T-helper 17 (Th17) cells produce the interleukin 17 (IL-17) family of cytokines in response to stimulation by interleukin 23 (IL-23), which is commonly associated with various human inflammatory and autoimmune disorders. The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is a nuclear receptor that has been identified as a key regulator of Th17 cell differentiation. Therefore, RORγt may be a potential drug target for IL-23/Th17-related autoimmune diseases and several inhibitors have been reported by groups in industry and academia. Our group has explored RORγt inhibitors based on a high-throughput screening campaign. Subsequent hit-to-lead optimization of several chemotypes led to the identification of methyl ester derivative 1. We will describe the identification of a novel series of a,a-dimethylphenylacetamide RORγt inhibitors, which were obtained by lead optimization of 1 through a structure–activity relationship (SAR) study and guided by a cocrystal structure analysis. These studies led to the discovery of a potent and orally bioavailable RORγt inhibitor, S18-000003. Oral administration of S18-000003 significantly inhibited IL-17 production in the skin of mice injected with IL-23 in a dose-dependent manner.

Discovery and evaluation of potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors

2019 Fall National Meeting

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