Identification of Selective ERRγ Inverse Agonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Estrogen-related receptor gamma (ERRγ) is a target for therapeutic intervention.
• GSK5182 (4) is a lead compound for developing ERRγ inverse agonists.

Purpose of the Study:

• To design, synthesize, and characterize novel ERRγ inverse agonists based on compound 4.
• To evaluate the pharmacological and in vitro ADMET properties of these new compounds.

Main Methods:

• Structural modification of scaffold 4 to introduce heterocyclic A-ring substituents.
• Assessment of binding affinity and functional activity for ERRγ inverse agonism.
• Evaluation of in vitro ADMET profiles and selectivity against related nuclear receptors.

Main Results:

• Several synthesized analogs exhibited potent ERRγ inverse agonist activity.
• Compound 15g showed high binding affinity (IC50 = 0.44 μM) and selectivity for ERRγ over ERRα, ERRβ, and ERα.
• Compound 15g achieved 95% transcriptional repression at 10 μM with acceptable in vitro ADMET properties.

Conclusions:

• A novel class of heterocyclic-substituted ERRγ inverse agonists was successfully developed.
• Compound 15g represents a promising drug candidate for targeting ERRγ-related diseases.
• The findings support further investigation of these compounds for therapeutic applications.