WO2017002838A1 - Composition for inhibiting renin-angiotensin system - Google Patents

Composition for inhibiting renin-angiotensin system Download PDF

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WO2017002838A1
WO2017002838A1 PCT/JP2016/069225 JP2016069225W WO2017002838A1 WO 2017002838 A1 WO2017002838 A1 WO 2017002838A1 JP 2016069225 W JP2016069225 W JP 2016069225W WO 2017002838 A1 WO2017002838 A1 WO 2017002838A1
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cyclo
lys
val
glu
tyr
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PCT/JP2016/069225
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French (fr)
Japanese (ja)
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伸哉 富貴澤
寿栄 鈴木
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サントリーホールディングス株式会社
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Priority to JP2017526386A priority Critical patent/JP6684277B2/en
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene

Definitions

  • the present invention relates to a composition for inhibiting a renin-angiotensin system. More specifically, a composition for inhibiting a renin-angiotensin system comprising a specific cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient, use of a specific cyclic dipeptide or a salt thereof for inhibiting the renin-angiotensin system, And a method for inhibiting the renin-angiotensin system.
  • the renin-angiotensin system is known to be involved in the regulation of blood pressure and the maintenance of homeostasis of body fluids and electrolytes in the body and is deeply involved in the development of hypertension.
  • angiotensin II which has peripheral capillary contraction action and stimulates sympathetic nerves and adrenal glands to promote the release of catecholamine, exhibits a high blood pressure raising action.
  • Angiotensin II also promotes the secretion of the adrenocortical hormone aldosterone, and therefore increases blood pressure through the mechanisms of promoting sodium reabsorption and increasing circulating blood flow.
  • angiotensin converting enzyme (also referred to as angiotensin I converting enzyme) present in the vascular endothelial cell membrane plays an important role. Therefore, captopril, enalapril, and the like that inhibit the activity of angiotensin converting enzyme are conventionally used as antihypertensive drugs. Since angiotensin converting enzyme produces angiotensin II and also has an action of degrading bradykinin having a vasodilating action, an angiotensin converting enzyme inhibitor can be expected to have a blood pressure lowering action also by a mechanism of bradykinin degradation inhibiting action.
  • Non-Patent Document 1 For the inhibition of angiotensin converting enzyme, it is known that linear peptides derived from food proteins are also useful. There have been many reports on its angiotensin converting enzyme inhibitory effect and blood pressure elevation-suppressing effect associated therewith. For example, many specific health foods containing sesame peptide (leucine-valine-tyrosine (LVY)) as a relevant component are put to practical use. (Non-Patent Document 1).
  • dipeptides in which two amino acids are combined are also attracting attention as functional substances. Dipeptides can be added with physical and chemical properties and new functions not found in single amino acids, and are expected to have a range of applications beyond single amino acids. Regarding the inhibition of angiotensin converting enzyme, it has been disclosed so far that specific linear dipeptides derived from seafood are useful (Patent Document 1).
  • angiotensin II In addition to inhibiting the production of angiotensin II, inhibition of the binding of angiotensin II to the angiotensin II receptor is also useful for inhibiting the renin-angiotensin system.
  • angiotensin II receptor There are two subtypes of angiotensin II receptor, AT-1 and AT-2. Among them, AT-1 is distributed in vascular smooth muscle, lung, liver, kidney, adrenal gland, ovary, spleen, brain and the like, and is involved in vasoconstriction and arteriosclerosis.
  • Angiotensin II receptor (AT-1) antagonists are used to inhibit the binding of angiotensin II to its receptor, which is particularly effective in the treatment of renin-dependent hypertension and has an excellent organ protective effect. is doing.
  • Examples of conventionally used drugs include losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan, and the like.
  • peptides it is disclosed that a tetrapeptide of alanine-leucine-proline-methionine (ALPM) is useful (Patent Document 2).
