Use of coelenterazine in the preparation of a medicament for treating a heart-related disease

Abstract

The present application discloses the application of coelenterazine or its salt in the preparation of a medicament for treating or preventing myocardial infarction, preferably myocardial infarction caused by insufficient blood supply, myocardial hypoxia and myocardial excessive oxygen consumption due to various causes such as coronary atherosclerosis, arrhythmia, respiratory failure, but not limited to the above inducers. Specifically, the medicament can inhibit or improve various myocardial infarction.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the use of a compound of formula (I) (code name CTZ) or a pharmaceutically acceptable salt thereof in the preparation of a treatment or prevention of heart disease caused by acute illness.

[0002] Background Technology

[0003] Myocardial infarction is a life-threatening disease caused by acute obstruction of the coronary arteries, leading to insufficient blood supply to the corresponding myocardial region and resulting in myocardial necrosis. This disease is mainly caused by multiple factors, including insufficient blood supply, myocardial hypoxia, and excessive myocardial oxygen consumption, resulting from various causes such as coronary atherosclerosis, arrhythmia, and respiratory failure. Stimulated by these risk factors, cardiac systolic and diastolic function changes, myocardial interstitial disorder occurs, myocardial fibrosis develops, and cardiomyocytes undergo apoptosis, severely impacting the patient's quality of life and even endangering their life. Summary of the Invention

[0004] Based on years of pharmacological and pathological mechanism research, the inventors have discovered that coronary tin (CTZ) can effectively treat acute heart disease induced by multiple factors such as acute coronary artery obstruction, insufficient blood supply to the heart, myocardial hypoxia, and excessive myocardial oxygen consumption, and can significantly improve heart-related pathological changes.

[0005] The purpose of this invention is to provide new uses for coelenterin (a compound of formula (I), coded 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 the treatment or prevention of myocardial infarction.

[0007]

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

[0009] Myocardial infarction has many precipitating factors; any factor that induces thrombus formation, plaque detachment from blood vessels, coronary artery spasm, or stenosis can cause the disease. When the heart's own blood supply channels are blocked for various reasons, the myocardium, deprived of blood supply, continues to function, leading to a continuous increase in oxygen consumption and an imbalance between oxygen supply and demand, which can result in myocardial necrosis. Considering the disease pathogenesis, this invention primarily targets 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 aforementioned precipitating factors; most preferably, it is used to treat pathological changes in cardiac tissue during 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 interstitial disorder, myocardial fibrosis, and cardiomyocyte apoptosis.

[0011] The aforementioned changes in cardiac tissue function include alterations in cardiac systolic and diastolic function, myocardial interstitial disorder, myocardial fibrosis, and cardiomyocyte apoptosis.

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

[0013] The medicament used in this invention contains an effective dose of a compound of formula (I) (CTZ). The effective dose can be the content in a unit dose form (e.g., a tablet, injection, pill, or injection), or it can be a unit dose (e.g., a dose per unit body weight) for the patient requiring treatment / prevention. In this invention, the effective dose (in terms of content) can be 10 μg to 1 g, preferably 0.1 mg to 500 mg, more preferably 1 mg to 100 mg.

[0014] The pharmaceutical compositions used in this invention typically also contain pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers refer to non-toxic fillers, stabilizers, diluents, adjuvants, or other pharmaceutical excipients. Examples include diluents and excipients such as water and physiological saline; fillers such as starch and sucrose; binders such as cellulose derivatives, alginate, gelatin, and / or polyvinylpyrrolidone; humectants such as glycerin; disintegrants such as agar, calcium carbonate, and / or sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as hexadecyl alcohol; adsorbent carriers such as kaolin and / or soap clay; and lubricants such as talc, calcium / magnesium stearate, and polyethylene glycol. Furthermore, the pharmaceutical compositions of this invention may further contain other excipients, such as flavoring agents and sweeteners. According to known techniques in the art, pharmaceutical compositions can be formulated into various dosage forms according to the therapeutic purpose and route of administration. Preferably, the composition is in a unit dosage form, such as a lyophilized form, tablet, capsule, powder, emulsion, injection, or spray. More preferably, the pharmaceutical composition is in an injectable dosage form (e.g., lyophilized powder for injection) or an oral dosage form (e.g., tablet, capsule). The drug can be administered via conventional routes, particularly enterically, such as orally, in tablet or capsule form, or parenterally, such as in injectable solutions or suspensions, topically, such as in lotions or gels, or in nasal or diagnostic forms.

