Application of h018JAK as active ingredient in preparation of medicine for treating rheumatoid arthritis

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of h018JAK as an active component in preparation of a medicine for treating rheumatoid arthritis. The H018 is a second-generation high-selectivity JAK1 inhibitor, and compared with a generic JAK inhibitor, the high selectivity of the H018 can provide better safety and effectiveness. The H018 is obtained by taking the filgotinib as a reference substance and carrying out continuous structural optimization, and both in-vivo and in-vitro evaluation test results show that the H018 is superior to the filgotinib.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to an application of h018JAK as an active ingredient in the preparation of a medicine for treating rheumatoid arthritis. Background Art

[0002] JAK (Janus kinase) is a non-receptor tyrosine kinase. It is activated after being stimulated by specific growth factors, growth hormones, chemokines, cytokines and various cell surface receptors, giving it tyrosine kinase activity and binding in pairs. Dimeric JAK can undergo spontaneous phosphorylation and bind to STAT protein, phosphorylating STAT transcription factor and transferring it to the cell nucleus, affecting DNA transcription and thus gene expression. The JAK-STAT signaling pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. The JAK family has four members: JAK1, JAK2, JAK3 and TYK2. Among them, JAK1 can mediate the signaling pathway activated by cytokines (such as interferon, IL-1β, IL-2, IL-6 tumor necrosis factor α, etc.), and the signaling of a large number of pro-inflammatory cytokines depends on JAK1. Inhibition of JAK2 will inhibit the signaling of erythropoietin, thrombopoietin and granulocyte colony stimulating factor, leading to thrombocytopenia and anemia; inhibition of JAK3 may lead to the lack of activity of T cells, NK cells and functional B cells, leading to severe combined immunodeficiency and life-threatening infections. Therefore, compared with pan-JAK inhibitors, JAK1 inhibitors have higher selectivity and provide better safety and efficacy.

[0003] In the development of rheumatoid arthritis (RA), inflammatory factors such as interleukin IL-1β and tumor necrosis factor α play an important role. These inflammatory factors mainly conduct signal transduction through JAK-STAT, NF-κB, MAPK and other pathways. Among them, the JAK-STAT signaling pathway mediated by JAK1 is an important signal transduction pathway. In addition, many type I and type II cytokines can bind to JAK1 to exert their effects. Therefore, inhibiting JAK1 is an important target for the treatment of RA. H018 controls the inflammatory response of rheumatoid arthritis by highly selectively inhibiting JAK1. Summary of the invention

[0004] The object of the present invention is to provide a use of h018JAK as an active ingredient in the preparation of a drug for treating rheumatoid arthritis.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A use of h018JAK as an active ingredient in the preparation of a drug for treating rheumatoid arthritis.

[0007] The h018JAK is used as an inhibitor to regulate the JAK-STAT signaling pathway by preventing the phosphorylation and activation of STATs, and is used to treat autoimmune diseases such as rheumatoid arthritis.

[0008] Compared with the prior art, the present invention has the following beneficial effects:

[0009] H018 is a second-generation highly selective JAK1 inhibitor. Compared with pan-JAK inhibitors, H018's high selectivity may provide better safety and efficacy. H018 is obtained through continuous structural optimization with Filgotinib as the reference. The results of in vivo and in vitro evaluation tests show that it is superior to Filgotinib. In vitro tests show that H018 is 3 times more active against JAK1 than Filgotinib, and its selectivity for JAK1 / 2 is comparable to that of Filgotinib. In stability, plasma protein binding rate, CYP inhibition, and hERG inhibition tests, H018 has good prospects for drugability. DETAILED DESCRIPTION

[0010] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0011] Example

[0012] A use of h018JAK as an active ingredient in the preparation of a drug for treating rheumatoid arthritis.

[0013] The h018JAK is used as an inhibitor to regulate the JAK-STAT signaling pathway by preventing the phosphorylation and activation of STATs, and is used to treat autoimmune diseases such as rheumatoid arthritis.

[0014] The candidate compounds of the H018 (JAK1) project have currently completed systematic in vitro efficacy evaluation, drugability evaluation, in vivo pharmacokinetic evaluation, in vivo pharmacodynamic evaluation, and repeated dosing toxicity evaluation.

[0015] JAK1 inhibitors provide a treatment option for RA patients, breaking the traditional treatment pathways of rheumatic drugs and biological drugs. They are still effective for patients who have poor responses to traditional DMARD and TNF inhibitor treatments, improving patients' health-related quality of life and having proven safety.

Claims

1. A use of h018JAK as an active ingredient in the preparation of a drug for treating rheumatoid arthritis.

2. The use of h018JAK according to claim 1 as an active ingredient in the preparation of a drug for treating rheumatoid arthritis, characterized in that The h018JAK is used as an inhibitor to regulate the JAK-STAT signaling pathway by preventing the phosphorylation and activation of STATs, and is used to treat autoimmune diseases such as rheumatoid arthritis.