阅读说明：本技术 鸟嘌呤核苷的新用途 (New application of guanosine ) 是由 李为民 罗雨蕉 陈海 何杨 吴琼 夏贞强 黄日东 于 2020-08-19 设计创作，主要内容包括：本发明属于药物技术领域,具体涉及鸟嘌呤核苷的新用途,具体是在在制备治疗哮喘药物或MAPK、NF-κB、STAT3抑制剂中的新用途。本发明针对现有技术中迫切需要开发更安全,更有效的哮喘治疗药物的问题。本发明发现在体外THP-1源性巨噬细胞炎症模型中,鸟嘌呤核苷通过抑制MAPK和NF-κB的激活抑制促炎因子IL-6的生成。在哮喘小鼠模型中,鸟嘌呤核苷降低了小鼠血浆OVA-IgE,降低IL-4、IL-6和IL-13的产生,减轻气道高反应性,减轻肺组织细胞浸润、气道炎症和胶原沉积。此外,鸟嘌呤核苷治疗组小鼠肺组织p-p38 MAPK,p-p65 NF-κB,p-IκBα、p-STAT3蛋白表达水平明显低于哮喘模型组。因而,本发明提供了鸟嘌呤核苷在制备p38 MAPK抑制剂、p65 NF-κB抑制剂、STAT3抑制剂或哮喘治疗药物中的用途。(The invention belongs to the technical field of medicaments, and particularly relates to a new application of guanosine, in particular to a new application in the preparation of asthma treatment medicaments or MAPK and NF-kappa B, STAT3 inhibitors. The invention aims at solving the problem that the development of safer and more effective asthma treatment medicines is urgently needed in the prior art. The invention discovers that in an in vitro THP-1 derived macrophage inflammation model, guanosine inhibits the generation of a proinflammatory factor IL-6 by inhibiting the activation of MAPK and NF-kB. In an asthmatic mouse model, guanosine lowers mouse plasma OVA-IgE, reduces IL-4, IL-6 and IL-13 production, reduces airway hyperreactivity, and reduces lung histiocyte infiltration, airway inflammation and collagen deposition. In addition, the expression levels of p-p38MAPK, p-p65 NF-kB, p-I kB alpha and p-STAT3 proteins in lung tissues of mice in a guanosine treatment group are obviously lower than those in an asthma model group. Therefore, the invention provides application of guanosine in preparing p38MAPK inhibitors, p65 NF-kB inhibitors, STAT3 inhibitors or asthma treatment drugs.)

1. Use of guanosine or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or an optical isomer thereof in the preparation of a medicament for treating asthma.

2. Use according to claim 1, characterized in that: the asthma is inhalation asthma, infectious asthma, mixed asthma, occupational asthma, chronic asthmatic bronchitis, exercise asthma or chronic asthma.

3. Use according to claim 1 or 2, characterized in that: the medicament is a medicament that reduces airway inflammation, reduces airway fibrosis, and/or reduces airway hyperreactivity.

4. A medicament for treating asthma, which is characterized in that: the medicine is prepared by taking guanosine as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

5. Use according to claim 4, characterized in that: the pharmaceutical product is in the form of pill, lotion, inhalant or spray.

6. Use of guanosine or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or an optical isomer thereof in the preparation of a p38MAPK inhibitor, a p65 NF-kB inhibitor or a STAT3 inhibitor.

7. Use according to claim 6, characterized in that:

the p38MAPK inhibitor is for use in the treatment of malignancy, inflammation or a disease of the nervous system, preferably, the p38MAPK inhibitor is for use in the treatment of cancer of the oral cavity, oropharyngeal, nasopharyngeal, respiratory, genitourinary, gastrointestinal, central or peripheral nervous system tissue, endocrine or neuroendocrine or hematopoietic, glioma, sarcoma, tumor, lymphoma, melanoma, fibroma, meningioma, brain, oropharyngeal, renal, biliary, pheochromocytoma, islet cell, Li-Fraumeni, thyroid, parathyroid, pituitary, adrenal, osteogenic sarcoma, neuroendocrine-II type I, breast, lung, head and neck, prostate, esophageal, tracheal, liver, bladder, stomach, pancreatic, ovarian, uterine, cervical, One or more of testicular cancer, colon cancer, rectal cancer, skin cancer, arthritis, inflammatory bowel disease, asthma, psoriasis, myocardial injury, stroke, alzheimer's disease, aids, chronic obstructive pulmonary disease, multiple myeloma, myelodysplastic syndrome, acute respiratory distress syndrome, coronary heart disease, acute coronary syndrome, major depression, dental pain, atherosclerosis, or neuropathic pain;

