Optimized Chemical Probes for REV-ERBα

• Published in: Journal of medicinal chemistry 2013-06, Vol.56 (11), p.4729-4737
• Main Authors: Trump, Ryan P, Bresciani, Stefano, Cooper, Anthony W. J, Tellam, James P, Wojno, Justyna, Blaikley, John, Orband-Miller, Lisa A, Kashatus, Jennifer A, Boudjelal, Mohamed, Dawson, Helen C, Loudon, Andrew, Ray, David, Grant, Daniel, Farrow, Stuart N, Willson, Timothy M, Tomkinson, Nicholas C. O
• Format: Article
• Language: English
• Subjects: Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Animals; Biological Availability; Carrier Proteins - metabolism; Cell Line; Circadian Rhythm; Glycine - analogs & derivatives; Glycine - chemical synthesis; Glycine - chemistry; Glycine - pharmacology; Humans; Liver X Receptors; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group D, Member 1 - agonists; Orphan Nuclear Receptors - metabolism; Peptide Fragments - metabolism; Radioligand Assay; RNA-Binding Proteins; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400458q

REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.