Structure-based discovery of pyrazolamides as novel ERRγ inverse agonists

Area of Science:

• Endocrinology
• Molecular Pharmacology

Background:

• Estrogen-related receptor-gamma (ERRγ) is an orphan nuclear receptor structurally similar to estrogen receptors.
• Current modulators of ERRγ lack selectivity, highlighting the need for novel agents.

Purpose of the Study:

• To identify and characterize novel selective inverse agonists for ERRγ.

Main Methods:

• Virtual screening was employed to identify initial hit compounds.
• Structure-based diversification and optimization were used to enhance potency and selectivity.

Main Results:

• Pyrazolamide 7 was identified as a novel ERRγ inverse agonist via virtual screening.
• Derivative 19 emerged as a potent and selective inverse agonist for ERRγ, outperforming existing modulators.
• Pyrazolamide 19 demonstrated strong binding affinity and inhibited key target genes (hepcidin, fibrinogen, gluconeogenic).

Conclusions:

• Pyrazolamide 19 represents a promising lead compound for developing therapeutics targeting ERRγ.
• The identified inverse agonist exhibits potential for antimicrobial, anticoagulant, and antidiabetic applications.