Application of coelenterazine in preparation of medicine for treating heart-related diseases

Abstract

The invention discloses an application of coelenterazine or a salt thereof in medicine preparation, the compound is used for treating or preventing myocardial infarction, preferably myocardial infarction caused by insufficient blood supply, myocardial anoxia and myocardial excessive oxygen consumption caused by various reasons such as coronary atherosclerosis, arrhythmia and respiratory failure, and the compound can be used for treating or preventing myocardial infarction caused by myocardial anoxia and myocardial excessive oxygen consumption caused by various reasons such as coronary atherosclerosis, arrhythmia and respiratory failure. However, the medicine is not limited to the inducer, and specifically, the medicine can inhibit or improve various myocardial infarction.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to the use of a compound of formula (I) (codenamed CTZ) or a pharmaceutically acceptable salt thereof in the preparation of a compound for treating or preventing heart disease caused by acute diseases.

[0002] Background Art

[0003] Myocardial infarction is a life-threatening disease caused by acute obstruction of the coronary arteries, which leads to insufficient blood supply to the corresponding myocardial area and myocardial necrosis. The disease is mainly caused by multiple factors such as insufficient blood supply, myocardial hypoxia and excessive myocardial oxygen consumption caused by various reasons such as coronary atherosclerosis, arrhythmia, respiratory failure, etc. Under the stimulation of these risk factors, changes in cardiac systolic and diastolic function, myocardial tissue interstitial disorder, myocardial fibrosis and myocardial cell apoptosis seriously affect the patient's quality of life and even endanger his life. Summary of the invention

[0004] Based on many years of research on pharmacology and pathological mechanisms, the inventors have discovered that coelenterazine (CTZ) can effectively treat acute diseases such as acute coronary artery obstruction, insufficient blood supply to the heart, myocardial hypoxia, and myocardial excessive oxygen consumption, which are induced by multiple factors, and heart-related pathological changes can be significantly improved.

[0005] The object of the present invention is to provide a new use of coelenterazine (compound of formula (I), codenamed CTZ).

[0006] Specifically, the present invention provides the use of a compound of formula (I) (CTZ) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing myocardial infarction.

[0007]

[0008] Preferably, the use of the present invention is in the preparation of a medicament for improving myocardial infarction.

[0009] There are many factors that induce myocardial infarction. Any factors that induce thrombosis, intravascular plaque detachment, coronary artery spasm or stenosis can cause the disease. When the heart's own blood supply channels are blocked due to various reasons, the myocardium that has lost blood supply continues to work, oxygen consumption continues to increase, and then there is an imbalance between oxygen supply and oxygen demand, which can lead to myocardial necrosis. Considering the mechanism of disease occurrence, the present invention is mainly aimed at heart diseases caused by acute coronary artery obstruction, insufficient blood supply to the heart, myocardial hypoxia and excessive myocardial oxygen consumption, but is not limited to the above-mentioned pathogenic factors; most preferably, it is used to treat pathological changes in cardiac tissue under the state of myocardial infarction.

[0010] Preferably, in the use of the present invention, the main pathological features of myocardial infarction are changes in cardiac systolic and diastolic function, myocardial tissue interstitial disorder, myocardial fibrosis and myocardial cell apoptosis.

[0011] The changes in cardiac tissue function include changes in cardiac contraction and relaxation function, myocardial tissue interstitial disorder, myocardial fibrosis and myocardial cell apoptosis.

[0012] Preferably, in the use of the present invention, the compound of formula (I) (CTZ) or a salt thereof has no statistically significant effect on blood sugar, blood pressure or body weight.

[0013] The drug used in the present invention contains an effective dose of the compound of formula (I) (CTZ). The effective dose can be the content of the drug in a unit dosage form (such as a tablet, a needle, a pill or a dose), or it can be a unit dose (such as a unit body weight dose) of the patient to be treated / prevented. In the present invention, the effective dose (in terms of content) can be 10 μg-1g, preferably 0.1mg-500mg, and more preferably 1mg-100mg.

