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: Research - peer-reviewArticle

  • 1 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.

LanguageEnglish (US)
Pages2743-2753
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume25
Issue number10
DOIs
StatePublished - May 15 2017

Fingerprint

Ethanolamine
Prodrugs
Blood-Brain Barrier
Amides
Esters
GC 1 compound
Therapeutics
Demyelinating Diseases
Thyroid Hormones
Multiple Sclerosis
Brain
Repair
Adrenoleukodystrophy
Inborn Genetic Diseases
Myelin Sheath
Pharmacokinetics
Pharmaceutical Preparations

ASJC Scopus subject areas

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

Cite this

Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. / Ferrara, Skylar J.; Meinig, J. Matthew; Placzek, Andrew T.; Banerji, Tapasree; McTigue, Peter; Hartley, Meredith D.; Sanford-Crane, Hannah S.; Banerji, Tania; Bourdette, Dennis; Scanlan, Thomas S.

In: Bioorganic and Medicinal Chemistry, Vol. 25, No. 10, 15.05.2017, p. 2743-2753.

Research output: Research - peer-reviewArticle

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. DOI: 10.1016/j.bmc.2017.03.047
Ferrara SJ, Meinig JM, Placzek AT, Banerji T, McTigue P, Hartley MD et al. Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. Bioorganic and Medicinal Chemistry. 2017 May 15;25(10):2743-2753. Available from, DOI: 10.1016/j.bmc.2017.03.047
Ferrara, Skylar J. ; Meinig, J. Matthew ; Placzek, Andrew T. ; Banerji, Tapasree ; McTigue, Peter ; Hartley, Meredith D. ; Sanford-Crane, Hannah S. ; Banerji, Tania ; Bourdette, Dennis ; Scanlan, Thomas S./ Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. In: Bioorganic and Medicinal Chemistry. 2017 ; Vol. 25, No. 10. pp. 2743-2753
@article{798411fdb8dd4dcfa35c695d622e1039,
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.",
author = "Ferrara, {Skylar J.} and Meinig, {J. Matthew} and Placzek, {Andrew T.} and Tapasree Banerji and Peter McTigue and Hartley, {Meredith D.} and Sanford-Crane, {Hannah S.} and Tania Banerji and Dennis Bourdette and Scanlan, {Thomas S.}",
year = "2017",
month = "5",
doi = "10.1016/j.bmc.2017.03.047",
volume = "25",
pages = "2743--2753",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "10",

}

TY - JOUR

T1 - Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration

AU - Ferrara,Skylar J.

AU - Meinig,J. Matthew

AU - Placzek,Andrew T.

AU - Banerji,Tapasree

AU - McTigue,Peter

AU - Hartley,Meredith D.

AU - Sanford-Crane,Hannah S.

AU - Banerji,Tania

AU - Bourdette,Dennis

AU - Scanlan,Thomas S.

PY - 2017/5/15

Y1 - 2017/5/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85016624413&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016624413&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2017.03.047

DO - 10.1016/j.bmc.2017.03.047

M3 - Article

VL - 25

SP - 2743

EP - 2753

JO - Bioorganic and Medicinal Chemistry

T2 - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 10

ER -