Targeting the IL-17 pathway has become in recent years a very attractive approach for the treatment of immuno-inflammatory diseases. IL-17 antibodies such as secukinumab have validated the interest of blocking IL-17 secretion for such therapy. The nuclear receptor RORγt is a master player in the regulation of IL-17. It does indeed play a key role in the differentiation and development of Th17 cells which secrete IL-17A and other pro-inflammatory cytokines like IL-17F and IL-22. Small molecule RORγt inhibitors could be useful for the treatment of various diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis or inflammatory bowel disease. An HTS has been run on Inventiva’s library (248000 Compounds) using a GAL4 transactivation assay leading to the discovery of a new series of quinoline sulfonamides as RORγ inhibitors, eventually giving rise to a lead compound showing a nice activity in vivo when administered p.o. both in a target engagement model as well as in a multiple sclerosis model (EAE). The synthesis, structure activity relationship (SAR) and biological activity of these derivatives will be presented.

Discovery of novel quinoline sulfonamide derivatives as potent, selective and orally active RORγ inverse agonists

256th National Meeting (2018)

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