[0014] The drugs used in the present invention usually also contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier used refers to a non-toxic filler, stabilizer, diluent, adjuvant or other formulation excipient. For example, diluents, excipients, such as water, physiological saline, etc.; fillers, such as starch, sucrose, etc.; binders, such as cellulose derivatives, alginates, gelatin and / or polyvinyl pyrrolidone; wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate and / or sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants, such as hexadecanol; adsorption carriers, such as kaolin and / or soap clay; lubricants, such as talc, calcium / magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition of the present invention may further contain other excipients, such as flavoring agents, sweeteners, etc. According to the known technology in the art, the pharmaceutical composition can be prepared into various dosage forms according to the needs of the treatment purpose and the route of administration. Preferably, the composition is a unit dosage form, such as a lyophilized agent, a tablet, a capsule, a powder, an emulsion, an aqueous injection or a spray, and more preferably, the pharmaceutical composition is an injection form (such as a lyophilized powder injection) or an oral dosage form (such as a tablet, a capsule). The drug can be administered by conventional routes, particularly enteral, such as oral, such as in the form of a tablet or capsule, or parenteral, such as in the form of an injectable solution or suspension, topically, such as in the form of a lotion or gel, or in the form of a nasal agent or a test agent.

[0015] The present invention will be described in detail below through specific embodiments and drawings. It should be particularly pointed out that these descriptions are only partial exemplary descriptions and do not constitute a limitation on the scope of the present invention. According to the discussion of this specification, many changes and modifications of the present invention are obvious to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The compound of formula (I) (CTZ) has an alleviating effect on changes in cardiac tissue function in mice with myocardial infarction (MI).

[0017] Figure 2 The compound (CTZ) of formula (I) regulates the interstitial disorder of myocardial tissue in mice with myocardial infarction (MI).

[0018] Figure 3 The compound (CTZ) of formula (I) has an alleviating effect on myocardial fibrosis in mice with myocardial infarction (MI) and a down-regulating effect on the expression of myocardial tissue fibrosis genes.

[0019] Figure 4 The compound (CTZ) of formula (I) has an alleviating effect on myocardial cell apoptosis and a down-regulating effect on the expression of apoptosis genes in myocardial tissue in mice with myocardial infarction (MI). DETAILED DESCRIPTION

[0020] The present invention is further described in the following examples. These examples are only for the purpose of illustrating the present invention, but are not intended to limit the scope of the present invention.

[0021] Example 1 The compounds of the present invention can significantly improve the changes in cardiac tissue function caused by myocardial infarction.

[0022] C57BL / 6J mice were randomly divided into 5 groups (6 mice in each group), namely:

[0023] Sham group: healthy C57BL / 6J mice, whose hearts were exposed but without ligation of the left anterior descending coronary artery.

[0024] Myocardial infarction (MI) group: The left anterior descending branch of the coronary artery was ligated in C57BL / 6J mice to establish a myocardial infarction (MI) mouse model, and an equal volume of normal saline was intraperitoneally injected.

[0025] Compound treatment group (MI+CTZ 5 mg / kg or 10 mg / kg): One day before model establishment, mice were intraperitoneally injected with the compound of formula (I) (CTZ) at a dose of 5 mg / kg or 10 mg / kg, 4% DMSO+30% PEG 300+5% Tween 80+ddH2O suspension, followed by ligation of the left anterior descending coronary artery. After ligation, the mice were continued to be intraperitoneally injected with the compound of formula (I) (CTZ) for 7 consecutive days.

[0026] Positive control group (MI + SCH772984 5 mg / kg): The day before the model was established, mice were intraperitoneally injected with 5 mg / kg of SCH772984, 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% saline suspension, followed by ligation of the left anterior descending coronary artery. After ligation, mice were continued to be intraperitoneally injected with SCH772984 for 7 consecutive days.

