Increasing Thyromimetic Potency through Halogen Substitution

Sobetirome is one of the most studied thyroid hormone receptor (TR)-selective thyromimetics in the field due to its excellent selectivity and potency. A small structural changereplacing the 3,5-dimethyl groups of sobetirome with either chlorine or bromineproduces significantly more potent compounds, both invitro and invivo. These halogenated compounds induce transactivation of a TR-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.