  • angiotensin II receptor (AT-1) antagonists may not only regulate blood pressure, but also have renal protective effects such as suppression of the onset of cardiovascular events such as stroke, myocardial infarction and heart attack, and reduction of proteinuria. Proven in large clinical trials.
  • an angiotensin converting enzyme inhibitor has been proven to protect organs.
  • linear peptides derived from food proteins appear to be effective.
  • the linear dipeptide has a problem that it lacks fat solubility because the amino group and carboxyl group, which are polar groups, are exposed at the terminal. Therefore, it may be difficult to mix a linear dipeptide at a high concentration into an oily base material such as vegetable oil, olive oil, fish oil, or rice germ oil.
  • linear dipeptides may be decomposed into free amino acids by the action of various peptidases such as carboxypeptidase and aminopeptidase secreted into the digestive tract (Non-patent Document 2). It is conceivable that becomes lower.
  • renin-angiotensin inhibitors that are highly effective, it is desirable that they have fewer side effects, can be applied to oily base materials, and have excellent absorbability into the body. It is done.
  • An object of the present invention is to provide a renin-angiotensin-based composition for suppressing renin-angiotensin that has high safety, is excellent in usability in formulation, and can be expected to be highly absorbed into the body.
  • Another object of the present invention is to provide a use of the composition for inhibiting the renin-angiotensin system, a method for inhibiting the renin-angiotensin system, and the like.
  • a cyclic dipeptide is a dipeptide having a cyclic structure formed by dehydration condensation of an amino group and a carboxyl group present at the end of a linear dipeptide.
  • various physiological activities have received attention.
  • the present inventors have diligently studied over 100 kinds of cyclic dipeptides composed of combinations of natural amino acids. Among them, specific cyclic dipeptides have angiotensin converting enzyme inhibitory action and / or angiotensin II receptor antagonistic action. Found for the first time to have. Based on this finding, the present inventors have completed the present invention.
  • a renin-angiotensin system-suppressing composition comprising a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
  • the cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Glu-His)], cyclotrypto Fany
  • Cyclic dipeptide or a salt thereof may be cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl Asparagine (Cyclo (Trp-Asn)), Cyclolysyl lysine (Cyclo (Lys-
  • the renin-angiotensin system inhibiting composition according to (1) which has an angiotensin II receptor antagonistic action, Cyclic dipeptide or a salt thereof may be cycloarginylphenylalanine [Cyclo (Arg-Phe)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloasparaginyllysine [Cyclo (Asn-Lys)], cyclolysylvaline [ Cyclo (Lys-Val)], cycloseryltyrosine [Cyclo (Ser-Tyr)], cycloaspartylglutamic acid [Cyclo (Asp-Glu)], cyclohistidylisoleucine [Cyclo (His-Ile)], cycloalanyl Glutamic acid [Cyclo (Ala-Glu)], cyclovalylglycine [Cyclo (Val-Gly)], cyclogluta
  • the renin-angiotensin system-suppressing composition according to any one of (1) to (3) which is used for suppressing blood pressure increase, for decreasing blood pressure, for protecting renal function, or for preventing or improving stroke or heart disease. object.
  • Function indications are “expect blood pressure drop”, “suppress blood pressure rise”, “moderate blood pressure rise”, “prevent hypertension”, “help to improve hypertension”.
  • the composition for inhibiting a renin-angiotensin system according to (6) which is selected from the group consisting of “protecting renal function” and “improves renal function”.
  • cyclic dipeptide having an amino acid as a structural unit or a salt thereof for suppressing the renin-angiotensin system
  • the cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (C
  • a method for inhibiting the renin-angiotensin system comprising using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
  • the cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Trp-Asn)), cyclolys
  • a composition having an excellent inhibitory effect on the renin-angiotensin system can be provided.
  • the composition of the present invention has an angiotensin converting enzyme inhibitory action and / or angiotensin II receptor antagonistic action, it is useful as an angiotensin converting enzyme inhibitory composition and / or angiotensin II receptor antagonistic composition.
