Optimized chemical probes for REV-ERBα

J Med Chem. 2013 Jun 13;56(11):4729-37. doi: 10.1021/jm400458q. Epub 2013 May 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis*
  • Amines / chemistry
  • Amines / pharmacology
  • Animals
  • Biological Availability
  • Carrier Proteins / metabolism
  • Cell Line
  • Circadian Rhythm
  • Glycine / analogs & derivatives
  • Glycine / chemical synthesis
  • Glycine / chemistry
  • Glycine / pharmacology
  • Humans
  • Liver X Receptors
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / agonists*
  • Orphan Nuclear Receptors / metabolism
  • Peptide Fragments / metabolism
  • RNA-Binding Proteins
  • Radioligand Assay
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology

Substances

  • Amines
  • Carrier Proteins
  • GSK4112
  • Liver X Receptors
  • NR1D1 protein, human
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Orphan Nuclear Receptors
  • PPARGC1B protein, human
  • Peptide Fragments
  • RNA-Binding Proteins
  • Thiophenes
  • Glycine