Carboxylic Acid Bioisosteres Boost Nurr1 Agonist Selectivity

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.