CN112263576A - Application of compound ZJU-37 in preparation of drugs for preventing and/or treating liver diseases - Google Patents
Application of compound ZJU-37 in preparation of drugs for preventing and/or treating liver diseases Download PDFInfo
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- CN112263576A CN112263576A CN202011063731.2A CN202011063731A CN112263576A CN 112263576 A CN112263576 A CN 112263576A CN 202011063731 A CN202011063731 A CN 202011063731A CN 112263576 A CN112263576 A CN 112263576A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention relates to the field of medicines, and particularly discloses application of a compound ZJU-37 shown in a formula I in preparation of medicines for preventing and/or treating liver diseases.
The invention discovers the application of the compound ZJU-37 in preparing the medicine for treating the liver diseases for the first time through extensive and intensive research, and develops the application field of the compound ZJU-37. Meanwhile, the invention provides a new treatment mode and a new treatment medicine for serious liver diseases such as severe hepatitis, liver failure and the like, has obvious liver protection and treatment effects and has obvious social benefits.
Description
Technical Field
The invention relates to the field of medicines, and particularly discloses application of a compound ZJU-37 in preparation of a medicine for preventing and/or treating liver diseases.
Background
Acute and chronic liver injury is a common disease in clinical at present, if the acute and chronic liver injury is not controlled and treated in time, the acute and chronic liver injury can develop into irreversible diseases such as severe hepatitis, liver failure and the like, wherein the fatality rate of the acute liver failure is as high as 80-97%. At present, no effective treatment means and medicine are available clinically for severe hepatitis and hepatic failure. Therefore, the development of new therapeutic drugs and development of new therapeutic means and methods are urgently needed to improve the survival rate of treating severe hepatitis. Studies have shown that the receptor interacting protein kinase RIP1 is involved in various liver diseases. The use of RIP1 protein kinase inhibitors can reduce cell death and relieve various inflammatory responses, but the specific mechanism is not clear. RIP1 kinase inhibition currently in clinical stage is mainly aimed at neurodegenerative diseases and autoimmune diseases, including ulcerative enteritis, psoriasis, rheumatoid arthritis and the like. Cell death in which RIP1 participates can promote tissue inflammation and injury, and even amplify tissue injury if not inhibited, so that development of the targeted RIP1 kinase activity has clinical requirements and wide application prospects.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a new application of a compound ZJU-37.
In a first aspect of the invention, there is provided the use of a compound of formula I ZJU-37 in the manufacture of a medicament for the prophylaxis and/or treatment of liver disease.
Preferably, the liver disease is liver injury, hepatitis, liver failure, liver tissue necrosis/apoptosis.
Wherein the liver injury may be acute liver injury. The hepatitis may be severe hepatitis. The liver failure may be acute liver failure.
In a second aspect of the invention, there is provided a novel use of a compound of formula I, ZJU-37, including the use for the preparation of any one or more of the following medicaments.
(1) Medicine capable of reducing ALT level
(2) Medicine capable of reducing AST level
(3) Medicine capable of reducing liver injury degree
(4) Medicine capable of relieving liver inflammation
(5) Medicine capable of reducing degree of hepatic tissue necrosis
(6) Medicine for reducing inflammatory cell infiltration
(7) Medicine for inhibiting secretion of inflammatory factor
(8) A drug for inhibiting apoptosis and programmed necrosis of liver tissue.
Compared with the prior art, the invention has the beneficial effects that:
the invention discovers the application of the compound ZJU-37 in preparing the medicine for treating the liver diseases for the first time through extensive and intensive research, and develops the application field of the compound ZJU-37. Meanwhile, the invention provides a new treatment mode and a new treatment medicine for serious liver diseases such as severe hepatitis, liver failure and the like, has obvious liver protection and treatment effects and has obvious social benefits.