[0027] The body weight of mice was monitored weekly and it was found that CTZ had no effect on body weight. Figure 1 A). Seven days after modeling, the mice were anesthetized with isoflurane and cardiac function was tested using a high-resolution small animal ultrasound imaging system. The results showed that cardiac function was significantly altered in the myocardial infarction state, which was alleviated by CTZ administration ( Figure 1 B). (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

[0028] Example 2 The compounds of the present invention can significantly improve the myocardial tissue interstitial disorder caused by myocardial infarction (MI).

[0029] Seven days after modeling, the mice were killed, and the heart tissues of the mice were fixed with 4% formalin, embedded in paraffin, and sliced ​​to 5 μm thickness, and then stained with hematoxylin & eosin (H&E) and wheat germ agglutinin (WGA) for microscopic examination. The results of H&E and WGA staining showed that myocardial infarction caused interstitial disorder in the myocardial tissue of mice, which was significantly alleviated by CTZ administration ( Figure 2 A). (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

[0030] Example 3 The compounds of the present invention can inhibit myocardial fibrosis and the expression of myocardial fibrosis genes in myocardial tissue of mice with myocardial infarction (MI).

[0031] Seven days after modeling, the mice were killed, and the heart tissues of the mice were fixed with 4% formalin, embedded in paraffin, and sliced ​​to 5 μm thickness for Masson staining and microscopic examination. The results of Masson staining showed that myocardial infarction (MI) can cause cardiac tissue fibrosis, which was significantly alleviated by CTZ administration ( Figure 3A). At the same time, we detected the expression of cardiac tissue fibrosis genes, and the results showed that myocardial infarction (MI) caused a significant upregulation of cardiac fibrosis genes, which was significantly alleviated by CTZ administration ( Figure 3 B). (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

[0032] Example 4 The compounds of the present invention can significantly inhibit myocardial cell apoptosis and the expression of myocardial tissue apoptosis genes caused by myocardial infarction (MI).

[0033] Seven days after modeling, the mice were killed, and the heart tissues were taken out, fixed with 4% formalin, embedded in paraffin, sliced ​​to 5 μm thickness, and then stained with Tunel and examined under a microscope. The results of Tunel staining showed that myocardial infarction (MI) caused apoptosis of heart tissue, which was significantly alleviated by CTZ administration ( Figure 4 A). At the same time, we detected the expression of apoptosis genes in cardiac tissues. The results showed that myocardial infarction (MI) caused a significant upregulation of cardiac apoptosis genes, which was significantly alleviated by CTZ administration ( Figure 4 B). (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

Claims

1. A use of coelenterazine in drug preparation, characterized in that: The drug is used to treat or prevent heart-related diseases; The structure of the coelenterazine is shown in formula (I): The active ingredient in the medicine comprises the coelenterazine or a pharmaceutically acceptable salt thereof.

2. The use of coelenterazine in drug preparation according to claim 1, characterized in that: The heart-related disease is myocardial infarction.

3. The use of coelenterazine in drug preparation according to claim 1 or 2, characterized in that: The heart-related diseases are changes in cardiac tissue function and cardiac pathological damage caused by myocardial infarction.

4. The use of coelenterazine in drug preparation according to claim 3, characterized in that: The changes in cardiac tissue function and cardiac pathological damage include changes in cardiac contraction and relaxation function, myocardial tissue interstitial disorder, myocardial fibrosis and myocardial cell apoptosis.

5. The use of coelenterazine in drug preparation according to claim 1, characterized in that: The heart-related diseases are caused by acute blockage of coronary arteries, insufficient blood supply to the heart, myocardial hypoxia and excessive myocardial oxygen consumption.

6. The use of coelenterazine according to any one of claim 1 in the preparation of a drug, characterized in that: The medicine also includes a pharmaceutically acceptable carrier.

Images