title: Increasing Thyromimetic Potency through Halogen Substitution.
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.
authors.affiliation: Department of Physiology & Pharmacology, Program in Chemical Biology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Devereaux
authors.affiliation: Department of Physiology & Pharmacology, Program in Chemical Biology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Skylar J
authors.initials: SJ
authors.lastname: Ferrara
authors.affiliation: Department of Physiology & Pharmacology, Program in Chemical Biology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Banerji
authors.affiliation: Department of Physiology & Pharmacology, Program in Chemical Biology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Placzek
authors.affiliation: Department of Physiology & Pharmacology, Program in Chemical Biology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
keywords: brain; central nervous system; thyroid hormones; thyromimetics