Abstact

Retinoic acid receptor-related orphan receptor gamma (RORgamma) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd 1, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp(3) carbons (Fsp(3)). Initial structure-activity relationship (SAR) exploration led to the identification of Cpd 17. Target specificity studies of Cpd 17 indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORgamma, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd 21, which exhibited significantly improved RORgamma inhibitory potency along with LE, and Fsp(3) compared to Cpd 1. These results highlight Cpd 21 as a promising lead compound to explore a novel clinical candidate for the development of RORgamma-targeted therapies.