Increasing Thyromimetic Potency through Halogen Substitution

Jordan Devereaux, Skylar J. Ferrara, Tania Banerji, Andrew T. Placzek, Thomas S. Scanlan

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Sobetirome is one of the most studied thyroid hormone receptor β (TRβ)-selective thyromimetics in the field due to its excellent selectivity and potency. A small structural change—replacing the 3,5-dimethyl groups of sobetirome with either chlorine or bromine—produces significantly more potent compounds, both in vitro and in vivo. These halogenated compounds induce transactivation of a TRβ-mediated cell-based reporter with an EC50value comparable to that of T3, access the central nervous system (CNS) at levels similar to their parent, and activate an endogenous TR-regulated gene in the brain with an EC50value roughly five-fold lower than that of sobetirome. Previous studies suggest that this apparent increase in affinity can be explained by halogen bonding between the ligand and a backbone carbonyl group in the receptor. This makes the new analogues potential candidates for treating CNS disorders that may respond favorably to thyroid-hormone-stimulated pathways.

Original languageEnglish (US)
Pages (from-to)2459-2465
Number of pages7
JournalChemMedChem
Volume11
Issue number21
DOIs
StatePublished - Nov 7 2016

Keywords

  • brain
  • central nervous system
  • thyroid hormones
  • thyromimetics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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