Drawings
FIG. 1 shows a comparison of the efficacy of compound ZJU-37 and Nec-1s on liver injury and systemic inflammation in a mouse model of acute liver failure; the graph A and the graph B show that the serum liver injury indexes ALT and AST levels of the LPS/GalN model group are obviously increased compared with those of a normal control group, the serum ALT and AST levels of a treatment group are obviously reduced, and the ALT and AST can be obviously improved by the compound ZJU-37 compared with commercial Nec-1 s. Serum ALT, AST can be reduced after Nec-1s treatment (LPS/GalN vs. Nec-1s:1053 + -107.7 vs.724.8 + -119.5). While ZJU-37 significantly reduced ALT (LPS/GalN vs. ZJU-37: 2110. + -. 307.2vs. 166. + -. 31.11) and AST (LPS/GalN vs. ZJU-37: 21053. + -. 107.7vs. 206.5. + -. 21.16) (FIG. A, B). We used CBA to measure the serum cytokine levels of each group. The results show that compound ZJU-37 reduces TNF α, IL-6, IFN- γ, MCP-1 production better than Nec-1s (FIGS. C-F). Also ZJU-37 can prolong mouse survival time compared to Nec-1s (FIG. G). The compound ZJU-37 or the commercialized Nec-1s with the same dose (5mg/kg) is administrated in the abdominal cavity 30 minutes before LPS/GalN modeling, and the compound ZJU-37 can obviously improve liver injury and general inflammation compared with the commercialized Nec-1 s.
FIG. 2 shows a comparison of compound ZJU-37 with Nec-1s for improvement of liver pathology and neutrophil infiltration in a mouse acute liver failure model; the graphs A and B show an LPS/GalN model group, and the HE staining of liver tissues shows that the necrosis of the liver tissues and the infiltration of inflammatory cells are obvious. The degree of necrosis of liver tissues and infiltration of inflammatory cells were significantly reduced in the compound ZJU-37-treated group and the Nec-1 s-treated group, compared to the model group (panels C, D); particularly, the compound ZJU-37 has the best curative effect, and pathological sections of liver tissues of mice show that the liver tissues have no necrosis and less inflammatory cell infiltration. By immunohistochemistry on liver neutrophils by using Ly6G, the result is consistent with HE staining, and the liver tissue neutrophile infiltration is remarkably reduced in both the compound ZJU-37 treatment group and the Nec-1s treatment group compared with the model group; especially, the compound ZJU-37 has obvious curative effect, and pathological sections of liver tissues of mice show that the liver tissues have no neutrophil infiltration (figures E-H). Scale bar 50 uM.
FIG. 3 shows a comparison of the compound ZJU-37 with Nec-1s for liver cell death in a mouse model of acute liver failure; the TUNEL positive cells in the LPS/D-GalN model group were significantly increased compared to the normal control group (panels A and B), while the normal control group had almost no TUNEL positive signal, indicating that a large number of liver cells were apoptotic in the model group. Expression of TUNEL was significantly down-regulated in the treatment group; especially, the compound ZJU-37 showed the best effect, and pathological liver tissue sections of mice showed that the TUNEL signal was hardly detected in liver tissues (panels C and D).
Detailed Description
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
The compound ZJU-37 of the invention is the prior art and can be prepared by the prior method.
EXAMPLE 1 preparation of a solution of Compound ZJU-37
The experimental method comprises the following steps: the compound ZJU-37 is prepared by diluting a stock solution of the compound ZJU-37 prepared after DMSO cosolvent with PBS before injection to prepare a solvent of the compound ZJU-37.
EXAMPLE 2 study of LPS/GalN-induced acute liver failure liver injury and systemic inflammation in mice with the Compounds ZJU-37 and Nec-1s
The experimental method comprises the following steps:
the animal model is a research tool for verifying whether a new therapeutic drug and a new therapeutic means are effective, and the currently internationally adopted animal models for simulating liver failure include drug-induced liver failure models (p-acetaminophen models, LPS/GalN models, thioacetamide models, carbon tetrachloride models and the like), acute liver ischemia models, partial hepatectomy models and the like. The LPS/GalN model has the advantages of good repeatability, unobvious extrahepatic toxicity, near-clinical hepatic injury performance and the like, and is an ideal hepatic failure animal model.
Male C57BL/6 mice (purchased from Nanjing Biopharmaceutical research institute) at six weeks of age were randomly divided into a normal control group, a model group (LPS/GalN group), a compound ZJU-37 treatment group (5mg/kg ZJU-37+ LPS/GalN group), and a compound Nec-1s treatment group (5mg/kg Nec-1s + LPS/GalN group). Intraperitoneal injection is carried out on the compounds ZJU-37 and Nec-1s, and LPS/GalN (40 mu g/kg LPS +800mg/kg D-GalN) is subjected to intraperitoneal injection molding after 30 minutes; the model group replaced the solvent of compound ZJU-37 with an equal volume of solvent; the normal control group was not treated. LPS/GalN modeling and eye ball picking method for 6 hours are adopted to take blood for biochemistry and CBA detection.
