By exploring varioussubstitutions at position 2 of the lupane scaffold, we have identifieda new and effective structural motif for RORγ inverse agonism.The resulting structure–activity relationship offers guidancefor the rational design of more potent and selective derivatives.This work provides a strong foundation for the development of triterpenoid-basedtherapies targeting Th17-driven diseases such as psoriasis and rheumatoidarthritis. The gene discussed is RORC; the disease is psoriasis.