showed the highest LXRα selectivity, with activity five to six times greater than their LXRβ activation (Table ). Compound 17 activated LXRα less potently than its closest structural relative among the fine-tuning compounds (EC50 < 0.1 µM, Supporting Table ). Compound 5 (LXRα: EC50 = 0.26 ± 0.01 µM; LXRβ: EC50 = 1.30 ± 0.03 µM) constituted only a minor structural modification of one of the fine-tuning compounds (compound 29, Figure ), which had an EC50 of 0.4 µM on LXRα and an EC50 of 0.18 µM on LXRβ. While compounds 5 and 29 were comparable in their agonistic effects on LXRα, compound 5 was more than seven times less potent than 29 on the beta subtype. As suggested by automated ligand-receptor docking, the preference for LXRα could be ascribed to the different positioning of compounds 5 and 29 in the LXRβ binding pocket (Figure ). While compounds 5 and 29 are predicted to adopt similar binding poses within the LXRα pocket (RMSD < 1.8 Å), compound 29 was predicted to engage in an additional CH3-π interaction in the binding