Structural optimization and in vitro profiling of N-phenylbenzamide-based farnesoid X receptor antagonists

Area of Science:

• Hepatology
• Molecular Pharmacology
• Drug Discovery

Background:

• The nuclear farnesoid X receptor (FXR) is a bile acid sensor crucial for liver function.
• FXR activation is a validated therapeutic strategy for liver disorders like non-alcoholic steatohepatitis.
• FXR antagonism is less explored, with a scarcity of potent small molecule antagonists.

Purpose of the Study:

• To systematically optimize a novel class of FXR antagonists.
• To achieve low nanomolar potency for FXR inhibition.
• To evaluate the potential of these antagonists for further in vitro and in vivo studies.

Main Methods:

• Systematic optimization of a novel chemical scaffold targeting FXR.
• Reporter gene assays to measure FXR activity.
• Assessment of FXR-regulated gene expression in hepatoma cells.
• Evaluation of toxicity, stability, and selectivity profiles.

Main Results:

• Developed a novel class of FXR antagonists with low nanomolar potency.
• The lead compound effectively antagonized baseline and agonist-induced FXR activity.
• Demonstrated repression of FXR-regulated genes in hepatoma cells.
• The compound exhibited favorable toxicity, stability, and selectivity profiles.

Conclusions:

• Successfully optimized potent small molecule FXR antagonists.
• The lead compound demonstrates significant potential for investigating FXR antagonism.
• These findings support further preclinical development for liver disease therapeutics.