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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
Published on: September 13, 2013
Optimized chemical probes for REV-ERBα.
Ryan P Trump1, Stefano Bresciani, Anthony W J Cooper
1Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA. ryan.p.trump@gsk.com
Journal of Medicinal Chemistry
|May 10, 2013
Summary
Researchers optimized REV-ERBα agonists for circadian rhythm regulation. Potent compounds suppressed BMAL and IL-6 expression, with one showing in vivo bioavailability.
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.
