CN112294815A - Application of compound BAY-876 in preparation of medicine for treating and/or preventing liver injury - Google Patents
Application of compound BAY-876 in preparation of medicine for treating and/or preventing liver injury Download PDFInfo
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- CN112294815A CN112294815A CN202011001796.4A CN202011001796A CN112294815A CN 112294815 A CN112294815 A CN 112294815A CN 202011001796 A CN202011001796 A CN 202011001796A CN 112294815 A CN112294815 A CN 112294815A
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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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]
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Abstract
The invention discloses application of a compound BAY-876 in preparing a medicine for treating and/or preventing liver injury, which can be prepared into a novel liver-protecting medicine. The invention carries out a large amount of experimental researches, and uses Lipopolysaccharide (LPS)/D-Galactosamine (D-Galactosamine, D-Gal) to establish a mouse model of acute liver injury. Research results show that the compound BAY-876 can obviously reduce the levels of glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase in plasma of mice with liver injury, reduce the levels of inflammatory factors such as TNF-alpha and IL-6 and the like, obviously improve liver tissue injury, reduce liver cell apoptosis and have obvious effect of preventing and treating liver injury. The invention provides a new candidate drug BAY-876 for treating liver injury.
Description
Technical Field
The invention relates to application of a compound BAY-876 in preparation of a medicine for treating and/or preventing liver injury, and belongs to the technical field of medicines.
Background
The liver is an important metabolic organ of the human body and plays an important physiological role. Acute liver injury can be caused by various reasons such as viruses, medicines, poisons, alcohol and the like, and serious patients can cause liver failure and induce multi-organ dysfunction and even death. The mechanism of acute liver injury is considered to be closely related to immune imbalance, and a large amount of proinflammatory factors secreted by activated kupffer cells, such as tumor necrosis factor-alpha (TNF-alpha), Interleukin-6 (Interleukin6, IL-6) induced liver cell massive necrosis and apoptosis, are the main pathogenic mechanisms for the development of diseases.
At present, although the medicines such as compound glycyrrhizin, bicyclol tablets and the like have certain effects clinically, specific treatment medicines are lacked, so that the research and development of medicines for treating liver injury are urgently needed.
Disclosure of Invention
The invention mainly aims to provide application of BAY-876 in preparing a medicament for preventing/treating liver injury. The chemical structural formula of the compound BAY-876 is as follows:
having a chemical formula of C24H16F4N6O2Molecular weight is 496.42;
the compounds are inhibitors of glucose transporter 1; the search shows that no medical application of the compound BAY-876 in preventing and treating liver injury exists at present.
Preferably, the liver injury of the present invention is acute liver injury.
Preferably, the medicament also comprises a pharmaceutically acceptable carrier.
Preferably, the pharmaceutically acceptable carrier is selected from the group consisting of: diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier and lubricant.
Preferably, BAY-876, its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer or said medicament, is formulated into tablet, powder, pill, injection, capsule, film, suppository, paste or granule.
Compared with the background technology, the technical scheme has the following advantages:
the results of the invention show that the compound BAY-876 can obviously reduce the levels of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) in the plasma of mice with liver injury, reduce the levels of inflammatory factors such as TNF-alpha and IL-6, obviously improve the liver tissue injury, reduce the liver cell apoptosis and have the obvious effect of preventing and treating the liver injury.
Drawings
The invention is further illustrated by the following figures and examples.
FIG. 1 is a graph showing the effect of BAY-876 on transaminase levels in liver-injured mice.
FIG. 2 shows the effect of inflammatory factors in BAY-876 liver injury mice.
FIG. 3 shows the effect of BAY-876 on liver histopathology in liver-injured mice.
FIG. 4 shows the effect of BAY-876 on the apoptosis of hepatocytes of liver-injured mice.
Detailed Description
1. Experimental Material
1.1 drugs and reagents for experiments
BAY-876 was purchased from Selleckchem.
1.2 Experimental animals and raising
Male C57BL/6 mice, 18-22g, male, supplied by Shanghai Jihui laboratory animals Breeding Co., Ltd., certification number: 20170012002547. feeding conditions are as follows: room temperature 20 + -2 deg.C, humidity 50% + -5%, alternate light and shade, moderate illumination, good ventilation, and free drinking and eating.
2. Method of producing a composite material
2.1 acute liver injury mouse model modeling method
A C57BL/6 mouse was pre-housed for a week and the acute liver injury mouse model was replicated by intraperitoneal injection of Lipopolysaccharides (LPS)/D-Galactosamine (D-Galactosamine).
2.2 Experimental groups
24 mice, C57, were randomly divided into 3 groups of 8 mice each. The test results are respectively a normal control group, a model group and a BAY-876 intervention group. The model group and BAY-876 intervention group were modeled with LPS (10. mu.g/kg) and D-Gal (700 mg/kg). Peanut oil (containing 1% dimethyl sulfoxide) is administered to the normal control group and the model group; BAY-8760.1 mg/kg dissolved in peanut oil (containing 1% dimethyl sulfoxide) was injected intraperitoneally 0.5h before molding by the above method. Mice were sacrificed at the end of the experiment and blood and liver tissue were left for use.
2.3 Biochemical detection of plasma
Plasma of mice was taken and ALT and AST levels were detected using a commercial kit.
