Optimized chemical probes for REV-ERBα.

Area of Science:

• Pharmacology and Molecular Biology
• Chronobiology and Metabolic Regulation

Background:

• REV-ERBα (NR1D1) is a key nuclear receptor regulating circadian rhythms and metabolic processes.
• Targeting REV-ERBα offers therapeutic potential for circadian rhythm disorders and associated pathologies.

Purpose of the Study:

• To optimize a series of REV-ERBα agonists derived from the GSK4112 scaffold.
• To enhance agonist potency, selectivity against LXRα, and in vivo pharmacokinetic properties.

Main Methods:

• Medicinal chemistry optimization of GSK4112-based REV-ERBα agonists.
• In vitro assessment of BMAL and IL-6 gene expression suppression in human cells.
• Evaluation of selectivity over liver X receptor alpha (LXRα).
• In vivo pharmacokinetic studies including intravenous (iv) and oral dosing.

Main Results:

• Identified potent REV-ERBα agonists (compounds 4, 10, 16, 23) that effectively suppress BMAL and IL-6 expression.
• Achieved excellent selectivity for REV-ERBα over LXRα for the optimized compounds.
• Compound 4 demonstrated favorable in vivo bioavailability following both iv and oral administration.

Conclusions:

• The optimized REV-ERBα agonists represent promising drug candidates for modulating circadian rhythm and related physiological functions.
• Compound 4's demonstrated in vivo bioavailability supports its further development for therapeutic applications targeting REV-ERBα.