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

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

doi:10.1016/j.bmc.2017.03.047

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

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

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2743-2753
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	25
Issue number	10
DOIs	https://doi.org/10.1016/j.bmc.2017.03.047
State	Published - 2017

Funding

Research reported in this publication was supported by a grant from the National Institutes of Health (DK 052798, T.S.S.), the OHSU Laura Fund for Innovation in Multiple Sclerosis, and the National Institutes of Health under Award Number T32DK007680 (support to S.J.F.) and the National Multiple Sclerosis Society (FG 2023A1/2M.D.H. and RG 5199A4/1 D.B.). Analytical support was provided by the Bioanalytical Shared Resource/Pharmacokinetics Core Facility, which is part of the University Shared Resource Program at Oregon Health & Sciences University. We thank L. Bleyle for her assistance with LC–MS/MS analysis. We would also like to thank Dr. Andrea DeBarber at the Portland State University BioAnalytical Mass Spectrometry Facility for HRMS.

Funders	Funder number
Portland State University BioAnalytical Mass Spectrometry Facility for HRMS
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	DK 052798
National Institute of Diabetes and Digestive and Kidney Diseases	T32DK007680
National Multiple Sclerosis Society
Oregon State University/Oregon Health and Science University

ASJC Scopus subject areas

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

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Ferrara, S. J., Meinig, J. M., Placzek, A. T., Banerji, T., McTigue, P., Hartley, M. D., Sanford-Crane, H. S., Banerji, T., Bourdette, D., & Scanlan, T. S. (2017). Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. Bioorganic and Medicinal Chemistry, 25(10), 2743-2753. https://doi.org/10.1016/j.bmc.2017.03.047

Ferrara, SJ, Meinig, JM, Placzek, AT, Banerji, T, McTigue, P, Hartley, MD, Sanford-Crane, HS, Banerji, T, Bourdette, D & Scanlan, TS 2017, 'Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration', Bioorganic and Medicinal Chemistry, vol. 25, no. 10, pp. 2743-2753. https://doi.org/10.1016/j.bmc.2017.03.047

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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.",

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AU - Bourdette, Dennis

AU - Scanlan, Thomas S.

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

Abstract

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