Optimized chemical probes for REV-ERBα.

REV-ERB alpha 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-ERB alpha agonists based on G5K4112 (1) for potency, selectivity, and bioavailability.(1) Potent REV-ERB alpha 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 LAR alpha. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.