The experimental results are as follows:
the experimental results are shown in fig. 1: the graph A and the graph B show that the serum liver injury indexes ALT and AST levels of the LPS/GalN model group are obviously increased compared with those of a normal control group, the serum ALT and AST levels of a treatment group are obviously reduced, and the ALT and AST can be obviously improved by the compound ZJU-37 compared with commercial Nec-1 s. Serum ALT, AST can be reduced after Nec-1s treatment (LPS/GalN vs. Nec-1s:1053 + -107.7 vs.724.8 + -119.5). While ZJU-37 significantly reduced ALT (LPS/GalN vs. ZJU-37: 2110. + -. 307.2vs. 166. + -. 31.11) and AST (LPS/GalN vs. ZJU-37: 21053. + -. 107.7vs. 206.5. + -. 21.16) (FIG. A, B). We used CBA to measure the serum cytokine levels of each group. The results show that compound ZJU-37 reduces TNF α, IL-6, IFN- γ, MCP-1 production better than Nec-1s (FIGS. C-F). Also ZJU-37 can prolong mouse survival time compared to Nec-1s (FIG. G). The compound ZJU-37 or the commercialized Nec-1s with the same dose (5mg/kg) is administrated in the abdominal cavity 30 minutes before LPS/GalN modeling, and the compound ZJU-37 can obviously improve liver injury and general inflammation compared with the commercialized Nec-1 s.
Namely, compared with the Nec-1s, the compound ZJU-37 can better reduce liver injury of mice acute liver failure induced by LPS/GalN and improve systemic inflammation under the condition of the same dosage.
EXAMPLE 3 study of LPS/GalN-induced acute liver failure liver pathology and neutrophil infiltration in mice by Compounds ZJU-37 and Nec-1s
The experimental method comprises the following steps:
male C57BL/6 mice (purchased from Nanjing Biopharmaceutical research institute) at six weeks of age were randomly divided into a normal control group, a model group (LPS/GalN group), a compound ZJU-37 treatment group (5mg/kg ZJU-37+ LPS/GalN group), and a compound Nec-1s treatment group (5mg/kg Nec-1s + LPS/GalN group). Intraperitoneal injection is carried out on the compounds ZJU-37 and Nec-1s, and LPS/GalN (40 mu g/kg LPS +800mg/kg D-GalN) is subjected to intraperitoneal injection molding after 30 minutes; the model group replaced the solvent of compound ZJU-37 with an equal volume of solvent; the normal control group was not treated. LPS/GalN model 6 hours later, leave the liver specimen and carry on HE and immune histochemical staining.
The experimental results are as follows:
the experimental results are shown in fig. 2: the graphs A and B show an LPS/GalN model group, and the HE staining of liver tissues shows that the necrosis of the liver tissues and the infiltration of inflammatory cells are obvious. The degree of necrosis of liver tissues and infiltration of inflammatory cells were significantly reduced in the compound ZJU-37-treated group and the Nec-1 s-treated group, compared to the model group (panels C, D); particularly, the compound ZJU-37 has the best curative effect, and pathological sections of liver tissues of mice show that the liver tissues have no necrosis and less inflammatory cell infiltration. By immunohistochemistry on liver neutrophils by using Ly6G, the result is consistent with HE staining, and the liver tissue neutrophile infiltration is remarkably reduced in both the compound ZJU-37 treatment group and the Nec-1s treatment group compared with the model group; especially, the compound ZJU-37 has obvious curative effect, and pathological sections of liver tissues of mice show that the liver tissues have no neutrophil infiltration (figures E-H). Scale bar 50 uM.
Namely, the compound ZJU-37 can better improve liver pathology of acute liver failure of mice induced by LPS/GalN and reduce infiltration of neutrophils under the condition of the same dosage.
EXAMPLE 4 Compound ZJU-37 inhibits apoptosis in liver tissue of LPS/GalN model mouse
The experimental method comprises the following steps:
male C57BL/6 mice (purchased from Nanjing Biopharmaceutical research institute) at six weeks of age were randomly divided into a normal control group, a model group (LPS/GalN group), a compound ZJU-37 treatment group (5mg/kg ZJU-37+ LPS/GalN group), and a compound Nec-1s treatment group (5mg/kg Nec-1s + LPS/GalN group). Intraperitoneal injection is carried out on the compounds ZJU-37 and Nec-1s, and LPS/GalN (40 mu g/kg LPS +800mg/kg D-GalN) is subjected to intraperitoneal injection molding after 30 minutes; the model group replaced the solvent of compound ZJU-37 with an equal volume of solvent; the normal control group was not treated. Liver tissue was left to TUNEL stain 6 hours after LPS/GalN modeling.
