Ester-to-Amide Rearrangement of Ethanolamine-Derived Prodrugs of Sobetirome with Increased Blood-Brain Barrier Penetration

Publication date: Available online 23 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Skylar J. Ferrara, J. Matthew Meinig, Andrew T. Placzek, Tapasree Banerji, Peter McTigue, Meredith D. Hartley, Hannah S. Sanford-Crane, Tania Banerji, Dennis Bourdette, Thomas S. Scanlan
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.

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