Increasing Thyromimetic Potency through Halogen Substitution

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 EC50 value 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 EC50 value 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. Modifying the structure of the potent TRβ‐selective thyroid hormone analogue sobetirome by replacing the 3,5‐dimethyl groups with chlorine or bromine to exploit halogen bonding interactions within the TR ligand binding domain gives compounds with significantly increased potency in vitro and in vivo while retaining distribution to the CNS. These improved characteristics make the new compounds attractive candidates for treating CNS demyelination diseases influenced by thyroid hormone stimulation.