Optimized chemical probes for REV-ERBα.
Trump RP., Bresciani S., Cooper AWJ., Tellam JP., Wojno J., Blaikley J., Orband-Miller LA., Kashatus JA., Boudjelal M., Dawson HC., Loudon A., Ray D., Grant D., Farrow SN., Willson TM., Tomkinson NCO.
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.