  • blood pressure lowering action can be obtained for hypertension as listed in the sub-item of metabolic syndrome diagnosis, and further, cardiovascular events such as stroke, myocardial infarction, heart attack, etc.
  • a renal protective effect such as suppression of onset and decrease of proteinuria can be obtained.
  • the cyclic dipeptide or salt thereof contained as an active ingredient in the composition of the present invention is high in safety because it is also contained in a heat-treated food protein-derived peptide, and side effects are extremely small compared to conventional pharmaceuticals. Conceivable.
  • the cyclic dipeptide is excellent in lipophilicity as compared with the linear dipeptide, and high concentration filling into the oily base material is also possible. Therefore, it can be said that the composition of this invention is excellent in the usability in formulation.
  • cyclic dipeptides are rich in fat solubility and are not dipeptides composed solely of peptide bonds, it is considered that they are resistant to the action of various peptide-degrading enzymes secreted into the digestive tract. Absorbability can also be expected.
  • FIG. 1 is a graph showing plasma concentrations of various dipeptides after oral administration.
  • Renin-angiotensin system refers to a system that regulates blood pressure based on the action of renin and angiotensinogen. Renin is a proteolytic enzyme secreted from the kidney and acts on angiotensinogen as a substrate to produce angiotensin I. This angiotensin I is converted into angiotensin II by the action of an angiotensin converting enzyme (also referred to herein as “angiotensin I converting enzyme”), and this angiotensin II causes an increase in blood pressure.
  • an angiotensin converting enzyme also referred to herein as “angiotensin I converting enzyme
  • suppression of the renin-angiotensin system means suppression of the above-described renin-angiotensin system for the suppression of blood pressure increase, blood pressure decrease, renal function protection, or prevention or improvement of stroke or heart disease. .
  • This “inhibition” encompasses all mechanisms of action of various factors related to the renin-angiotensin system inhibition.
  • One specific example is inhibition of angiotensin converting enzyme.
  • the inhibitory activity of angiotensin converting enzyme can be measured according to known methods. For example, hippuric acid obtained by acting on the synthetic substrate Hippuryl-His-Leu is extracted with ethyl acetate, concentrated to dryness, and re-dissolved. And the absorbance at 228 nm is measured.
  • the inhibitory activity of an angiotensin converting enzyme can also be measured using a commercially available kit or the like.
  • renin-angiotensin system inhibition includes inhibition of binding of angiotensin II to an angiotensin II receptor (AT-1 or AT-2).
  • Inhibition of binding of angiotensin II to its receptor is addressed using a substance having an angiotensin II receptor antagonism (ie, an action that antagonizes angiotensin II and inhibits angiotensin II binding to the angiotensin II receptor). It is possible.
  • Angiotensin II receptor antagonism can be evaluated according to a known method. For example, using cells expressing angiotensin II receptor, changes in intracellular calcium ion concentration when angiotensin II is added are measured.
  • Evaluation can be made by comparing measured values in the presence and absence of the sample. More specifically, the angiotensin II receptor antagonistic action is greater as the measured value in the sample is lower than the measured value in the absence of the sample (ie, the change in intracellular calcium ion concentration is smaller). Can be evaluated.
  • cyclic dipeptide refers to a cyclic dipeptide having a diketopiperazine structure formed by dehydration condensation of an amino group and a carboxyl group of an amino acid. Say. Therefore, the cyclic dipeptide is distinguished from the chain dipeptide.
  • cyclic dipeptide or its salt may be collectively called a cyclic dipeptide.
  • any order thereof may be used, for example, [Cyclo (Met-Arg)] and [Cyclo (Arg-Met)] and Represent the same cyclic dipeptide.
