Crude samples of all 28 test compounds were analyzed at a single concentration for LXRα and LXRβ activation, with two independent biological duplicates (Figure ). The test compound concentration was roughly adjusted to 10 µM based on the HPLC traces of the samples. Compounds 1-17 displayed ≥ 3-fold LXR activation in this preliminary screening, potentially corresponding to up to 68% actives among the 25 synthesized molecules. Compounds 6 (52-fold LXRα activation) and 15 (60-fold LXRβ activation) exhibited the strongest response in the primary screening. All compounds showing more than two-fold LXR activation possessed a hexafluoro-2-phenyl-isopropanoyl moiety, suggesting particular relevance of this molecular feature for the observed bioactivity. This feature was also present in 12 of the fine-tuning compounds (29%), with an additional 4 (10%) and 8 (20%) fine-tuning compounds possessing a hexafluoro-2-aryl-isopropanoyl moiety and an aryl-trifluoromethyl motif, respectively. All compounds showing more than 10-fold LXRα activation in the preliminary screening were selected for full characterization of the dose-response curve. Compound 7 was excluded because of its cytotoxicity. Compound 1 (two-fold LXRα activation) was included in the follow-up study because of its novel atomic scaffold, which is not present in any molecule annotated for LXRs in ChEMBL27 or in a repository for nuclear receptor bioactivity.