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Updated: Oct 10, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor

Yuanying Fang1,2, Lamees Hegazy1,2, Brian N Finck3

  • 1Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, Missouri 63110, United States.

Journal of Medicinal Chemistry
|December 10, 2021
PubMed

Insights

Farnesoid X receptor (FXR) modulators offer therapeutic potential for metabolic diseases. This review details recent medicinal chemistry advancements in FXR ligand discovery, focusing on structure-activity relationships and therapeutic applications.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Hepatology
  • Metabolic Diseases

Background:

  • Farnesoid X receptor (FXR) is a key regulator of bile acid, lipid, amino acid, and glucose metabolism, as well as hepatic inflammation, regeneration, and fibrosis.
  • FXR is a validated drug target for metabolic diseases including NAFLD, NASH, and chronic kidney disease.
  • Despite numerous FXR ligands developed, challenges remain due to side effects from long-term administration.

Purpose of the Study:

  • To provide a comprehensive overview of medicinal chemistry research on FXR modulators from 2018 to the present.
  • To discuss diverse synthetic FXR modulator structures, including steroidal and non-steroidal ligands.
  • To analyze structure-activity relationships (SARs) and explore therapeutic applications of novel FXR modulators.

Main Methods:

  • Literature review focusing on peer-reviewed publications and clinical trial data from 2018 onwards.
  • Analysis of diverse chemical structures of synthetic FXR modulators.
  • Evaluation of reported structure-activity relationships (SARs) and preclinical/clinical outcomes.

Main Results:

  • Significant progress in the design and synthesis of novel FXR ligands with improved efficacy and safety profiles.
  • Identification of diverse steroidal and non-steroidal FXR modulators with varying SARs.
  • Advancement of several FXR modulator candidates into clinical trials for metabolic and liver diseases.

Conclusions:

  • Medicinal chemistry efforts continue to yield promising FXR modulators for metabolic diseases.
  • Understanding SARs is crucial for developing FXR-targeted therapies with reduced side effects.
  • Continued research is essential to fully realize the therapeutic potential of FXR modulators.

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