Encouraged by the beneficial impact of modifications in the acidic side chain on potency and selectivity, we probed further derivatization in this region of 6 (Table ). A methyl group in α-position of the carboxylic acid moiety (33) slightly enhanced potency on Nurr1 suggesting further optimization potential. The corresponding α-ethyl (34) and α-isopropyl (35) analogues failed to exhibit enhanced inverse Nurr1 agonism but achieved improved selectivity over RXR. Rigidization of the propanoic acid chain of 6 in an acrylate motif (36) was highly preferred in terms of inverse Nurr1 agonism and enhanced potency and selectivity by a factor of ~10. Introduction of the favored α-methyl group from 33 to the acrylate structure in 37, a β-methyl group (38) and α,β-dimethyl substitution (39) were not favored, however, and attempts to replace the acrylic acid by a bioisosteric trans- (40) or cis- (41) cyclopropanecarboxylic acid motif also resulted in reduced potency. 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 .