Discovery of novel and selective farnesoid X receptor antagonists through structure-based virtual screening,...

Area of Science:

• Biochemistry
• Pharmacology
• Metabolic Diseases

Background:

• Farnesoid X receptor (FXR) regulates bile acids, lipids, and glucose metabolism.
• FXR inhibition shows potential for treating metabolic syndrome and lipid disorders by reducing cholesterol and LDL-C.
• Novel FXR antagonists are needed for therapeutic development.

Purpose of the Study:

• To identify and characterize novel FXR antagonists.
• To evaluate the efficacy of a novel scaffold of p-acetylaminobenzene sulfonate derivatives.
• To assess the therapeutic potential of compound F44-A13 in preclinical models.

Main Methods:

• Multistage screening to identify FXR antagonists.
• In vitro cellular assays to assess FXR inhibition and selectivity.
• In vivo pharmacological studies in C57BL/6 mice.

Main Results:

• Compound F44-A13, a p-acetylaminobenzene sulfonate derivative, was identified as a potent FXR antagonist (IC50 = 1.1 μM).
• F44-A13 demonstrated high selectivity for FXR over eleven other nuclear receptors.
• In vitro and in vivo studies showed F44-A13 effectively reduced cholesterol, triglycerides, and LDL-C levels, and suppressed FXR target genes.

Conclusions:

• F44-A13 is a highly selective FXR antagonist with significant lipid-lowering effects.
• This compound represents a promising molecule for further FXR research.
• F44-A13 may serve as a basis for developing new treatments for metabolic diseases with lipid disorders.