In line with the SOSA concept, we focused on small structural modifications which failed to provide a major improvement in inverse Nurr1 agonist potency. Further optimization may require a scaffold hop or incorporation of greater structural changes and will also have to address the lack of selectivity over the related receptors Nur77 and NOR1. Nevertheless, the inverse Nurr1 agonists obtained from oxaprozin are endowed with sub-micromolar binding affinity, robust inhibition of Nurr1 activity at low micromolar concentrations and favorable PK properties and thus provide a substantial advance over previously available compounds. In silico and in vitro binding studies on oxaprozin-derived inverse Nurr1 agonists enabled a robust binding site hypothesis in a pocket located behind the activation helix 12 which contributes to molecular understanding of Nurr1 and may aid future computer-aided Nurr1 ligand design. Moreover, application of oxaprozin-derived inverse Nurr1 agonists in phenotypic experiments in N27 rat dopaminergic neurons revealed anti-proliferative and neurotoxin-sensitizing effects of pharmacological Nurr1 inhibition further supporting the transcription factor's neuroprotective role.