Sulfoximines as potent RORγ inverse agonists.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Retinoid-related Orphan Receptor gamma (RORγ) is a key target for autoimmune diseases.
• High lipophilicity of potent RORγ inverse agonists hinders clinical development.
• Novel strategies are needed to develop RORγ modulators with improved physicochemical properties.

Purpose of the Study:

• To investigate the impact of replacing the hydroxymethyl group in RORγ modulators.
• To explore the tolerance of increased polarity at this position.
• To identify novel RORγ inverse agonists with reduced lipophilicity and preserved potency.

Main Methods:

• Structure-Activity Relationship (SAR) studies were conducted.
• Systematic replacement of the hydroxymethyl moiety with various functional groups.
• Evaluation of RORγ inverse agonist potency and physicochemical properties.
• Pharmacological assessment in the in vivo mouse Imiquimod psoriasis model.

Main Results:

• Identification of sulfoximine derivatives as effective RORγ modulators.
• Demonstrated that increased polarity can be tolerated at the targeted position.
• Sulfoximine derivatives exhibited potent inverse agonism of RORγ.
• Pharmacological activity was confirmed in a relevant preclinical model of psoriasis.

Conclusions:

• Sulfoximine derivatives represent a promising new class of RORγ inverse agonists.
• This approach successfully addressed the lipophilicity challenge in RORγ modulator design.
• The identified compounds hold potential for the treatment of RORγ-mediated diseases like psoriasis.