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Development of a Potent Nurr1 Agonist Tool for In Vivo Applications
[Image: see text] Nuclear receptor related 1 (Nurr1) is a neuroprotective transcription factor and an emerging target in neurodegenerative diseases. Despite strong evidence for a role in Parkinson’s and Alzheimer’s disease, pharmacological control and validation of Nurr1 are hindered by a lack of su...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10184128/ https://www.ncbi.nlm.nih.gov/pubmed/37127285 http://dx.doi.org/10.1021/acs.jmedchem.3c00415 |
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author | Vietor, Jan Gege, Christian Stiller, Tanja Busch, Romy Schallmayer, Espen Kohlhof, Hella Höfner, Georg Pabel, Jörg Marschner, Julian A. Merk, Daniel |
author_facet | Vietor, Jan Gege, Christian Stiller, Tanja Busch, Romy Schallmayer, Espen Kohlhof, Hella Höfner, Georg Pabel, Jörg Marschner, Julian A. Merk, Daniel |
author_sort | Vietor, Jan |
collection | PubMed |
description | [Image: see text] Nuclear receptor related 1 (Nurr1) is a neuroprotective transcription factor and an emerging target in neurodegenerative diseases. Despite strong evidence for a role in Parkinson’s and Alzheimer’s disease, pharmacological control and validation of Nurr1 are hindered by a lack of suitable ligands. We have discovered considerable Nurr1 activation by the clinically studied dihydroorotate dehydrogenase (DHODH) inhibitor vidofludimus calcium and systematically optimized this scaffold to a Nurr1 agonist with nanomolar potency, strong activation efficacy, and pronounced preference over the highly related receptors Nur77 and NOR1. The optimized compound induced Nurr1-regulated gene expression in astrocytes and exhibited favorable pharmacokinetics in rats, thus emerging as a superior chemical tool to study Nurr1 activation in vitro and in vivo. |
format | Online Article Text |
id | pubmed-10184128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-101841282023-05-16 Development of a Potent Nurr1 Agonist Tool for In Vivo Applications Vietor, Jan Gege, Christian Stiller, Tanja Busch, Romy Schallmayer, Espen Kohlhof, Hella Höfner, Georg Pabel, Jörg Marschner, Julian A. Merk, Daniel J Med Chem [Image: see text] Nuclear receptor related 1 (Nurr1) is a neuroprotective transcription factor and an emerging target in neurodegenerative diseases. Despite strong evidence for a role in Parkinson’s and Alzheimer’s disease, pharmacological control and validation of Nurr1 are hindered by a lack of suitable ligands. We have discovered considerable Nurr1 activation by the clinically studied dihydroorotate dehydrogenase (DHODH) inhibitor vidofludimus calcium and systematically optimized this scaffold to a Nurr1 agonist with nanomolar potency, strong activation efficacy, and pronounced preference over the highly related receptors Nur77 and NOR1. The optimized compound induced Nurr1-regulated gene expression in astrocytes and exhibited favorable pharmacokinetics in rats, thus emerging as a superior chemical tool to study Nurr1 activation in vitro and in vivo. American Chemical Society 2023-04-26 /pmc/articles/PMC10184128/ /pubmed/37127285 http://dx.doi.org/10.1021/acs.jmedchem.3c00415 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Vietor, Jan Gege, Christian Stiller, Tanja Busch, Romy Schallmayer, Espen Kohlhof, Hella Höfner, Georg Pabel, Jörg Marschner, Julian A. Merk, Daniel Development of a Potent Nurr1 Agonist Tool for In Vivo Applications |
title | Development
of a Potent Nurr1 Agonist Tool for In
Vivo Applications |
title_full | Development
of a Potent Nurr1 Agonist Tool for In
Vivo Applications |
title_fullStr | Development
of a Potent Nurr1 Agonist Tool for In
Vivo Applications |
title_full_unstemmed | Development
of a Potent Nurr1 Agonist Tool for In
Vivo Applications |
title_short | Development
of a Potent Nurr1 Agonist Tool for In
Vivo Applications |
title_sort | development
of a potent nurr1 agonist tool for in
vivo applications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10184128/ https://www.ncbi.nlm.nih.gov/pubmed/37127285 http://dx.doi.org/10.1021/acs.jmedchem.3c00415 |
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