2.4 inflammatory factor detection
Mouse plasma was taken and TNF-. alpha.and IL-6 levels in plasma were measured using ELISA kit.
2.5 HE staining of liver tissue
Mouse liver tissue specimens were fixed in 4% paraformaldehyde, embedded in paraffin, and sectioned. Pathological changes of liver tissues were observed by 200-fold optical microscope using hematoxylin-eosin staining.
2.6 TUNEL method apoptosis assay: paraffin sections of liver tissue were stained according to the procedure described in the TUNEL kit. After staining, the cell nucleus is brownish (brown) and is apoptotic cell, 20 visual fields are randomly selected under a high power lens to count the number of the apoptotic cell.
3. Statistical analysis
Data mining
Expressed as t-test or one-way anova, p<A difference of 0.05 is statistically significant.
4. Results of the experiment
4.1 Effect of BAY-876 on transaminase levels in liver-injured mice.
The transaminase level can directly reflect the severity of acute liver injury, and compared with a normal control group, the ALT and AST levels of the mouse plasma of the model group are obviously increased, and the difference is significant; ALT and AST levels were significantly reduced in the BAY-876 intervention group compared to the model group. BAY-876 significantly reduced plasma transaminase levels in mice with acute liver injury (see FIG. 1).
4.2 the effects of inflammatory factors in BAY-876 liver injury mice.
After LPS/D-Gal treatment, the plasma TNF-alpha and IL-6 levels of the model mice were significantly higher than those of the normal control group. BAY-876 intervenes in the group with significantly lower plasma TNF-alpha and IL-6 levels than in the model group. BAY-876 remarkably inhibits the production of TNF-alpha and IL-6 inflammatory factors in mice with acute liver injury (as shown in figure 2).
4.3 the effect of BAY-876 on the liver histopathology in liver-injured mice.
The morphological results of the liver tissue sections of the mice in the model group show that: hepatic lobule structure destruction, liver congestion, bleeding, massive hepatocyte degeneration, necrosis with inflammatory cell infiltration in mice. BAY-876 can obviously reduce pathological changes such as liver congestion and hepatocyte necrosis of mice with acute liver injury. BAY-876 can obviously reduce the liver histomorphology abnormality of mice with acute liver injury (as shown in figure 3).
4.4 the effect of BAY-876 on the apoptosis of hepatocytes of liver-injured mice.
The liver tissue apoptotic cells of the model group mice are obviously increased compared with those of the normal control group; following administration of BAY-876, the number of apoptotic cells was significantly reduced. BAY-876 significantly reduced hepatocyte apoptosis in mice with acute liver injury (see FIG. 4).
Animal models of acute liver injury, established using the LPS/D-Gal combination, have been used as a mature model for studying the mechanisms of clinical liver disease and for evaluating the effects of hepatoprotectors. The pharmacodynamic test results show that the compound BAY-876 can obviously reduce the level of transaminase in plasma of a model mouse, obviously relieve pathological damage of liver tissues, obviously inhibit the levels of TNF-alpha and IL-6 inflammatory factors and relieve the apoptosis of liver cells induced by LPS/D-Gal. The experimental research result proves that the compound BAY-876 has good effect of preventing and treating liver injury.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the present invention is not limited thereto, and equivalent changes and modifications made according to the spirit of the present invention should be covered thereby.
Claims (5)
1. The application of the compound BAY-876 in preparing the medicine for treating and/or preventing liver injury, wherein the chemical structural formula of the compound BAY-876 is as follows:
2. use according to claim 1, characterized in that: the liver injury is acute liver injury.
3. Use according to claim 1 or 2, characterized in that: the medicine also comprises a pharmaceutically acceptable carrier.
4. Use according to claim 3, characterized in that: the pharmaceutically acceptable carrier is selected from the group consisting of: diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier and lubricant.
5. Use according to claim 1 or 2, characterized in that: BAY-876, pharmaceutically acceptable salt, solvate, stereoisomer, tautomer or the above medicine, and making into tablet, powder, pill, injection, capsule, pellicle, suppository, unguent or granule.
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| CN202011001796.4A CN112294815B (en) | 2020-09-22 | 2020-09-22 | Application of compound BAY-876 in preparation of medicine for treating and/or preventing liver injury |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115364224A (en) * | 2022-08-25 | 2022-11-22 | 杭州天玑济世生物科技有限公司 | Use of GLUT1 inhibitors as inducers of mitophagy |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106029647A (en) * | 2013-12-20 | 2016-10-12 | 拜耳制药股份公司 | Glucose transport inhibitors |
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- 2020-09-22 CN CN202011001796.4A patent/CN112294815B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106029647A (en) * | 2013-12-20 | 2016-10-12 | 拜耳制药股份公司 | Glucose transport inhibitors |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115364224A (en) * | 2022-08-25 | 2022-11-22 | 杭州天玑济世生物科技有限公司 | Use of GLUT1 inhibitors as inducers of mitophagy |
| CN115364224B (en) * | 2022-08-25 | 2024-02-02 | 杭州天玑济世生物科技有限公司 | Use of GLUT1 inhibitors as mitochondrial autophagy inducers |
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| CN112294815B (en) | 2021-08-31 |
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