Application of 4N heterocyclic compound as inhibitor for Th17 cell differentiation

Abstract

The invention discloses application of a 4N heterocyclic compound as an inhibitor for Th17 cell differentiation. In virtue of a luciferase activity screening system based on the activity of transcription factors, it is found that the 4N heterocyclic compound with a general formula as described in the specification has capability in inhibiting the key transcription factor ROR gamma t of Th17 cell differentiation and the inhibition capability EC50 is in a range of 0.2 to 1.5 [mu]M. In-vitro Th17 cell differentiation experiments prove that the 4N heterocyclic compound is capable of inhibiting Th17 differentiation, including substantially reducing the transcription expression of ROR gamma t, inhibiting the transcription expression of the effector molecules IL17A and IL17F of Th17 and obviously inhibiting the secretion level of IL17A cytokines in a culture. The 4N heterocyclic compound is expected to be developed into a drug used for treating autoimmune diseases, especially psoriasis, systematic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, asthma or inflammatory intestinal diseases.

Description

technical field [0001] The invention relates to a new application of the compound, in particular to the application of the 4N heterocyclic compound as a Th17 cell differentiation inhibitor. 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. 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. Recent studies have shown that a novel T cell subset, Th17 cells, is associated with the development of human autoimmune diseases a...

AI Technical Summary

Problems solved by technology

At present, the natural ligand of RORγt has not been found, but two recent studies 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, attenuating the clinical symptoms of mouse autoimmune disease EAE

However, digoxin and its derivatives are highly toxic (Paula et al., 2005), and although SR1001 can effectively inhibit the differentiation of Th17 cells in vitro, in vivo experiments even at high concentrations (40 mg / 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

Images