Development of a Potent Nurr1 Agonist Tool for In Vivo Applications

  • J Med Chem. 2023 Apr 26. doi: 10.1021/acs.jmedchem.3c00415.
Jan Vietor  1 ,  Christian Gege  2 ,  Tanja Stiller  1 ,  Romy Busch  1 ,  Espen Schallmayer  3 ,  Hella Kohlhof  2 ,  Georg Höfner  1 ,  Jörg Pabel  1 ,  Julian A Marschner  1 ,  Daniel Merk  1  3
Affiliations
  • 1. Department of Pharmacy, Ludwig-Maximilians-Universität (LMU) München, 81377 Munich, Germany.
  • 2. Immunic AG, 82166 Gräfelfing, Germany.
  • 3. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
PMID: 37127285 DOI: 10.1021/acs.jmedchem.3c00415
Abstract

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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