Based on the rather flat SAR of the propanoic acid side chain and the PAINS character of the acrylic acid analogue 36 disqualifying this motif for further optimization, we next evaluated the SAR of the extended butyric acid analogue 31. In addition to its favorable potency, this motif offered access to chain modifications with incorporation of heteroatoms to enhance polarity and simultaneously reduce binding affinity to the highly lipophilic RXR ligand binding site (Table ). The latter was indeed evident from the oxazolylmethylglycine derivative 42 which retained inverse Nurr1 agonism with similar potency as 6 but exhibited no activity on RXR. The tertiary N-methylglycine analogue 43 revealed no improvement over 42 pointing to little optimization potential of alternative Nsubstituents. Hence, we probed further amino acid conjugates (44-47), but introduction of the favored α-methyl substituent of 33 in the alanine conjugate 44 diminished inverse Nurr1 agonism and α-isobutyl (45), α-phenyl (46) and α-benzyl (47) moieties were also not favored. Chiral resolution and in vitro testing of 35 and 46 revealed no substantial differences between the respective enantiomers (Figure ). 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. 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 .