1,5-Disubstituted Acylated 2-Amino-4,5-dihydroimidazoles as a New Class of Retinoic Acid Receptor-Related Orphan Receptor (ROR) Inhibitors

A growing body of evidence suggests a pathogenic role for pro-inflammatory T helper 17 cells (Th17) in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type I diabetes, and psoriasis-diseases for which no curative treatment is currently available. The nuclear retinoic acid receptor-related orphan receptors alpha and gamma (ROR alpha/gamma), in particular the truncated isoform ROR gamma t that is specifically expressed in the thymus, play a critical role in the activation of a pro-inflammatory Th17 response, and ROR gamma inverse agonists have shown promise as negative regulators of Th17 for the treatment of autoimmune diseases. Our study underscores the screening of a large combinatorial library of 1,5-disubstituted acylated 2-amino-4,5-dihydroimidazoles using a demonstrated synthetic and screening approach and the utility of the positional scanning libraries strategy for the rapid identification of a novel class of ROR inhibitors. We identified compound 1295-273 with the highest activity against ROR gamma (3.3 mu M IC50) in this series, and almost a two-fold selectivity towards this receptor isoform, with 5.3 and 5.8 mu M IC50 against ROR alpha and ROR beta cells, respectively.