  • cyclic dipeptides In cyclic dipeptides, the terminal portions of two amino acids are linked via an amide bond (that is, the cyclic dipeptide has a cyclic structure formed by the amide bond between the amino terminus and the carboxy terminus. Therefore, cyclic dipeptides are more lipophilic than linear dipeptides with polar carboxyl groups or amino groups exposed at the molecular end (particularly linear dipeptides of the same amino acid composition). It has the characteristics. Therefore, cyclic dipeptides are superior in gastrointestinal permeability and membrane permeability compared to linear dipeptides. This is also clear from the results of compound permeation tests using rat inverted intestinal tracts reported in the past (J. Pharmacol, 1998, 50: 167-172). Cyclic dipeptides are also considered to have increased resistance to various peptidases due to their specific structure.
  • Cyclic dipeptide or a salt thereof contained as an active ingredient in the present invention includes cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyl lysine [Cyclo (Ala- Lys)], cycloglutamyl tyrosine (Cyclo (Glu-Tyr)), cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine (Cyclo (Glu-Tyr)) -His)], cyclotryptophanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (C
  • the cyclic dipeptide or salt thereof contained as an active ingredient is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)].
  • Cycloalanyl lysine (Cyclo (Ala-Lys)), cycloglutamyl tyrosine (Cyclo (Glu-Tyr)), cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys) )], Cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl asparagine [Cyclo (Trp-Asn)], cyclolysyl lysine [Cyclo (Lys-Lys)], cyclovalylserine [Cyclo (Val-Ser )], Cycloisoleucylserine [Cyclo (Ile-Ser)], and cycloarginyltyrosine [Cyclo (Arg-Tyr)], preferably one or two or more selected from the group consisting of , Serial and
  • cycloisoleucine serine [Cyclo (Ile-Ser)]
  • cycloaspartyl lysine [Cyclo (Asp-Lys)]
  • cycloglutamyl histidine [Cyclo (Glu-His)] 1 or 2 or more selected from the group consisting of cyclolysyllysine [Cyclo (Lys-Lys)] and cycloarginyltyrosine [Cyclo (Arg-Tyr)]
  • cycloisoleucylserine [Cyclo ( Ile-Ser)] and / or cycloarginyl tyrosine [Cyclo (Arg-Tyr)].
  • the cyclic dipeptide or salt thereof contained as an active ingredient is cycloarginylphenylalanine [Cyclo (Arg-Phe)], cyclolysylphenylalanine [Cyclo (Lys- Phe)], cycloasparaginyl lysine (Cyclo (Asn-Lys)), cyclolysyl valine (Cyclo (Lys-Val)), cycloseryl tyrosine (Cyclo (Ser-Tyr)), cycloaspartyl glutamic acid (Cyclo (Asp -Glu)], cyclohistidylisoleucine (Cyclo (His-Ile)), cycloalanylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloglutamylphenyla
  • the ring More preferably, three or more selected from dipeptides or salts thereof are used as active ingredients.
  • cyclic dipeptides or salts thereof cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartylglutamic acid [Cyclo (Asp-Glu)], cyclovalylvaline [Cyclo (Val-Val)], and
  • One or two or more selected from the group consisting of cycloasparaginyl lysine [Cyclo (Asn-Lys)] is preferred, and cycloglutamyltyrosine [Cyclo (Glu-Tyr)] and / or cyclovalylvaline [Cyclo ( Val-Val)] is more preferable.
  • cyclic dipeptide salt refers to any pharmacologically acceptable salt (including inorganic salts and organic salts) of the cyclic dipeptide, such as sodium salt and potassium salt of the cyclic dipeptide. , Calcium salt, magnesium salt, ammonium salt, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate , Fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, and the like), but are not limited thereto. Cyclic dipeptide salts can be readily prepared by those skilled in the art by any method known in the art.
  • the cyclic dipeptide used in the present invention can be prepared according to a method known in the art. For example, it may be produced by a chemical synthesis method, an enzymatic method, or a microbial fermentation method, or may be synthesized by dehydration and cyclization of a linear peptide. JP 2003-252896 A, Journal of Peptide ⁇ Science, 10, 737-737, 2004.
