We commenced our SAR evaluation by probing the importance of the phenyl substituents and the carboxylic acid side chain of 6 (Table ). While 6 blocked Nurr1 activity with an IC50 value of 40 µM and 26% remaining activity, removal of either phenyl substituent in 4- (7) or 5-position (8) was detrimental for inverse Nurr1 agonism. Removal of the polar side chain in methyl analogue 9 markedly reduced and inverted activity on Nurr1 to weak agonism. Interestingly, the corresponding amine 10 retained inverse agonism. Changing the geometry of the scaffold from oxazole 6 to isoxazole 11 was not tolerated. Hence, the general skeleton and fatty acid mimetic structure of 6 seemed favorable for Nurr1 modulator development and was retained for further SAR evaluation. 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 . e Too toxic for characterization at higher concentrations.