Carboxylic Acid Bioisosteres Boost Nurr1 Agonist Selectivity

  • J Med Chem. 2025 Aug 14;68(15):16212-16226. doi: 10.1021/acs.jmedchem.5c01140.
Tanja Stiller  1 ,  Christian Gege  2 ,  Wael Saeb  3 ,  Jan Vietor  1 ,  Úrsula López-García  1 ,  Romy Busch  1 ,  Hella Kohlhof  2 ,  Daniel Vitt  2 ,  Daniel Merk  1
Affiliations
  • 1. Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • 2. Immunic AG, 82166 Gräfelfing, Germany.
  • 3. RebisLab R&D GmbH, 82152 Planegg-Martinsried, Germany.
PMID: 40674328 DOI: 10.1021/acs.jmedchem.5c01140
Abstract

Nuclear receptor related 1 (Nurr1) is a neuronal ligand-activated transcription factor implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and multiple sclerosis, which has fueled the development of Nurr1 modulators. Among them, the clinically studied Dihydroorotate Dehydrogenase (DHODH) inhibitor vidofludimus was found to exhibit strong Nurr1 agonism. Here, we aimed to establish a vidofludimus-derived Nurr1 agonist lacking DHODH inhibitor potency as a tool. We explored bioisosteric replacement of the drug's carboxylate motif and succeeded in boosting selectivity for Nurr1 over DHODH to >100-fold. Dopaminergic neural cells treated with the optimized tetrazole-based Nurr1 agonist revealed induction of genes involved in neuroprotection and neuronal health, supporting the potential of Nurr1 activation in neurodegenerative diseases.

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