A Concise and Modular Approach to Generate Novel RORγ Agonists.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Pharmacology

Background:

• Retinoid-related Orphan Receptor gamma (RORγ) agonists are less explored than inhibitors, with limited clinical candidates.
• Existing RORγ inhibitors like VTP-43742 and JTE-151 show therapeutic potential.
• Developing novel RORγ agonists is crucial for expanding therapeutic options.

Purpose of the Study:

• To design and synthesize novel selective RORγ agonists.
• To overcome challenges of poor physicochemical properties in RORγ agonist development.
• To validate the efficacy of newly discovered RORγ agonists in vivo.

Main Methods:

• Virtual generation and assessment of RORγ agonists from inhibitor scaffolds.
• Structure-based design focusing on ligand efficiency and lipophilicity.
• Multi-parameter optimization and in vivo validation in a syngeneic mouse model.

Main Results:

• Identification of a cyclic amine carboxylate core as optimal for druglike properties.
• Successful synthesis of novel selective RORγ agonists.
• Demonstration of in vivo efficacy of the novel agonists after oral administration.

Conclusions:

• Functionality switching from RORγ inhibitors is a viable strategy for novel agonist discovery.
• The developed RORγ agonists possess favorable physicochemical properties and in vivo activity.
• This research provides promising new candidates for RORγ-targeted therapies.