the p65NF- κ B inhibitor is for use in the treatment of malignancy, inflammation or a nervous system disease, preferably the p65NF- κ B inhibitor is for use in the treatment of one or more of leukemia, lymphoma, multiple myeloma, non-small cell lung cancer, nasopharyngeal carcinoma, breast cancer, colon cancer, gastric cancer, pancreatic cancer, bladder cancer, prostate cancer, ovarian cancer, liver cancer, hodgkin's disease, thyroid cancer, melanoma, atherosclerosis, bone resorption, cardiac hypertrophy, heart failure, ischemia/reperfusion, multiple sclerosis, muscular dystrophy, chronic obstructive pulmonary disease, systemic inflammatory response syndrome, neuropathological diseases, inflammatory bowel disease, arthritis, asthma, lupus, tumorigenesis, viral infection, diabetes, alzheimer's disease, aids or depression;

the STAT3 inhibitor is used for treating malignant tumor, skin disease, inflammation or autoimmune disease, preferably, the STAT3 inhibitor is used for treating one or more of breast cancer, ovarian cancer, head and neck squamous cell carcinoma, prostate cancer, malignant melanoma, multiple myeloma, lymphoma, brain tumor, non-small cell liver cancer, leukemia, psoriasis, lichen planus, skin tumor, basal cell epithelioma, eczematoid cancer, inflammatory lung disease, asthma, chronic nephritis, gastritis, pancreatitis, obstructive nephropathy, diabetic glomerulopathy, retinitis, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, thyroid dysfunction, juvenile diabetes, multiple sclerosis, idiopathic thrombocytopenic purpura, ulcerative colitis, autoimmune hepatitis or primary biliary cirrhosis.

8. A p38MAPK inhibitor, characterized by: the medicine is prepared by taking guanosine as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

9. A p65NF- κ B inhibitor, characterized by: the medicine is prepared by taking guanosine as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

10. A STAT3 inhibitor characterized by: the medicine is prepared by taking guanosine as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a new application of guanosine in preparation of MAPK, NF-kappa B, STAT3 inhibitors or medicines for treating asthma.

Background

Asthma is one of the most common chronic non-infectious diseases, with an adult asthma prevalence of 4.3%. The prevalence of asthma increases year by year, and it is estimated that the prevalence of asthma increases to 3.582 billion and increases by 12.6% from 1990 to 2015; in 2015 40 million people died from asthma. Although inhaled glucocorticoids (ICS) are the first line of care medication for most patients, compliance with ICS is very poor in children and adults, and a small proportion of patients are resistant to glucocorticoids. Because patients believe that short-acting β 2 agonists (SABA) are more familiar and more acceptable, cheaper, and safer than ICS. Thus, only 5.6% of asthma patients in china receive conventional ICS therapy. However, treatment with SABA alone increases the risk of asthma exacerbation and death according to the global initiative for asthma control (GINA). Therefore, there is an urgent need to develop safer and more effective asthma treatment drugs.

Guanosine is an endogenous nucleoside, one of the raw materials for synthesizing DNA and RNA. In the medical industry, the main application of the compound is to be used as an intermediate for synthesizing ribavirin and acyclovir. In the food industry, the disodium guanylate serving as a main raw material of the disodium guanylate is mixed with disodium inosinate, which is called I + G for short, and the mixture is added into monosodium glutamate to form second-generation and third-generation monosodium glutamate, so that the monosodium glutamate has a very wide market.

The action of guanosine on asthma and the molecular mechanism thereof have not been reported at present.

Disclosure of Invention

The invention aims to solve the problem that the development of safer and more effective asthma treatment drugs is urgently needed in the prior art, and provides the application of guanosine in preparing the asthma treatment drugs.

