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 language | English (US) |
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Pages (from-to) | 2459-2465 |
Number of pages | 7 |
Journal | ChemMedChem |
Volume | 11 |
Issue number | 21 |
DOIs | |
State | Published - Nov 7 2016 |
Keywords
- brain
- central nervous system
- thyroid hormones
- thyromimetics
ASJC Scopus subject areas
- Drug Discovery
- General Pharmacology, Toxicology and Pharmaceutics
- Molecular Medicine
- Biochemistry
- Pharmacology
- Organic Chemistry