Angiotensin-converting enzyme inhibitors

Abstract

To provide a novel angiotensin-converting enzyme inhibitor.SOLUTION: An angiotensin-converting enzyme inhibitor contains at least one selected from the group consisting of an aliphatic carboxylic acid and a salt thereof as an active ingredient. In the angiotensin-converting enzyme inhibitor, the aliphatic carboxylic acid is an aliphatic hydroxy acid. In the angiotensin-converting enzyme inhibitor, the aliphatic hydroxy acid is at least one selected from lactic acid, malic acid and citric acid.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to angiotensin-converting enzyme inhibitors. [Background technology]

[0002] In recent years, the increase in lifestyle-related diseases such as hypertension caused by diet, lack of exercise, mental stress, smoking, genetic factors, etc. has become a problem.

[0003] Drugs used to treat hypertension include calcium (Ca) antagonists, which lower blood pressure by dilating blood vessels; angiotensin-converting enzyme (ACE) inhibitors, which lower blood pressure by suppressing the production of angiotensin II, which has a blood pressure-raising effect; and angiotensin receptor blockers (ARBs), which lower blood pressure by inhibiting the binding of angiotensin II to receptors (e.g., angiotensin II Type 1 receptors). There are various mechanisms of action for treating hypertension.

[0004] As a composition that suppresses the production of angiotensin II, for example, Patent Document 1 describes an angiotensin-converting enzyme inhibitor that contains as an active ingredient a compound having specific physicochemical properties and a basic skeleton of a substance having a structure having a furan ring and a hydroxyl group. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2018-16618 A Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have found that aliphatic carboxylic acids have angiotensin-converting enzyme inhibitory activity. The present invention is based on this novel finding and has an object to provide a novel angiotensin-converting enzyme inhibitor. [Means for solving the problem]

[0007] The present invention relates to an angiotensin-converting enzyme inhibitor containing, as an active ingredient, at least one member selected from the group consisting of aliphatic carboxylic acids and salts thereof.

[0008] The angiotensin-converting enzyme inhibitor contains at least one selected from the group consisting of aliphatic carboxylic acids and salts thereof as an active ingredient, and therefore exhibits angiotensin-converting enzyme inhibitory action.

[0009] In one embodiment, the aliphatic carboxylic acid may be an aliphatic hydroxy acid, which provides a more excellent angiotensin converting enzyme inhibitory effect.

[0010] In one embodiment, the aliphatic hydroxy acid may be at least one selected from the group consisting of lactic acid, malic acid, and citric acid, which provides a more excellent angiotensin converting enzyme inhibitory effect.

[0011] In one embodiment, the angiotensin converting enzyme inhibitor may be an antihypertensive agent.

[0012] In one embodiment, the angiotensin converting enzyme inhibitor may be an inflammatory response suppressant.

[0013] In one embodiment, the angiotensin converting enzyme inhibitor may be an organ protective agent.

[0014] The present invention also relates to a food or drink composition for inhibiting angiotensin-converting enzyme, which contains, as an active ingredient, at least one member selected from the group consisting of aliphatic carboxylic acids and salts thereof. Effect of the Invention

[0015] According to the present invention, a novel angiotensin-converting enzyme inhibitor can be provided. [Brief description of the drawings]

[0016] [Figure 1] 1 is a graph showing the results of measuring the fluorescence intensity of fluorescent metabolites when malic acid is used as the aliphatic carboxylic acid. [Diagram 2] 1 is a graph showing the results of measuring the fluorescence intensity of fluorescent metabolites when citric acid is used as the aliphatic carboxylic acid. [Diagram 3] 1 is a graph showing the results of calculating the ACE inhibitory activity rate when malic acid or citric acid is used as the aliphatic carboxylic acid. [Figure 4] 1 is a graph showing the results of calculating the ACE inhibitory activity rate when lactic acid is used as the aliphatic carboxylic acid. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Hereinafter, an embodiment of the present invention will be described in detail. Note that the present invention is not limited to the following embodiment.

[0018] The angiotensin-converting enzyme inhibitor according to this embodiment contains at least one selected from the group consisting of aliphatic carboxylic acids and salts thereof as an active ingredient.

[0019] (Active ingredient) The active ingredient of the angiotensin-converting enzyme inhibitor according to this embodiment is at least one selected from the group consisting of aliphatic carboxylic acids and salts thereof.