The invention provides application of guanosine or pharmaceutically acceptable salts thereof, or crystal forms thereof, or stereoisomers thereof, or optical isomers thereof in preparing a medicament for treating asthma.

Preferably, the asthma is asthma of inhalation, asthma of infection, asthma of mixed type, occupational asthma, chronic asthmatic bronchitis, exercise asthma or chronic asthma.

Preferably, the drug is one that reduces airway inflammation, reduces airway fibrosis, and/or reduces airway hyperreactivity.

Preferably, the pharmaceutical product is in the form of a pill, lotion, inhalant or spray.

The invention also provides a medicine for treating asthma, which is prepared by taking guanosine as an active component and adding pharmaceutically acceptable auxiliary materials or auxiliary components.

Preferably, the pharmaceutical product is in the form of a pill, lotion, inhalant or spray.

The invention also provides application of guanosine or pharmaceutically acceptable salts thereof, or crystal forms thereof, or stereoisomers thereof, or optical isomers thereof in preparation of p38MAPK inhibitors, p65 NF-kappa B inhibitors or STAT3 inhibitors.

Preferably, the first and second liquid crystal materials are,

a p38MAPK inhibitor for use in the treatment of malignancy, inflammation or a disease of the nervous system, preferably, the p38MAPK inhibitor is for use in the treatment of cancer of the oral cavity, oropharyngeal, nasopharyngeal, respiratory, genitourinary, gastrointestinal, central or peripheral nervous system tissue, endocrine or neuroendocrine or hematopoietic, glioma, sarcoma, tumor, lymphoma, melanoma, fibroma, meningioma, brain, oropharyngeal, renal, biliary, pheochromocytoma, islet cell, Li-Fraumeni, thyroid, parathyroid, pituitary, adrenal, osteogenic sarcoma, neuroendocrine-II type I and II, breast, lung, head and neck, prostate, esophageal, tracheal, liver, bladder, stomach, pancreatic, ovarian, uterine, cervical, Testicular cancer, colon cancer, rectal cancer, skin cancer, arthritis, inflammatory bowel disease, asthma, psoriasis, myocardial injury, stroke, alzheimer's disease, aids, chronic obstructive pulmonary disease, multiple myeloma, myelodysplastic syndrome, acute respiratory distress syndrome, coronary heart disease, acute coronary syndrome, major depression, dental pain, atherosclerosis, or neuropathic pain;

a p65NF- κ B inhibitor for use in the treatment of malignancy, inflammation or a nervous system disease, preferably, the p65NF- κ B inhibitor is for use in the treatment of a combination of one or more of leukemia, lymphoma, multiple myeloma, non-small cell lung cancer, nasopharyngeal carcinoma, breast cancer, colon cancer, gastric cancer, pancreatic cancer, bladder cancer, prostate cancer, ovarian cancer, liver cancer, hodgkin's disease, thyroid cancer, melanoma, atherosclerosis, bone resorption, cardiac hypertrophy, heart failure, ischemia/reperfusion, multiple sclerosis, muscular dystrophy, chronic obstructive pulmonary disease, systemic inflammatory response syndrome, neuropathological diseases, inflammatory bowel disease, arthritis, asthma, lupus, tumorigenesis, viral infection, diabetes, alzheimer's disease, aids or depression;

STAT3 inhibitor is for use in the treatment of a malignancy, a skin disease, an inflammation, or an autoimmune disease, preferably STAT3 inhibitor is for use in the treatment of a combination of one or more of breast cancer, ovarian cancer, head and neck squamous cell carcinoma, prostate cancer, malignant melanoma, multiple myeloma, lymphoma, brain tumor, non-small cell liver cancer, leukemia, psoriasis, lichen planus, a skin tumor, basal cell epithelioma, eczematoid cancer, inflammatory lung disease, asthma, chronic nephritis, gastritis, pancreatitis, obstructive renal disease, diabetic glomerulopathy, retinitis, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, thyroid dysfunction, juvenile diabetes, multiple sclerosis, idiopathic thrombocytopenic purpura, ulcerative colitis, autoimmune hepatitis, or primary biliary cirrhosis.

The invention also provides a p38MAPK inhibitor, which is prepared by taking guanosine as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

The invention also provides a p65 NF-kB inhibitor, which is prepared by taking guanosine as an active component and adding pharmaceutically acceptable auxiliary materials or auxiliary components.

