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Retinoicacid receptor-related orphan receptor C (RORc, RORγ, or NR1F3)is a nuclear receptor that plays a major role in the production ofinterleukin (IL)-17. Considerable efforts have been directed towardthe discovery of selective RORc inverse agonists as potential treatmentsof inflammatory diseases such as psoriasis and rheumatoid arthritis.Using the previously reported tertiary sulfonamide 1asa starting point, we engineered structural modifications that significantlyimproved human and rat metabolic stabilities while maintaining a potentand highly selective RORc inverse agonist profile. The most advancedδ-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone),possessed favorable RORc cellular potency with 75-fold selectivityfor RORc over other ROR family members and >200-fold selectivityover 25 additional nuclear receptors in a cell assay panel. The favorablepotency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependentinhibition of IL-17 in a PK/PD model support the evaluation of 27in preclinical studies. [ABSTRACT FROM AUTHOR]

The medicinal chemistry communityhas directed considerable effortstoward the discovery of selective inhibitors of interleukin-2 inducibleT-cell kinase (ITK), given its role in T-cell signaling downstreamof the T-cell receptor (TCR) and the implications of this target forinflammatory disorders such as asthma. We have previously discloseda structure- and property-guided lead optimization effort which resultedin the discovery of a new series of tetrahydroindazole-containingselective ITK inhibitors. Herein we disclose further optimizationof this series that resulted in further potency improvements, reducedoff-target receptor binding liabilities, and reduced cytotoxicity.Specifically, we have identified a correlation between the basicityof solubilizing elements in the ITK inhibitors and off-target antiproliferativeeffects, which was exploited to reduce cytotoxicity while maintainingkinase selectivity. Optimized analogues were shown to reduce IL-2and IL-13 production in vivo following oral or intraperitoneal dosingin mice. [ABSTRACT FROM AUTHOR]