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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. (1) 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.

Original publication




Journal article


J Med Chem

Publication Date





4729 - 4737


Amines, Animals, Biological Availability, Carrier Proteins, Cell Line, Circadian Rhythm, Glycine, Humans, Liver X Receptors, Mice, Mice, Inbred C57BL, Nuclear Receptor Subfamily 1, Group D, Member 1, Orphan Nuclear Receptors, Peptide Fragments, Radioligand Assay, Structure-Activity Relationship, Thiophenes