The invention also provides a STAT3 inhibitor which is prepared by taking guanosine as an active component and adding pharmaceutically acceptable auxiliary materials or auxiliary components.

By "pharmaceutically acceptable" is meant that the carrier, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form, and is physiologically compatible with the recipient.

"salts" are acid and/or base salts of a compound or a stereoisomer thereof with inorganic and/or organic acids and/or bases, and also include zwitterionic (inner) salts, as well as quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound, or a stereoisomer thereof, may be obtained by appropriately (e.g., equivalentlymixing) a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.

The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

Through the results of relevant experimental studies, the following results are found: in an in vitro model of THP-1 derived macrophage inflammation, guanosine inhibits the production of the proinflammatory factor IL-6 by inhibiting the activation of MAPK and NF- κ B. In an asthmatic mouse model, guanosine lowers mouse plasma OVA-IgE, reduces IL-4, IL-6 and IL-13 production, reduces airway hyperreactivity, and reduces lung histiocyte infiltration, airway inflammation and collagen deposition. In addition, the expression levels of p-p38MAPK, p-p65 NF-kB, p-I kB alpha and p-STAT3 proteins in lung tissues of mice in a guanosine treatment group are obviously lower than those in an asthma model group.

Therefore, guanosine can be used as an active ingredient for preparing asthma treatment medicines, and can also be used as a p38MAPK inhibitor, a p65 NF-kappa B inhibitor and a STAT3 inhibitor, wherein the p38MAPK inhibitor can be used for treating malignant tumors, inflammations or nervous system diseases, and therefore, the invention can also be used as a medicine for treating malignant tumors, inflammations or nervous system diseases; the p65 NF-kB inhibitor can be used for treating malignant tumor, inflammation or nervous system diseases, so the invention can also be used as a medicament for treating malignant tumor, inflammation or nervous system diseases; STAT3 inhibitors are useful in the treatment of malignancies, skin diseases, inflammation, or autoimmune diseases, and thus, the present invention is also useful as a treatment for malignancies, skin diseases, inflammation, or autoimmune diseases.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 is a graph showing the effect of guanosine, uridine and dexamethasone on the total leukocyte count in OVA-induced alveolar lavage fluid of asthmatic mice in example 1 of the present invention;

FIG. 2 is an H & E staining of lung tissue in example 1 of the present invention;

FIG. 3 is MASSON staining of lung tissue in example 2 of the present invention;

FIG. 4 is a graph of enhanced expiratory pause (Penh) for various groups of mice after challenge with different concentrations of acetylcholine chloride in example 3 of the present invention;

FIG. 5 shows the expression levels of IL-4, IL-6 and IL-13 in lung tissues of each group of mice in example 4 of the present invention;

FIG. 6 is a graph showing the levels of OVA-IgE in the plasma of various groups of mice in example 5 of the present invention;

FIG. 7 is a graph showing mRNA levels of inflammatory mediators in lung tissues of various groups of mice in example 6 of the present invention;

FIG. 8 shows the detection of the expression of p-p38MAPK in mouse lung tissue by the immunohistochemical method in example 7 of the present invention;

FIG. 9 shows the level of phosphorylation of p38MAPK and total protein expression in mouse lung tissue detected by immunoblotting assay in example 7 of the present invention;

FIG. 10 shows the level of NF- κ B phosphorylation and total protein expression in mouse lung tissue detected by immunoblotting in example 8 of the present invention;

FIG. 11 shows the detection of p-STAT3 and STAT3 in mouse lung tissues by immunoblotting assay in example 8 of the present invention; p-I kappa B alpha and I kappa B alpha protein expression levels;

FIG. 12 is a graph showing the effect of guanosine and uridine on the expression level of IL-6 from THP-1-derived macrophages in example 9 of the present invention;

FIG. 13 is a graph showing the effect of guanosine and uridine on the expression level of the THP-1 derived macrophage p38MAPK protein in example 10 of the present invention;

FIG. 14 is a graph showing the effect of guanosine and uridine on the expression level of THP-1 derived macrophage protein in example 11 of the present invention.

Detailed Description

The technical solution of the present invention is further illustrated by the following specific examples: