptor (FXR) has been identified as a promising strategy for the treatment of MASH by regulating multiple pathogenesis. In this study, a new series of FXR agonists bearing piperidine scaffold was designed to reduce the high lipophilicity of the existing FXR agonists.
View Article and Find Full Text PDFThe dichotomous roles of microbial-modified bile acids 7-oxo-DCA and isoDCA in intestinal tumorigenesis.
Proc Natl Acad Sci U S A
November 2024
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.
The gut microbiota has a significant impact on the development and function of intestinal epithelial cells (IECs) by modifying bile acid (BA) metabolites. Recently, specific gut microbiome-derived BAs, such as 7-oxo-deoxycholic acid (7-oxo-DCA) and isodeoxycholic acid (isoDCA), have been identified to be shifted inversely in colitis and hepatic liver diseases. Although the responsible gut microbes have been identified, metabolites' effects on IECs remain largely unclear.
View Article and Find Full Text PDFDesign, synthesis and FXR partial agonistic activity of anthranilic acid derivatives bearing aryloxy moiety as therapeutic agents for metabolic dysfunction-associated steatohepatitis.
Bioorg Chem
December 2024
Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China. Electronic address:
Farnesoid X receptor (FXR) is considered a promising therapeutic target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Increasing evidence suggests that targeting FXR with full agonists may lead to side effects. FXR partial agonists, which moderately activate FXR signaling, are emerging as a feasible approach to mitigate side effects and address MASH.
View Article and Find Full Text PDFDesign, Synthesis, and Pharmacological Evaluation of Dual FXR-LIFR Modulators for the Treatment of Liver Fibrosis.
J Med Chem
October 2024
Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, Naples I-80131, Italy.
Although multiple approaches have been suggested, treating mild-to-severe fibrosis in the context of metabolic dysfunction associated with liver disease (MASLD) remains a challenging area in drug discovery. Pathogenesis of liver fibrosis is multifactorial, and pathogenic mechanisms are deeply intertwined; thus, it is well accepted that future treatment requires the development of multitarget modulators. Harnessing the 3,4,5-trisubstituted isoxazole scaffold, previously described as a key moiety in Farnesoid X receptor (FXR) agonism, herein we report the discovery of a novel class of hybrid molecules endowed with dual activity toward FXR and the leukemia inhibitory factor receptor (LIFR).
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!