Optimized chemical probes for REV-ERB alpha

Trump, Ryan P. and Bresciani, Stefano and Cooper, Anthony W. J. and Tellam, James P. and Wojno, Justyna and Blaikley, John and Orband-Miller, Lisa A. and Kashatus, Jennifer A. and Boudjelal, Mohamed and Dawson, Helen C. and Loudon, Andrew and Ray, David and Grant, Daniel and Farrow, Stuart N. and Willson, Timothy M. and Tomkinson, Nicholas C. O. (2013) Optimized chemical probes for REV-ERB alpha. Journal of Medicinal Chemistry, 56 (11). pp. 4729-4737. ISSN 0022-2623

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Abstract

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.