As an approved drug, oxaprozin (6) offers drug-like properties per definition and is an attractive lead structure for the development of Nurr1 modulators following the selective optimization of side-activities (SOSA) concept. As a critical step in this endeavor, we aimed to obtain oxaprozin-derived Nurr1 modulators exhibiting selectivity over RXR. We have performed an extensive systematic SAR study on 6 as Nurr1 and RXR modulator addressing all structural elements of the chemotype. The SAR of 6 on Nurr1 and RXR diverged substantially, and although Nurr1 was rather restrictive, we succeeded in identifying various structural modifications driving selectivity for Nurr1 over RXR. These findings enabled the design of inverse Nurr1 agonists with no activity on RXR and demonstrate that inhibition of Nurr1 activity is not a secondary effect of RXR modulation.