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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...

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Autores principales: Vietor, Jan, Gege, Christian, Stiller, Tanja, Busch, Romy, Schallmayer, Espen, Kohlhof, Hella, Höfner, Georg, Pabel, Jörg, Marschner, Julian A., Merk, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
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.
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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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