To evaluate the suitability of the oxaprozin-derived inverse Nurr1 agonist scaffold for in vivo studies, we evaluated pharmacokinetic parameters of selected compounds in vitro (Figure -e, Table ). Predicted PK properties (SwissADME ) were generally favorable with high bioavailability and brain penetration scores (Table ). This was also evident in a parallel artificial membrane permeability assay (PAMPA) revealing similarly high membrane permeation of the amides 53, 55, 57, and 58 as the reference drug propranolol (Figure , Table ). The lead 6 and 36 were slightly less permeable. A cellular blood-brain-barrier (BBB) model additionally indicated comparable brain penetration of the amide 53 and the brain-penetrant reference antipyrine offering an improvement over the lead 6 (Figure ). Moreover, in vitro microsomal stability tests demonstrated long half-lives for 6 and the corresponding unsaturated derivative 36 (Figure ). The amides 53, 55, 57, and 58 revealed lower resistance against microsomal degradation but sufficient stability of 53, 57, and 58 to be used as tools. Only 55 was rapidly degraded. Nurr1 modulation with ligands is poorly understood from a structural perspective and only few ligand bound co-crystal structures are available. To establish a binding site hypothesis for the inverse Nurr1 agonists derived from 6, we employed the close relative Nur77 of Nurr1, which has been co-crystallized with several modulators binding to four different sites within its LBD and mapped these regions to Nurr1 for docking. While no reasonable binding modes of 6 were predicted for three surface pockets derived from Nur77 (not shown), we observed potential interaction with the PGA1 binding site (Figure ). This observation agreed with the original hypothesis of mimicking the COX metabolite PGA1 in the binding site with COX inhibitors which led to the discovery of NSAIDs like 6 as NR4A modulators . Docking of 6 to the Nurr1:PGA1 complex (PDB ID 5Y41) suggested binding between helices 4/5, 11 and 12 with polar contacts of the carboxylic acid motif to Arg515 and the backbone of His516 similar to PGA1. The 4,5diphenyloxazole protruded towards the hydrophobic pocket accommodating the lipophilic tail of PGA1.