After systematic SAR elucidation for all parts of the oxaprozin scaffold as inverse Nurr1 agonist (summarized in Figure ), we eventually aimed to combine the obtained knowledge in fused derivatives focusing on modifications that provided improved potency (Table ). 55 comprising the 2-chlorophenyl motif in 5-position (19) and the N,N-dimethylpropanamide (53) revealed no additive improvement in potency. Similarly, incorporation of the favored α-methyl group of 33 in the propanamide (56) and fusion of the acrylate (36) and N,N-dimethylamide (53) motifs failed to enhance inverse Nurr1 agonism (57). For the shorter oxazolylacetic acid scaffold of 30, with the 5-(2-chlorophenyl) residue of 19 or the N,N-dimethylamide of 53 was also not productive (58-60). These results further underscore the restrictive SAR of the oxaprozin scaffold as Nurr1 modulator and the challenge in the development of inverse Nurr1 agonists. Nevertheless, extensive and systematic SAR evaluation of 6 yielded several selective inverse Nurr1 agonists with improved potency and remarkable efficacy in blocking Nurr1 activity. Based on these characteristics, compounds 30, 36, 53 and 55 emerge as leads for further optimization and as potential early tools to study the biology of Nurr1. This was also supported by ligand efficiency metrics (Table ) characterizing 30, 36, 53 and 55 as improved inverse Nurr1 agonists compared to the lead 6. These compounds were hence broadly characterized for Nurr1 binding and modulation as well as for their selectivity profiles in the nuclear receptor family. >5.9