[0020] An aliphatic carboxylic acid is a carboxylic acid having an aliphatic group. The aliphatic carboxylic acid may be an aliphatic carboxylic acid (fatty acid) having one carboxy group or an aliphatic carboxylic acid having two or more carboxy groups.

[0021] The fatty acid may be a saturated fatty acid or an unsaturated fatty acid. The unsaturated fatty acid may be a fatty acid having one unsaturated bond (monounsaturated fatty acid) or a fatty acid having two or more unsaturated bonds (polyunsaturated fatty acid). The number of unsaturated bonds (double bonds) in the unsaturated fatty acid may be, for example, 1 to 10, 1 to 8, or 1 to 5. The unsaturated bonds in the unsaturated fatty acid may be either trans or cis.

[0022] The fatty acid may be linear or branched. The number of carbon atoms of the fatty acid may be, for example, 1 to 15, and from the viewpoint of angiotensin converting enzyme inhibitory activity, it is preferably 2 to 10, and more preferably 3 to 6. The fatty acid may have a functional group such as a hydroxyl group, an amino group, or a carbonyl group in addition to a carboxyl group, and from the viewpoint of angiotensin converting enzyme inhibitory activity, it preferably has a hydroxyl group. Specific examples of the fatty acid include lactic acid.

[0023] The aliphatic carboxylic acid having two or more carboxy groups may be a saturated aliphatic carboxylic acid or an unsaturated aliphatic carboxylic acid. The unsaturated aliphatic carboxylic acid may be an aliphatic carboxylic acid having one unsaturated bond (monounsaturated aliphatic carboxylic acid) or a fatty acid having two or more unsaturated bonds (polyunsaturated aliphatic carboxylic acid). The number of unsaturated bonds (double bonds) in the unsaturated aliphatic carboxylic acid may be, for example, 1 to 10, 1 to 8, or 1 to 5. The unsaturated bonds in the unsaturated aliphatic carboxylic acid may be either trans or cis.

[0024] The aliphatic carboxylic acid having two or more carboxy groups may be, for example, an aliphatic carboxylic acid having 2 to 5 carboxy groups, and is preferably an aliphatic carboxylic acid having two or three carboxy groups from the viewpoint of angiotensin converting enzyme inhibitory activity. The aliphatic carboxylic acid having two or more carboxy groups may be linear or branched. The number of carbon atoms of the aliphatic carboxylic acid having two or more carboxy groups may be, for example, 2 to 15, and is preferably 2 to 10, more preferably 3 to 6, from the viewpoint of angiotensin converting enzyme inhibitory activity. The aliphatic carboxylic acid having two or more carboxy groups may have a functional group such as a hydroxy group, an amino group, or a carbonyl group in addition to the carboxy group, and is preferably a hydroxy group from the viewpoint of angiotensin converting enzyme inhibitory activity. Specific examples of the aliphatic carboxylic acid having two or more carboxy groups include malic acid and citric acid.

[0025] As described above, the aliphatic carboxylic acid may have a functional group such as a hydroxy group, an amino group, or a carbonyl group in addition to a carboxy group, and preferably has a hydroxy group from the viewpoint of angiotensin converting enzyme inhibitory activity. That is, the aliphatic carboxylic acid is preferably an aliphatic hydroxy acid from the viewpoint of angiotensin converting enzyme inhibitory activity. Examples of the aliphatic hydroxy acid include glycolic acid, hydroxybutyric acid, glyceric acid, tartaric acid, lactic acid, malic acid, and citric acid, and from the viewpoint of angiotensin converting enzyme inhibitory activity, lactic acid, malic acid, and citric acid are preferred. The aliphatic carboxylic acid may be one type alone or a mixture of two or more types.

[0026] The salt of the aliphatic carboxylic acid is not particularly limited as long as it is acceptable for use as a food or drink, a quasi-drug, or a pharmaceutical. Specific examples of the salt of the aliphatic carboxylic acid include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as magnesium salt and calcium salt. The salt of the aliphatic carboxylic acid may be a hydrate.

[0027] The angiotensin-converting enzyme inhibitor according to this embodiment may contain, as an active ingredient, one kind of aliphatic carboxylic acid or a salt thereof, or may contain two or more kinds of aliphatic carboxylic acids or salts thereof.

[0028] The angiotensin converting enzyme inhibitor according to the present embodiment has an angiotensin converting enzyme inhibitory effect. Angiotensin converting enzyme (ACE, also called ACEI or ACE1) converts angiotensin I to angiotensin II. Angiotensin II binds to angiotensin II Type 1 receptor (AT1R) to activate the signal of AT1R. AT1R is a G protein-coupled receptor present in blood vessels, liver, kidney, adrenal cortex, etc.

