Optimized chemical probes for REV-ERB alpha

Ryan P. Trump, Stefano Bresciani, Anthony W. J. Cooper, James P. Tellam, Justyna Wojno, John Blaikley, Lisa A. Orband-Miller, Jennifer A. Kashatus, Mohamed Boudjelal, Helen C. Dawson, Andrew Loudon, David Ray, Daniel Grant, Stuart N. Farrow, Timothy M. Willson, Nicholas C. O. Tomkinson

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4729-4737
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number11
DOIs
Publication statusPublished - 13 Jun 2013

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Keywords

  • rhythms
  • ligand
  • GSK4112
  • beta
  • cells
  • modulation
  • circadian behaviour
  • metabolism
  • macrophages
  • clock

Cite this

Trump, R. P., Bresciani, S., Cooper, A. W. J., Tellam, J. P., Wojno, J., Blaikley, J., ... Tomkinson, N. C. O. (2013). Optimized chemical probes for REV-ERB alpha. Journal of Medicinal Chemistry, 56(11), 4729-4737. https://doi.org/10.1021/jm400458q