Marine Sterol Derivatives Emerge as RORγ-Preferential Inverse Agonists
- A semi-synthetic route to the marine sterol 23-demethylgorgosterol, which bears a cyclopropyl group, yielded its unnatural diastereomer and a set of derivatives.
- Across FXR, LXRα and RORα/β/γ, the compounds showed essentially no FXR or LXRα activity, but several acted as RORγ inverse agonists.
- Alcohol and bromide analogues favored RORγ, whereas oxidizing the terminal alcohol to an acid broadened activity to all three isoforms, so the side-chain terminus appears to govern ROR activity and selectivity.
💡 Points Based on the abstract
Clean silence on FXR and LXRα is what I'd care about most, since sterol scaffolds usually light up every oxysterol-sensing receptor. The alcohol-to-acid switch turning RORγ preference into pan-ROR activity hints at a polar head-group contact in the pocket, making the tail the tuning knob. Semi-synthesis keeps the cyclopropyl side chain accessible, but a non-steroidal comparison should precede any claim of novelty.
Demethylgorgosterol-derived steroids as a new class of RORγ-preferential inverse agonists ↗