[0029] Angiotensin II binds to AT1R and releases Ca into the cytoplasm. 2+ This causes blood vessels to constrict and blood pressure to rise. Therefore, by inhibiting angiotensin converting enzyme and suppressing the production of angiotensin II, it is possible to suppress the rise in blood pressure. In this case, the angiotensin converting enzyme inhibitor according to the present embodiment can also be called a blood pressure rise suppressant.

[0030] When angiotensin II is received by AT1R in vascular endothelial cells, an inflammatory response is induced through an increase in ROS (reactive oxygen species), induction of chemokine expression, and promotion of release of inflammatory cytokines. Therefore, by inhibiting angiotensin converting enzyme and suppressing the production of angiotensin II, the inflammatory response can be suppressed. In this case, the angiotensin converting enzyme inhibitor according to the present embodiment can also be called an inflammatory response suppressant.

[0031] Angiotensin II binds to AT1R in kidney tissue, thereby increasing intraglomerular pressure, thereby causing an increase in proteinuria and / or an increase in glomerular filtration rate. Therefore, by inhibiting angiotensin converting enzyme and suppressing the production of angiotensin II, an increase in proteinuria and / or an increase in glomerular filtration rate can be suppressed. In addition, angiotensin II acts on the adrenal gland, promotes the secretion of aldosterone, and causes cardiac hypertrophy. Therefore, by inhibiting angiotensin converting enzyme and suppressing the production of angiotensin II, cardiac hypertrophy can be suppressed. In these cases, the angiotensin converting enzyme inhibitor according to this embodiment can be called an organ protecting agent, since it protects organs such as the kidney and the heart.

[0032] The content of the active ingredient in the angiotensin-converting enzyme inhibitor according to this embodiment can be appropriately set depending on the specific aspect (eg, form, usage, dosage, etc.) of the angiotensin-converting enzyme inhibitor.

[0033] When the angiotensin converting enzyme inhibitor according to the present embodiment is orally administered (ingested), the oral administration (ingestion) amount per day may be, for example, 600mg or more, 650mg or more, 700mg or more, 750mg or more, 800mg or more, 850mg or more, 900mg or more, 950mg or more, or 1000mg or more. From the viewpoint of angiotensin converting enzyme inhibitory action, there is no particular limit to the upper limit of the oral administration (ingestion) amount per day described above, but from the viewpoint of reducing the manufacturing cost, it may be, for example, 20000mg or less, 15000mg or less, 10000mg or less, 8000mg or less, or 6000mg or less. In addition, the oral administration (ingestion) amount per day is preferably an amount per 60kg-body weight.

[0034] For example, when the angiotensin-converting enzyme inhibitor of this embodiment is used to be orally administered (ingested) three times per day, if the angiotensin-converting enzyme inhibitor contains 200 mg or more of active ingredient, the oral administration (ingestion) amount per day will be 600 mg or more.

[0035] The content of the active ingredient in the angiotensin converting enzyme inhibitor according to this embodiment is appropriately set according to the specific aspect of the angiotensin converting enzyme inhibitor (for example, form, usage and dosage, etc.), but in one aspect, the content of the active ingredient in the angiotensin converting enzyme inhibitor according to this embodiment may be, for example, 600mg or more, 650mg or more, 700mg or more, 750mg or more, 800mg or more, 850mg or more, 900mg or more, 950mg or more, or 1000mg or more based on the total amount of the angiotensin converting enzyme inhibitor. This makes it possible to easily achieve the above-mentioned daily oral administration (oral intake) amount. The upper limit of the content of the active ingredient in the angiotensin converting enzyme inhibitor according to this embodiment may be, for example, 20000mg or less, 15000mg or less, 10000mg or less, 8000mg or less, or 6000mg or less.

[0036] The angiotensin converting enzyme inhibitor according to the present embodiment may be administered orally (ingested orally) or parenterally, but is preferably administered orally (ingested orally). The angiotensin converting enzyme inhibitor may be administered (ingested) once a day, or may be administered (ingested) in multiple doses a day.

[0037] The angiotensin-converting enzyme inhibitor according to this embodiment may be administered (ingested) to humans or non-human mammals.

[0038] (Other ingredients) The angiotensin-converting enzyme inhibitor of this embodiment may consist only of the above-mentioned active ingredient, or, depending on the specific form of the angiotensin-converting enzyme inhibitor, may contain, in addition to the above-mentioned active ingredient, other ingredients acceptable for use in foods and beverages, quasi-drugs, or pharmaceuticals.

