Next, we studied the SAR around the two phenyl residues by systematically introducing additional substituents (Tables and). Only few modifications were tolerated on the 4-phenyl moiety (12-17, Table ) with 2-methyl (12), 3-chloro (15), 4-methyl ( ) and 4-chloro (17) substituents fully disrupting activity. A methyl group in 3-position (14) was tolerated but the inactivity of the 3-chloro analogue 15 indicated no avenue to improvement in this position. Only a 2-chloro substituent (13) provided a slight improvement in potency but concomitantly diminished efficacy. This SAR was in strong contrast to RXR, where several structural variations on the 4-phenyl residue considerably promoted potency. The 4-phenyl motif hence seemed to hold little optimization potential towards selective Nurr1 modulation and we therefore turned our attention to the 5-phenyl residue. 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 .