1426802-50-7

Usage

Uses

Used in Pharmaceutical Industry:
ROR gamma-t-IN-1 is used as a therapeutic agent for the treatment of autoimmune diseases, particularly multiple sclerosis. It functions by inhibiting the development and pathogenic function of Th17 cells, which are implicated in the pathology of these conditions. In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, GSK805 has been shown to significantly reduce the severity of the disease when administered orally at a dosage of 10 mg/kg daily.
Additionally, ROR gamma-t-IN-1 may be used as a research tool for studying the role of RORγt in various biological processes and the development of Th17 cells, as well as for identifying potential targets for the treatment of other immune-related disorders.

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Relevant academic research and scientific papers

Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists

GSK805 (1) is a potent RORγt inverse agonist, but a drawback of 1 is its low solubility, leading to a limited absorption in high doses. We have explored detailed structure-activity relationship on the amide linker, biaryl and arylsulfonyl moieties of 1 trying to improve solubility while maintaining RORγt activity. As a result, a novel series of carboxyl-containing biaryl urea derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. Compound 3i showed potent RORγt inhibitory activity and subtype selectivity with an IC50 of 63.8 nM in RORγ FRET assay and 85 nM in cell-based RORγ-GAL4 promotor reporter assay. Reasonable inhibitory activity of 3i was also achieved in mouse Th17 cell differentiation assay (76percent inhibition at 0.3 μM). Moreover, 3i had greatly improved aqueous solubility at pH 7.4 compared to 1, exhibited decent mouse PK profile and demonstrated some in vivo efficacy in an imiquimod-induced psoriasis mice model.

Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors

A novel series of biaryl amides was identified as RORγt inhibitors through core replacement of a starting hit 1. Structure-activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. Compounds 9a and 9g demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration.

NOVEL COMPOUNDS

Disclosed are novel retinoid-related orphan receptor gamma (RORy) modulators and their use in the treatment of diseases mediated by RORy.