Application of quinoline-sulfamide compound as inhibitor for Th17 cell differentiation

Abstract

The invention discloses an application of a quinoline-sulfamide compound as an inhibitor for Th17 cell differentiation. Through a luciferase activity screening system based on the transcription factor activity, it is found that the quinoline-sulfamide compound with the structural formula shown in the description (X is a halogen element) has the capability of inhibiting key transcription factor RORgammat for Th17 cell differentiation, the inhibition capability EC50 is 0.391[mu]M; an in vitro Th17 cell differentiation experiment proves that the compound has the function of inhibiting Th17 differentiation, specifically, including obviously reducing the transcription expression of RORgammat, and inhibiting the transcription expression of effector molecule IL17A of Th17, and further, the secretion level of the IL17A cell factor in a culture is also obviously inhibited. The compound and a hydrochloride derivative thereof are expected to be developed into the medicines for treating autoimmune diseases, in particular psoriasis, systemic lupus erythematosus, multiple sclerosis, rheumatic arthritis, asthma or inflammatory bowel diseases.

Description

technical field [0001] The present invention relates to a new application of compounds, in particular to the application of quinoline-sulfonamide compounds as Th17 cell differentiation inhibitors. Background technique [0002] Autoimmune diseases affect about 5% of the population, and more than 70 human diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, asthma, and inflammatory bowel disease, are associated with autoimmune disorders (Goodnow et al. ,2005). At present, the treatment of autoimmune diseases mainly relies on some non-selective immunosuppressants, which have limited curative effect and large side effects, so there is no very effective drug for the treatment of autoimmune diseases in clinical practice. Therefore, it is an urgent clinical need to develop new autoimmune drugs with high efficacy and low side effects. The latest research shows that Th17 cells, a new T cell subset, are related to the occurrence of human autoimmune diseases and r...

AI Technical Summary

Problems solved by technology

At present, the natural ligand of RORγt has not been found, but two recent studies have found that the synthetic molecule digoxin and its derivatives (Huhe et al., 20011; Fujita-Sato et al., 2011) and SR1001 (Solt et al., 2011) can specifically Sexually binds to the ligand domain of RORγt, inhibits the function of RORγt and reduces the differentiation ability of Th17 cells, attenuating the clinical symptoms of mouse autoimmune disease EAE

However, digoxin and its derivatives have strong toxicity (Paula et al., 2005), and although SR1001 molecule can effectively inhibit the differentiation of Th17 cells in vitro, even at high concentrations (40mg / kg) in vivo experiments , can only slightly alleviate the clinical symptoms of EAE

In addition, SR1001 can interact with other RORs with poor selectivity (Solt et al., 2011)

On the one hand, these studies show that inhibiting the function of RORγt to treat autoimmune diseases is a feasible solution, but an ideal target drug has not yet been found

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