After probing the SAR of the phenyl substituents as well as various propanoic and butyric side chain modifications, we studied the role of the carboxylic acid in 6 as remaining element for potential optimization (Table ). Bioisosteric replacements of the carboxylic acid continued the trend of a flat SAR as the tetrazole 48, oxadiazolone 49 and N-sulfonylamide 50 were equipotent to the carboxylic acid 6. Despite not improving inverse Nurr1 agonism, these modifications consistently disrupted activity on RXR and thus improved selectivity. These observations further underline the divergent SAR of the oxaprozin scaffold as Nurr1 and RXR modulator demonstrating that inhibition of Nurr1 is not achieved indirectly via RXR activation. Amide replacement of the carboxylic acid was more productive in terms of improved inverse Nurr1 agonism. A primary amide (51) was tolerated with a loss in efficacy while the corresponding N-methyl amide (52) and the N,N-dimethyl amide 53 achieved remarkable efficacy blocking Nurr1 to only 4-6% remaining activity. Inversion of the amide (54) was also tolerated with strong inverse agonist efficacy. a Cellular activities on Nurr1 and RXRα were determined in uniform Gal4 hybrid reporter gene assays. Data are the mean±S.E.M., n≥3. Remaining activity (rem. act.) refers to 0.1% DMSO treated cells. b The selectivity index (SI) was calculated by dividing the EC50 for RXRα activation by the IC50 for Nurr1 inhibition. c Activity data on RXR have been reported previously . d Activity data on Nurr1 have been reported previously .