ROR gamma t activity inhibition compound and preparation method and application thereof

Abstract

The invention relates to an ROR gamma t activity inhibition compound and a preparation method and application thereof. The ROR gamma t activity inhibition compound has the following structural formula(A). Research finds that the compound with the structural formula (A) has a good ROR gamma t activity inhibition effect. Specifically, a luciferase activity reporting system and a Th17 cell differentiation experiment prove that the compound can inhibit the transcription effect of a key transcription factor ROR gamma t of Th7 cell differentiation; transcription expression of target genes IL17A andIL17F molecules of ROR gamma t can be inhibited, expression of IL17A with protein level detected by a flow cytometry in cells is also obviously inhibited, and it is proved that the compound moleculehas an obvious Th17 cell activity inhibition function. Therefore, the compound can be used for preparing a corresponding activity inhibition preparation, and a lead structure is provided for researchand development of drugs for treating autoimmune diseases.

Description

Technical field [0001] Technical Field The present invention relates to synthetic drugs, more particularly to a RORγt inhibiting active compounds and preparation method and application. Background technique [0002] Currently, autoimmune disease affects about 5% of the population of the world, including psoriasis, multiple sclerosis complications, rheumatoid arthritis, asthma and inflammatory bowel disease, including about 70 kinds of human diseases are associated with autoimmune disorders For (Goodnow et al., 2005). Current treatments of autoimmune diseases depends on the number of non-selective immunosuppressive agents, their limited efficacy and side effects, thus not yet clinically very specific treatment of autoimmune disorders. Therefore, the development of new high efficacy side effects of low self-immunity drugs become a urgent clinical need. [0003] Studies have shown that the occurrence of the relevant human Th17 cells and autoimmune diseases and related animal model o...

AI Technical Summary

Problems solved by technology

At present, the natural ligand of RORγt has not been found, but two recent studies have found the artificial molecule digoxin and its derivatives (Huh et al., 20011; Fujita-Sato et al., 2011) and SR1001 (Solt et al. .,2011) can specifically bind to the ligand domain of RORγt, inhibit the function of RORγt and reduce the differentiation ability of Th17 cells, weakening 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, in vivo experiments even at high concentrations (40mg / kg), 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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