Structure Optimization of 12β-O-γ-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist/Modulator...

Area of Science:

• Pharmacology
• Hepatology
• Medicinal Chemistry

Background:

• The farnesoid X receptor (FXR) is a key regulator of bile acid, lipid, and glucose metabolism, making it a therapeutic target for metabolic diseases.
• FXR dysfunction is implicated in cholestasis, diabetes, hyperlipidemia, and cancer, highlighting the need for novel FXR modulators.

Purpose of the Study:

• To design and synthesize novel oleanolic acid (OA) derivatives with potential FXR modulating activity.
• To evaluate the efficacy of these derivatives in preclinical models of liver disease.

Main Methods:

• Synthesis of oleanolic acid derivatives featuring 12β-O-(γ-glutamyl) groups.
• Yeast one-hybrid assay for preliminary structure-activity relationship (SAR) analysis.
• In vivo studies in BDL rats and HFD mice to assess liver health and fibrosis.

Main Results:

• Compound 10b was identified as a potent and selective FXR antagonist.
• Compound 10b upregulated the CYP7A1 gene and demonstrated significant inhibition of liver lipid accumulation and fibrosis in vivo.
• Molecular modeling suggested a unique binding interaction of 10b within the FXR ligand-binding domain.

Conclusions:

• 12-glutamyl OA derivative 10b exhibits promising therapeutic potential for nonalcoholic steatohepatitis (NASH).
• Compound 10b's distinct mechanism, including CYP7A1 upregulation, differentiates it from existing OA derivatives.