  • an animal and plant derived peptide heat-treated product rich in cyclic dipeptide can be obtained by further heat-treating an animal and plant derived peptide obtained by subjecting a raw material containing animal and plant derived protein to enzyme treatment or heat treatment. From these points, the cyclic dipeptide or salt thereof used in the present invention may be chemically or biologically synthesized, or may be obtained from an animal or plant derived peptide.
  • Animal and Plant Derived Peptide in the present specification is not particularly limited.
  • soybean peptide, tea peptide, malt peptide, milk peptide, placenta peptide, collagen peptide and the like can be used.
  • Animal and plant-derived peptides may be prepared and used from animal or plant-derived proteins or raw materials containing proteins, but commercially available products may also be used.
  • Soybean peptide refers to a low molecular weight peptide obtained by subjecting soy protein to enzyme treatment or heat treatment to lower the molecular weight of the protein. Soybeans (scientific name: Glycine max) used as a raw material can be used without restriction of varieties and production areas, and can also be used in processed products such as pulverized products.
  • tea peptide refers to a low molecular weight peptide derived from tea obtained by subjecting a tea (including tea leaves or tea husk) extract to enzyme treatment or heat treatment to lower the protein.
  • a tea leaf used as an extraction raw material, a tea leaf (scientific name: Camellia sinensis) manufactured tea leaf leaf, stem, etc. that can be extracted and used can be used.
  • the form is not limited to large leaves or powders. The harvest time of tea leaves can also be selected appropriately according to the desired flavor.
  • malt peptide refers to a malt-derived low molecular weight peptide obtained by subjecting an extract obtained from malt or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of the protein.
  • malt peptide used as a raw material can be used without restriction of varieties and production areas, barley malt obtained by germinating barley seeds is particularly preferably used. In the present specification, barley malt may be simply referred to as “malt”.
  • milk peptide is a product obtained by decomposing milk protein, which is a component derived from natural milk, into a molecule in which at least several amino acids are bound. More specifically, it is obtained by hydrolyzing milk protein such as whey (whey protein) or casein with an enzyme such as proteinase, and filtering and sterilizing and / or concentrating and drying the filtrate. Examples include whey peptides and casein peptides.
  • placenta peptide placenta is the placenta of mammals and has been used as a health food, cosmetics, and pharmaceutical material in recent years because of its excellent functionality.
  • placenta peptide refers to a placenta that has been solubilized and reduced in molecular weight by enzyme treatment or subcritical treatment.
  • extracts obtained from plant placenta are used in health foods, cosmetics, etc. as having a physiological effect equivalent to placenta derived from placenta. be called.
  • the “placenta peptide” in the present specification includes those obtained by subjecting plant placenta to enzyme treatment or subcritical treatment, solubilization and low molecular weight.
  • Collagen peptide refers to a low molecular peptide obtained by subjecting collagen or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of collagen.
  • Collagen is a major protein in animal connective tissue and is the most abundant protein in mammalian bodies including humans.
  • high temperature heat treatment means that the treatment is performed for a certain period of time at a temperature of 100 ° C. or higher and a pressure exceeding atmospheric pressure.
  • a pressure-resistant extraction device, a pressure cooker, an autoclave, or the like can be used according to conditions.
  • the temperature in the high-temperature heat treatment is not particularly limited as long as it is 100 ° C or higher, but is preferably 100 ° C to 170 ° C, more preferably 110 ° C to 150 ° C, and still more preferably 120 ° C to 140 ° C.
  • this temperature shows the value which measured the exit temperature of the extraction column, when using a pressure-resistant extraction apparatus as a heating apparatus, and when using an autoclave as a heating apparatus, it is the temperature of the center temperature in a pressure vessel. The measured value is shown.
  • the pressure in the high-temperature heat treatment is not particularly limited as long as it is a pressure exceeding atmospheric pressure, but is preferably 0.101 MPa to 0.79 MPa, more preferably 0.101 MPa to 0.60 MPa, and even more preferably 0.101 MPa to 0. 48 MPa.
