S18-000003 is a potent, selective and orally active inhibitor of retinoic acid receptor-related orphan receptor-gamma-t (RORγt) , with an IC 50 of <30 nM towards human RORγt in competitive binding assays. S18-000003 shows selectivity for RORγt over other ROR family members (IC 50 >10 μM). S18-000003 can be used for the research of psoriasis with low risk of thymic aberrations
In Vitro
S18-000003 inhibits human and mouse RORγt-dependent transactivation, with IC 50 s of 0.029 and 0.34 μM respectively in cell-based GAL4 promoter reporter assays. S18-000003 (0.003-0.3 μM; 7 d) dose-dependently inhibits Th17 cell differentiation from human naive CD4 + T cells, with an IC 50 of 0.024 μM. S18-000003 (0.1-3 μM; 4 d) inhibits the differentiation of mouse Th17 cells from splenic naive CD4 + T cells, with an IC 50 of 0.20 μM. S18-000003 (0.03-1 μM; 3 d) reduces the IL-17 production in human PBMCs in a dose-dependent manner, and does not inhibit either the production of other cytokines (IL-2, IL-4, IL-10 and IFN-g) or cell proliferation. S18-000003 (0.1-3 μM; 3 d) reduces IL-17 and IL-22 production in PBMCs from psoriatic mice in a dose-dependent manner. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
S18-000003 (30-100 mg/kg; p.o.) inhibits IL-17 production in the skin of IL-23-treated mice in a dose-dependent manner . S18-000003 (0.1-8%; 100mL; topically administration once daily for 14 days) ameliorates psoriasis-like lesions in TPA-induced K14.Stat3C transgenic mice, and has little impact on the thymus. S18-000003 (0.5 mg/kg; i.v.) exhibits the half-life (3.2 h), AUC (1930 ng•h/mL), CL tot (4.33 mL/min/kg) and Vd ss in rats . S18-000003 (1 mg/kg; p.o.) exhibits the oral bioavailability (54.5%), C max (185 ng/mL), AUC (2110 ng•h/mL) and T max (4 h) in rats . MCE has not independently confirmed the accuracy of these methods. They are for reference only.
