Discovery of biaryls as RORγ inverse agonists by using structure-based design

Area of Science:

• Immunology
• Molecular Biology
• Medicinal Chemistry

Background:

• Retinoid-related orphan receptor gamma (RORγ) is a key regulator of pro-inflammatory gene expression in lymphocytes.
• RORγ-driven inflammation is implicated in autoimmune diseases including Crohn's disease, arthritis, and psoriasis.
• Inverse agonists targeting RORγ present a therapeutic avenue for managing inflammatory conditions.

Purpose of the Study:

• To optimize two RORγ inverse agonists: a known compound (T0901317) and an internally screened compound (Compound 1).
• To develop novel RORγ inverse agonists with potential anti-inflammatory properties.

Main Methods:

• Utilized internal X-ray crystallography data to guide drug design.
• Designed and synthesized two focused chemical libraries based on structural insights.
• Evaluated the optimized inverse agonists for their potential to modulate RORγ activity.

Main Results:

• Successfully designed novel biaryl compounds as RORγ inverse agonists.
• Structural information from X-ray crystallography was instrumental in the optimization process.
• The new series shows promise for further development as anti-inflammatory agents.

Conclusions:

• Optimization of RORγ inverse agonists is feasible and can lead to novel therapeutic candidates.
• Targeting RORγ offers a promising strategy for treating inflammatory and autoimmune diseases.
• The developed biaryl series represents a significant advancement in RORγ inverse agonist discovery.