N-1H-benzimidazol-5-ylbenzenesulfonamide derivatives as potent hPXR agonists

Area of Science:

• Pharmacology
• Molecular Biology
• Medicinal Chemistry

Background:

• The Human Pregnane X Receptor (hPXR) is a nuclear receptor crucial for drug metabolism and detoxification.
• hPXR regulates drug-metabolizing enzymes and transporters, playing a key role in protecting tissues from toxic substances.
• Highly active hPXR agonists hold therapeutic potential for various human diseases.

Purpose of the Study:

• To identify and characterize novel, potent agonists of the human Pregnane X Receptor (hPXR).
• To explore chemical modifications of an initial ligand to enhance hPXR activation.
• To evaluate the therapeutic potential of identified hPXR agonists.

Main Methods:

• Utilized an in vitro screening reporter system to identify hPXR activators.
• Synthesized and chemically modified compounds based on the N-1H-benzimidazol-5-ylbenzenesulfonamide scaffold.
• Assessed compound potency using EC50 values and evaluated target gene induction (CYP3A4, CYP2B6) in human hepatocytes.

Main Results:

• Identified a potent family of hPXR agonists featuring the N-1H-benzimidazol-5-ylbenzenesulfonamide scaffold.
• Discovered compound 6n (N-(1-benzyl-1H-benzimidazol-5-yl)-2,3,4,5,6-pentamethylbenzenesulfonamide) with subnanomolar EC50 values.
• Demonstrated efficient protection of hPXR against trypsin digestion and induced CYP3A4 and CYP2B6 expression in human hepatocytes.

Conclusions:

• The identified N-1H-benzimidazol-5-ylbenzenesulfonamide derivatives are highly potent hPXR agonists.
• These compounds exhibit significant therapeutic promise due to their ability to activate hPXR and its downstream targets.
• Further development of these agonists could lead to novel treatments for diseases involving hPXR modulation.