  • the high-temperature heat treatment time is not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but is preferably about 15 minutes to 600 minutes, more preferably about 30 minutes to 500 minutes, and even more preferably about 60 minutes to 300 minutes. It is.
  • the high-temperature heat treatment conditions for the animal and plant derived peptides are not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but preferably [temperature: pressure: time] is [100 ° C. to 170 ° C .: 0.101 MPa to 0.001. 79 MPa: 15 minutes to 600 minutes], more preferably [110 ° C. to 150 ° C .: 0.101 MPa to 0.60 MPa: 30 minutes to 500 minutes], even more preferably [120 ° C. to 140 ° C .: 0.101 MPa to 0 48 MPa: 60 minutes to 300 minutes].
  • the specific cyclic dipeptide in the heat-treated product of animal and plant derived peptides does not satisfy the desired content, the specific cyclic dipeptide that is deficient may be appropriately added using other animal or plant derived peptides, commercial products, or synthetic products. it can.
  • One embodiment of the present invention is a renin-angiotensin system inhibiting composition containing a specific cyclic dipeptide or a salt thereof as an active ingredient.
  • composition for inhibiting renin-angiotensin system of the present invention comprises cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)].
  • the number of cyclic dipeptides or salts thereof contained in the renin-angiotensin system inhibiting composition of the present invention is not particularly limited, but the present invention may include three or more selected from the above-mentioned cyclic dipeptides or salts thereof. preferable.
  • composition for inhibiting renin-angiotensin system of the present invention comprises cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyl from the viewpoint of angiotensin converting enzyme inhibitory effect.
  • Lysine (Cyclo (Ala-Lys)), cycloglutamyl tyrosine (Cyclo (Glu-Tyr)), cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleuyl lysine (Cyclo (Ile-Lys)), cyclo Glutamylhistidine (Cyclo (Glu-His)), cyclotryptophanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cyclo One or more cyclic dipeptides selected from the group consisting of isoleucylserine [Cyclo (Ile-Ser)] and cycloarginyltyrosine [Cyclo (Arg-Tyr)] or salts thereof as active
  • the composition of the present invention preferably contains three or more selected from the cyclic dipeptides or salts thereof as active ingredients.
  • cyclic dipeptides or salts thereof cycloisoleucine serine [Cyclo (Ile-Ser)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclo
  • One or more selected from the group consisting of lysyl lysine [Cyclo (Lys-Lys)] and cycloarginyl tyrosine [Cyclo (Arg-Tyr)] are preferred, and cycloisoleucine serine [Cyclo (Ile- Ser)] and / or cycloarginyl tyrosine [Cyclo (Arg-Tyr)].
  • the renin-angiotensin system inhibiting composition of the present invention from the viewpoint of angiotensin II receptor antagonistic effect, cycloarginylphenylalanine [Cyclo (Arg-Phe)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], Cycloasparaginyl lysine (Cyclo (Asn-Lys)), cyclolysyl valine (Cyclo (Lys-Val)), cycloseryltyrosine (Cyclo (Ser-Tyr)), cycloaspartyl glutamic acid (Cyclo (Asp-Glu)) Cyclohistidylisoleucine (Cyclo (His-Ile)), cycloalanyl glutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloglutamylphenylalanine (
  • the composition of the present invention preferably contains three or more selected from the cyclic dipeptides or salts thereof as active ingredients.
  • cyclic dipeptides or salts thereof cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartylglutamic acid [Cyclo (Asp-Glu)], cyclovalylvaline [Cyclo (Val-Val)], and cycloaspara
  • ginyllysine [Cyclo (Asn-Lys)] are preferred, and cycloglutamyltyrosine [Cyclo (Glu-Tyr)] and / or cyclovalylvaline [Cyclo (Val- Val)] is more preferable.
  • the content of the cyclic dipeptide or the salt thereof in the renin-angiotensin system inhibiting composition of the present invention may be an amount that can achieve the desired effect of the present invention in consideration of its administration form, administration method, etc. It is not particularly limited.