[0015] The present invention will now be described in detail with reference to specific embodiments and accompanying drawings. It should be particularly noted that these descriptions are merely illustrative and do not constitute a limitation on the scope of the invention. Many variations and modifications of the invention will be apparent to those skilled in the art based on the discussion herein. Attached Figure Description

[0016] Figure 1 The compound (CTZ) of formula (I) is shown to alleviate the changes in cardiac tissue function in mice with myocardial infarction (MI).

[0017] Figure 2 The regulatory effect of compound (CTZ) of formula (I) on myocardial interstitial disorder in mice with myocardial infarction (MI).

[0018] Figure 3 The compound (CTZ) of formula (I) alleviates myocardial fibrosis in mice with myocardial infarction (MI) and downregulates the expression of myocardial fibrosis genes.

[0019] Figure 4 The compound (CTZ) of formula (I) alleviates apoptosis of cardiomyocytes and downregulates the expression of apoptosis genes in myocardial tissue in mice with myocardial infarction (MI). Detailed Implementation

[0020] The present invention is further illustrated in the following embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

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

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

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

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

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

[0026] Positive control group (MI+SCH772984 5mg / kg): Mice were intraperitoneally injected with SCH772984 at a dose of 5mg / kg one day before model establishment. The suspension consisted of 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% saline. Subsequently, the left anterior descending coronary artery was ligated. After ligation, mice were continuously injected intraperitoneally with SCH772984 for 7 consecutive days.

[0027] Weekly monitoring of mouse body weight revealed that CTZ had no effect on body weight. Figure 1 A). Seven days after modeling, mice were anesthetized with isoflurane, and cardiac function was assessed using a high-resolution small animal ultrasound imaging system. Results showed significant changes in cardiac function during myocardial infarction, which were 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 to the model group).

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

[0029] Seven days after modeling, mice were sacrificed, and their heart tissue was collected. The tissue was fixed in 4% formalin, embedded in paraffin, sectioned to a thickness of 5 μm, and stained with hematoxylin and eosin (H&E) and wheat germ agglutinin (WGA) for microscopic examination. H&E and WGA staining results showed that myocardial infarction caused interstitial disorder in the mouse myocardial tissue, 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 to the model group).

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

[0031] Seven days after modeling, mice were sacrificed, and heart tissue was collected. The tissue was fixed in 4% formalin, embedded in paraffin, sectioned to a thickness of 5 μm, stained with Masson's solution, and examined microscopically. Masson staining results showed that myocardial infarction (MI) can cause cardiac tissue fibrosis, and CTZ treatment significantly alleviated this condition. Figure 3A). Simultaneously, we examined the expression of cardiac fibrosis genes, and the results showed that myocardial infarction (MI) significantly upregulated these genes, and CTZ administration provided significant relief. 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 to 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 induced by myocardial infarction (MI).

[0033] Seven days after modeling, mice were sacrificed, and heart tissue was harvested, fixed in 4% formalin, embedded in paraffin, sectioned to a thickness of 5 μm, and then subjected to Tunel staining and microscopic examination. Tunel staining results showed that myocardial infarction (MI) induced cardiac tissue apoptosis, which was significantly alleviated by CTZ administration. Figure 4 A). Simultaneously, we examined the expression of apoptosis genes in cardiac tissue, and the results showed that myocardial infarction (MI) significantly upregulated cardiac apoptosis genes, and administration of CTZ provided significant relief. 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 to the model group).

Claims

1. The application of a coelenterate in drug preparation, characterized in that, The aforementioned medication is used to treat or prevent heart-related diseases; The structure of the coelenterate is shown in formula (I): ； The active ingredient in the drug comprises the coelenterin or a pharmaceutically available salt thereof; The heart-related disease mentioned is myocardial infarction.

2. The application of coelenterate in drug preparation according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable carriers.

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