Generating selectivity over RXR was a key objective of this study and achieved with the inverse Nurr1 agonists 30, 36, 53 and 55. However, the typical fatty acid mimetic structure of oxaprozin and derivatives suggests potential interaction also with other related receptors and we hence profiled the activity of the optimized compounds on fatty acid and lipid-sensing nuclear receptors (Figure ). 30, 36, 53 and 55 were favorably selective and only revealed slight agonism on peroxisome proliferator-activated receptors (PPARs) as off-target activity which was most pronounced for the shortened oxaprozin analogue 30. On the NR4A receptors Nur77 and NOR-1, 30, 36, 53 and 55 expectedly exhibited similar activity as on Nurr1 (Table ). Previous evaluation of the scaffold as cyclooxygenase (COX) inhibitor demonstrated that increasing the length and/or branching of the alkanoic side chain and replacement of the carboxylic acid by an amide and was not tolerated . The amide derivatives 53, 55 and 58 were thus favored in terms of Nurr1 preference over COX inhibition. This was also supported by computational target prediction using a consensus of three publicly available tools which generally suggested favorable selectivity profiles (Figure ).