title: Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration.
abstract: Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Skylar J
authors.initials: SJ
authors.lastname: Ferrara
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Meinig
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Placzek
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Tapasree
authors.initials: T
authors.lastname: Banerji
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: McTigue
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Meredith D
authors.initials: MD
authors.lastname: Hartley
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Hannah S
authors.initials: HS
authors.lastname: Sanford-Crane
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Tania
authors.initials: T
authors.lastname: Banerji
authors.affiliation: Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Bourdette
authors.affiliation: Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States. Electronic address: scanlant@ohsu.edu.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
mesh_terms: D000085:Acetates / Q000737:chemistry*; D000284:Administration, Oral; D000577:Amides / Q000737:chemistry; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004952:Esters / Q000737:chemistry; D019856:Ethanolamine / Q000737:chemistry*; D006207:Half-Life; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D012372:ROC Curve
chemical_list: D000085:Acetates; D000577:Amides; D004952:Esters; C413355:GC 1 compound; D010636:Phenols; D011355:Prodrugs; D019856:Ethanolamine