[0039] (Angiotensin-converting enzyme inhibitor form) The angiotensin converting enzyme inhibitor according to the present embodiment may be in any form, such as a solid, a liquid (including a solution and a suspension), a paste, etc. In addition, the angiotensin converting enzyme inhibitor according to the present embodiment may be in any form, such as a tablet (orally disintegrating tablet, chewable tablet, film-coated tablet, etc.), a capsule, a powder, a granule, a liquid (syrup, jelly, etc.), an ointment, a plaster, etc.

[0040] Specific Embodiments of Angiotensin-Converting Enzyme Inhibitors The angiotensin converting enzyme inhibitor according to the present embodiment can be prepared, for example, as a food and drink composition (beverage and food), a quasi-drug, or a pharmaceutical. Examples of beverages include water, soft drinks, fruit juice drinks, carbonated drinks, milk drinks, alcoholic drinks, sports drinks, and nutritional drinks. Examples of foods include bread, noodles, rice, tofu, dairy products, soy sauce, miso, and confectionery. Examples of food and drink compositions include health foods, functional foods, special purpose foods, nutritional supplements, supplements, and foods for specified health uses.

[0041] The angiotensin converting enzyme inhibitor according to the present embodiment is preferably a food and drink composition (angiotensin converting enzyme inhibiting food and drink composition) because it can be easily taken on a daily basis. The form of the angiotensin converting enzyme inhibiting food and drink composition according to the present embodiment can be any of those described above, and is preferably a beverage (angiotensin converting enzyme inhibiting beverage) because it can be easily taken on a daily basis.

[0042] (Method of manufacturing angiotensin-converting enzyme inhibitors) The angiotensin converting enzyme inhibitor according to the present embodiment can be obtained by blending, for example, the above-mentioned active ingredients according to the specific embodiment. In this case, as the active ingredients, the aliphatic carboxylic acid or its salt, the aliphatic carboxylic acid or its salt itself may be used, or a composition containing the aliphatic carboxylic acid or its salt (for example, fruit juice such as lemon juice, grapefruit juice, orange juice, mandarin orange juice, plum juice, apple juice, strawberry juice, pear juice, or processed products such as yogurt, cheese, and sake) may be used.

[0043] (Action and effect) The angiotensin-converting enzyme inhibitor of this embodiment contains at least one selected from the group consisting of aliphatic carboxylic acids and their salts as an active ingredient, and by administering (ingesting) the angiotensin-converting enzyme inhibitor, it is possible to suppress blood pressure rise, suppress inflammatory responses, and protect organs. EXAMPLES

[0044] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to the following examples.

[0045] <Test Example 1: Evaluation of angiotensin-converting enzyme inhibitory effect 1> The angiotensin-converting enzyme (ACE) inhibitory effect of malic acid was evaluated. The ACE inhibitory activity in Test Example 1 and Test Example 2 described below was measured with reference to the method described in a non-patent document (Biomedical Research: 2011, Vol. 6, p. 407-411).

[0046] Specifically, 100 mM HEPES solution (pH 7.5), 300 mM NaCl, 60 μM fluorescent substrate (Nma-Phe-His-Lys(Dnp)), 2.5 μM ZnCl2, 6 mU / mL rabbit lung-derived ACE, 0.02% Tween20, 0.02% NaN3, and an aliphatic carboxylic acid solution (malic acid solution) were added to a final volume of 50 uL, and the mixture was incubated at 37°C for 80 minutes while measuring the fluorescence intensity of the reaction product every 5 minutes. The final concentrations of the malic acid solution were 7.46, 14.9, 22.4, 29.8, and 37.3 mM.

[0047] The fluorescence intensity of the fluorescent metabolites generated by the decomposition of the fluorescent substrate by ACE was measured using a fluorescence plate reader (Ex: 340 nm, Em: 440 nm). The results are shown in Figure 1. In Figure 1, the CNTs are shown when an equal amount of ultrapure water was added instead of the aliphatic carboxylic acid solution.

[0048] The difference between the fluorescence intensity 5 minutes after the start of the reaction and the fluorescence intensity 25 minutes after the start of the reaction was calculated as the amount of change in fluorescence intensity. The amount of change in fluorescence intensity at each concentration of the aliphatic carboxylic acid solution compared to the amount of change in fluorescence intensity when the reaction was carried out without the addition of the aliphatic carboxylic acid solution was taken as the relative activity [%]. The ACE activity inhibition rate [%] was calculated by subtracting the value of the relative activity from 100%. The results are shown in Table 1 and Figure 3.

