Discovery of biaryl carboxylamides as potent RORγ inverse agonists

Area of Science:

• Immunology
• Medicinal Chemistry
• Structural Biology

Background:

• RORγt (Retinoid-related Orphan Receptor gamma t) is a critical regulator of pro-inflammatory gene expression.
• Its activity is implicated in the pathology of numerous human immune-mediated diseases.
• Inhibition of RORγt has shown therapeutic benefits in preclinical models by reducing pathogenic cytokine production, such as IL-17.

Purpose of the Study:

• To identify and develop novel inverse agonists for RORγt.
• To explore a structure-based design approach for creating potent and selective RORγt inhibitors.
• To validate the therapeutic potential of these compounds in preclinical settings.

Main Methods:

• Structure-based drug design was employed to develop a biaryl-carboxylamide series of RORγt inverse agonists.
• Co-crystal structures of lead compounds (16 and 48) with the RORγt protein were determined.
• Key molecular interactions, including hydrogen bonding with His479, were analyzed to understand inverse agonism.
• Oral bioavailability was assessed in rodent models.

Main Results:

• A novel series of potent and selective RORγt inverse agonists was successfully identified and developed.
• Co-crystal structures confirmed the design strategy and highlighted critical interactions, such as hydrogen bonding with His479, essential for enhanced inverse agonism.
• The developed compounds demonstrated oral bioavailability in rodent models, indicating potential for in vivo efficacy.

Conclusions:

• The biaryl-carboxylamide series represents a promising class of RORγt inverse agonists.
• Structure-based design is an effective strategy for developing potent RORγt inhibitors.
• These findings support the therapeutic potential of RORγt inverse agonists for treating immune-mediated inflammatory diseases.