The experimental results are as follows:
the experimental results are shown in fig. 3: the TUNEL positive cells in the LPS/D-GalN model group were significantly increased compared to the normal control group (panels A and B), while the normal control group had almost no TUNEL positive signal, indicating that a large number of liver cells were apoptotic in the model group. Expression of TUNEL was significantly down-regulated in the treatment group; especially, the compound ZJU-37 showed the best effect, and pathological liver tissue sections of mice showed that the TUNEL signal was hardly detected in liver tissues (panels C and D).
Namely, the compound ZJU-37 can better improve the liver cell death of mice acute liver failure induced by LPS/GalN. This may also be a potential mechanism for the difference in the potency of the two drugs.
The above examples are intended to illustrate the disclosed embodiments of the invention and are not to be construed as limiting the invention. In addition, various modifications of the methods and compositions set forth herein, as well as variations of the methods and compositions of the present invention, will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been specifically described in connection with various specific preferred embodiments thereof, it should be understood that the invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described embodiments which are obvious to those skilled in the art to which the invention pertains are intended to be covered by the scope of the present invention.
Claims (10)
1. The application of a compound ZJU-37 in the formula I in preparing a medicament for preventing and/or treating liver diseases.
2. Use according to claim 1, characterized in that: the liver disease is liver injury, hepatitis, liver failure, or liver tissue necrosis/apoptosis.
3. Use of compound ZJU-37 for the manufacture of a medicament for reducing ALT levels.
4. Use of compound ZJU-37 in the manufacture of a medicament for reducing AST levels.
5. Application of a compound ZJU-37 in preparing a medicine for relieving liver injury degree.
6. Application of a compound ZJU-37 in preparing a medicament for relieving liver inflammation.
7. Application of a compound ZJU-37 in preparing a medicine for reducing the degree of hepatic tissue necrosis.
8. Application of a compound ZJU-37 in preparing a medicine for reducing inflammatory cell infiltration.
9. Application of a compound ZJU-37 in preparing a medicament for inhibiting secretion of inflammatory factors.
10. Application of a compound ZJU-37 in preparing a medicine for inhibiting apoptosis and programmed necrosis of liver tissues.
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| CN202011063731.2A CN112263576A (en) | 2020-09-30 | 2020-09-30 | Application of compound ZJU-37 in preparation of drugs for preventing and/or treating liver diseases |
| PCT/CN2020/136273 WO2022068075A1 (en) | 2020-09-30 | 2020-12-14 | Application of compound zju-37 in preparation of drug for preventing and/or treating liver diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619619A (en) * | 2017-01-06 | 2017-05-10 | 浙江大学 | Application of compound HUBIN-1 in preparation of drug for preventing and/or treating liver inflammatory diseases |
| CN110759895A (en) * | 2018-07-25 | 2020-02-07 | 浙江大学 | Novel RIP1/RIP3 dual-target inhibitor and application thereof in treatment of multi-target disease with one drug |
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| AU2002363655A1 (en) * | 2001-11-14 | 2003-05-26 | Novartis Ag | Non-peptide somatostatin receptor ligands |
| EP1663184A2 (en) * | 2003-08-29 | 2006-06-07 | The Brigham And Women's Hospital, Inc. | Hydantoin derivatives as inhibitors of cellular necrosis |
| CN101674826A (en) * | 2005-12-20 | 2010-03-17 | 哈佛大学校长及研究员协会 | Chemical compound, screening and Therapeutic Method |
| SG11201704764PA (en) * | 2014-12-11 | 2017-07-28 | Harvard College | Inhibitors of cellular necrosis and related methods |
| CN108191835A (en) * | 2018-01-09 | 2018-06-22 | 中国药科大学 | It is a kind of novel to contain pyrrole ring and indoline structure RIP1 kinase inhibitors and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619619A (en) * | 2017-01-06 | 2017-05-10 | 浙江大学 | Application of compound HUBIN-1 in preparation of drug for preventing and/or treating liver inflammatory diseases |
| CN110759895A (en) * | 2018-07-25 | 2020-02-07 | 浙江大学 | Novel RIP1/RIP3 dual-target inhibitor and application thereof in treatment of multi-target disease with one drug |
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