Structural Tuning of Vidofludimus for High-Efficacy NR4A Agonism.

The nerve growth factor IB-like receptors (NR4A) are (neuro)protective transcription factors as part of the immediate early response and hold potential in various pathologies, including neurodegeneration. Despite recent progress in NR4A ligand development, high-quality chemical tools to probe phenotypic effects of NR4A modulation are still rare, and a selective agonist with strong efficacy is lacking. Here, we developed a potent and selective NR4A activator equipped with distinctly high agonist efficacy building on the scaffold of the dihydroorotate dehydrogenase inhibitor and nuclear receptor-related 1 agonist vidofludimus. We identified structural modifications conveying potency, selectivity, and efficacy via systematic structure-activity relationship elucidation, and fusion of favored motifs eventually enabled multiparameter optimization to a chemical tool meeting highest quality criteria for biological studies.