Th17 cells have been identified as a major player in autoimmunity. An important transcription factor during Th17 differentiation and responsible for IL-17A and F transcription, which are key cytokines in a Th17 response, is RORgt.We were able to identify inhibitors of IL-17A and IL-17F secretion in a single-digit nanomolar to subnanomolar range which proved to be potent RORgt inhibitors.The potential for treating autoimmune diseases with such inhibitors has been evaluated in an animal model for psoriasis, in which mice bearing a skin-specific vs. ubiquitous I?Ba knockout were used. Topical application of a lead compound in both models resulted in a complete phenotypical recovery in the skin-specific variant and a clearly prolonged survival in the ubiquitous knockout animal.Within an SLE model in MRLlpr/lpr mice, oral administration of a lead compound resulted in complete survival of all animals within a timeframe resulting in 50% mortality in the control group.

Small molecule inhibitors of IL-17A and IL-17F secretion for the treatment of autoimmune diseases

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.