Demethylgorgosterol-derived steroids as a new class of RORγ-preferential inverse agonists

23-Demethylgorgosterol is an unusual marine sterol scaffold characterized by an atypical 22,23-cyclopropyl-containing side chain and an uncommon sterol substitution pattern. Its recent access through an efficient semi-synthetic route enables systematic structural diversification. In this study, we completed the semi-synthesis and prepared the unnatural diastereomer together with a series of structurally diverse intermediates and derivatives. Based on their structural similarity to sterols and oxysterols, these compounds were evaluated for modulation of the ligand-activated nuclear receptors farnesoid X receptor (FXR), liver X receptor α (LXRα), and the retinoic acid receptor-related orphan receptors RORα, RORβ, and RORγ. While little or no activity was observed at FXR and LXRα, several derivatives displayed low-micromolar inverse agonism at RORγ. Alcohol- and bromide-bearing derivatives showed a pronounced preference for RORγ, whereas oxidation of the terminal alcohol to the corresponding carboxylic acid broadened activity across all three ROR isoforms, yielding a low-micromolar pan-ROR inverse agonist with a modest preference for RORγ. These findings identify the terminal region of the cyclopropyl side chain as a key structural feature associated with ROR activity, efficacy, and isoform preference and establish demethylgorgosterol-derived structures as a natural product-inspired scaffold for the exploration of RORγ-preferential and pan-ROR inverse agonists.