Sobetirome prodrug esters with enhanced blood–brain barrier permeability

Andrew T. Placzek, Skylar J. Ferrara, Meredith D. Hartley, Hannah S. Sanford-Crane, J. Matthew Meinig, Thomas S. Scanlan

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

There is currently great interest in developing drugs that stimulate myelin repair for use in demyelinating diseases such as multiple sclerosis. Thyroid hormone plays a key role in stimulating myelination during development and also controls the expression of important genes involved in myelin repair in adults. Because endogenous thyroid hormone in excess lacks a generally useful therapeutic index, it is not used clinically for indications other than hormone replacement; however, selective thyromimetics such as sobetirome offer a therapeutic alternative. Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood–brain-barrier (BBB) and we endeavored to increase the BBB permeability of sobetirome using a prodrug strategy. Ester prodrugs of sobetirome were prepared based on literature reports of improved BBB permeability with other carboxylic acid containing drugs and BBB permeability was assessed in vivo. One sobetirome prodrug, ethanolamine ester 11, was found to distribute more sobetirome to the brain compared to an equimolar peripheral dose of unmodified sobetirome. In addition to enhanced brain levels, prodrug 11 displayed lower sobetirome blood levels and a brain/serum ratio that was larger than that of unmodified sobetirome. Thus, these data indicate that an ester prodrug strategy applied to sobetirome can deliver increased concentrations of the active drug to the central nervous system (CNS), which may prove useful in the treatment of CNS disorders.

Original languageEnglish (US)
Pages (from-to)5842-5854
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number22
DOIs
StatePublished - 2016

Keywords

  • Blood–brain barrier
  • Prodrug
  • Thyromimetics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Placzek, A. T., Ferrara, S. J., Hartley, M. D., Sanford-Crane, H. S., Meinig, J. M., & Scanlan, T. S. (2016). Sobetirome prodrug esters with enhanced blood–brain barrier permeability. Bioorganic and Medicinal Chemistry, 24(22), 5842-5854. https://doi.org/10.1016/j.bmc.2016.09.038