[0049] [Table 1]

[0050] The angiotensin-converting enzyme (ACE) inhibitory effect of citric acid was evaluated in the same manner as in the case of malic acid above, except that 48 μM fluorescent substrate (Nma-Phe-His-Lys(Dnp)) was used instead of 60 μM fluorescent substrate (Nma-Phe-His-Lys(Dnp)) and 5 mU / mL rabbit lung derived ACE was used instead of 6 mU / mL rabbit lung derived ACE. The final concentrations of the citric acid solution were 7.81, 10.4, 13.0, 15.6, 20.8, 26.0, and 31.2 mM.

[0051] The results of measuring the fluorescence intensity of fluorescent metabolites when citric acid was used as the aliphatic carboxylic acid are shown in Figure 2. In Figure 2, the CNTs are shown when an equal amount of ultrapure water was added instead of the aliphatic carboxylic acid solution.

[0052] The results of calculating the ACE inhibitory activity rate when citric acid was used as the aliphatic carboxylic acid are shown in Table 2 and FIG.

[0053] [Table 2]

[0054] As shown in Tables 1 and 2 and FIG. 3, malic acid and citric acid were found to have angiotensin-converting enzyme inhibitory effects. <Test Example 2: Evaluation of angiotensin-converting enzyme inhibitory effect 2> The angiotensin-converting enzyme (ACE) inhibitory effect of lactic acid was evaluated. 100 mM HEPES solution (pH 7.5), 300 mM NaCl, 20 μM fluorescent substrate (Nma-Phe-His-Lys (Dnp)), 2.5 μM ZnCl2, 2 mU / mL rabbit lung-derived ACE, 0.02% Tween20, 0.02% NaN3, and lactic acid solution were added to a final volume of 50 uL, and incubated at 37°C for 60 minutes. After 60 minutes had elapsed from the start of the reaction, 100 uL of 0.1 M ethanolamine solution (pH 9.5) was added to stop the reaction. The final concentrations of the lactic acid solution were 10.0, 20.0, and 50.0 mM.

[0055] The fluorescence intensity of the fluorescent metabolites generated by the decomposition of the fluorescent substrate by ACE was measured using a fluorescence plate reader (Ex: 340 nm, Em: 440 nm).

[0056] The fluorescence intensity after 60 minutes of reaction was treated as the amount of change in fluorescence intensity due to the reaction. The fluorescence intensity at each concentration of lactic acid solution was taken as the relative activity [%] compared to the amount of change in fluorescence intensity when an equal amount of ultrapure water was added instead of the lactic acid solution and the reaction was allowed to proceed. The ACE activity inhibition rate [%] was calculated by subtracting the relative activity value from 100%. The results are shown in Table 3 and Figure 4.

[0057] [Table 3]

[0058] As shown in Table 3 and FIG. 4, lactic acid was found to have an angiotensin-converting enzyme inhibitory effect.

Claims

1. At least one selected from the group consisting of aliphatic carboxylic acids and salts thereof; the aliphatic carboxylic acid is an aliphatic hydroxy acid, The angiotensin-converting enzyme inhibitor, wherein the aliphatic hydroxy acid is at least one selected from the group consisting of lactic acid, malic acid and citric acid.

2. At least one selected from the group consisting of aliphatic carboxylic acids and salts thereof; the aliphatic carboxylic acid is an aliphatic hydroxy acid, The aliphatic hydroxy acid is at least one selected from the group consisting of lactic acid, malic acid, and citric acid, An antihypertensive agent that suppresses blood pressure rise by inhibiting angiotensin-converting enzyme.

3. At least one selected from the group consisting of aliphatic carboxylic acids and salts thereof; the aliphatic carboxylic acid is an aliphatic hydroxy acid, The aliphatic hydroxy acid is at least one selected from the group consisting of lactic acid, malic acid, and citric acid, An inflammatory response suppressant that suppresses inflammatory responses by inhibiting angiotensin-converting enzyme.

4. At least one selected from the group consisting of aliphatic carboxylic acids and salts thereof; the aliphatic carboxylic acid is an aliphatic hydroxy acid, The aliphatic hydroxy acid is at least one selected from the group consisting of lactic acid, malic acid, and citric acid, An organ protector that protects organs by inhibiting angiotensin-converting enzyme.

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