Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration

•Prodrugs of thyromimetic sobetirome increase CNS exposure of parent drug.•Ethanolamine-derived promoieties undergo O,N acyl migration.•Pharmacokinetics of sobetirome and lead prodrug described.•Lead prodrug found more potent than sobetirome at target engagement in the brain.