Design, synthesis and structure-activity relationship studies of novel partial FXR agonists for the treatment of...

Area of Science:

• Hepatology
• Medicinal Chemistry
• Pharmacology

Background:

• Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition with no approved pharmacotherapy.
• Farnesoid X receptor (FXR) agonists are investigated for NAFLD treatment, with a focus on partial agonists for improved safety.
• Existing chemical scaffolds for partial FXR agonists require expansion to discover novel therapeutic agents.

Purpose of the Study:

• To synthesize and identify novel partial FXR agonists with improved chemical diversity.
• To evaluate the efficacy of newly developed partial FXR agonists in preclinical models of nonalcoholic steatohepatitis (NASH).

Main Methods:

• Structure-activity relationship (SAR) study utilizing a bioisosteric strategy based on a known partial FXR agonist.
• Synthesis of a novel series of partial FXR agonists.
• In vivo evaluation of lead compounds in methionine-choline deficient (MCD) induced db/db mice, a NASH model.

Main Results:

• Identification of a novel partial FXR agonist, compound 13, exhibiting superior agonistic activity within the synthesized series.
• Compound 13 demonstrated significant alleviation of hepatic steatosis in MCD-induced db/db mice.
• Significant improvement in hepatic function indices was observed in mice treated with compound 13.

Conclusions:

• Compound 13 represents a promising novel partial FXR agonist.
• The identified compound warrants further investigation as a potential therapeutic lead for NAFLD and NASH.
• The bioisosteric strategy proved effective in expanding the chemical space for partial FXR agonists.