  • the total content of cyclic dipeptides or salts thereof in the composition of the present invention is 1.0 ⁇ 10 ppm / Brix or more, preferably 1.0 ⁇ 10 2 ppm / Brix or more. 5.0 ⁇ 10 3 ppm / Brix or less, preferably 3.0 ⁇ 10 3 ppm / Brix or less.
  • cycloaspartylphenylalanine [Cyclo (Asp-Phe)]
  • cycloglutamylphenylalanine [Cyclo (Glu-Phe)]
  • cycloalanyl lysine [Cyclo (Ala-Lys)] in the renin-angiotensin system inhibiting composition of the present invention.
  • the content of the cyclic dipeptide or a salt thereof is represented by the amount per Brix as described above.
  • amount per Brix means an amount determined by a value corresponding to a mass percentage of a sucrose solution at 20 ° C. (an aqueous solution containing only sucrose as a solute).
  • ppm used in the present specification means ppm of weight / volume (w / v), and 1.0 ppm / Brix is 0.1 mg / wt when the specific gravity of the solvent is 1. Converted to mL and converted to 0.01% by weight.
  • the content of the cyclic dipeptide or a salt thereof can be measured according to a known method. For example, it can be measured by using LC-MS / MS or a saccharimeter.
  • the “renin-angiotensin system” refers to a system in which blood pressure is regulated based on the action of renin and angiotensinogen.
  • Various factors are involved in the system, one of which is an angiotensin converting enzyme.
  • Angiotensin converting enzyme is present in pulmonary capillaries and the like, and has an action of converting angiotensin I into angiotensin II.
  • the converted angiotensin II binds to a receptor present in the adrenal cortex and promotes aldosterone synthesis and secretion from the adrenal cortex.
  • aldosterone promotes the reabsorption of sodium in the renal collecting duct, thereby increasing the amount of fluid and causing a pressor action. Therefore, inhibition of angiotensin converting enzyme contributes to suppression of production of angiotensin II, thereby obtaining an antihypertensive action and an antihypertensive action.
  • factors involved in the renin-angiotensin system include angiotensin II and angiotensin II receptor (AT-1 or AT-2) in relation to the above contents.
  • angiotensin II binds to the angiotensin II receptor and promotes aldosterone synthesis and secretion, resulting in a pressor effect. Therefore, inhibiting the binding of angiotensin II to the angiotensin II receptor contributes to suppression of aldosterone synthesis and secretion, thereby obtaining an increase in blood pressure and an effect of lowering blood pressure.
  • Inhibition of binding of angiotensin II to its receptor is addressed using a substance having an angiotensin II receptor antagonism (ie, an action that antagonizes angiotensin II and inhibits angiotensin II binding to the angiotensin II receptor). It is possible.
  • the renin-angiotensin system-suppressing composition of the present invention can contain any additive and any commonly used component in addition to the cyclic dipeptide or a salt thereof, depending on the form.
  • these additives and / or ingredients include vitamins such as vitamin E and vitamin C, bioactive ingredients such as minerals, nutritional ingredients, and fragrances, as well as excipients and binders incorporated in the formulation. , Emulsifiers, tonicity agents (isotonic agents), buffers, solubilizers, preservatives, stabilizers, antioxidants, colorants, coagulants, or coating agents, but are not limited thereto. It is not something.
  • composition for inhibiting renin-angiotensin system of the present invention is characterized by containing the aforementioned cyclic dipeptide or a salt thereof as an active ingredient, and the active ingredient can contribute to the inhibitory effect of renin-angiotensin system.
  • Inhibition of the renin-angiotensin system includes inhibition of angiotensin converting enzyme and inhibition of binding of angiotensin II to its receptor (AT-1 or AT-2). As shown in the examples, it has an inhibitory action on angiotensin converting enzyme and an antagonistic action on angiotensin II receptor.
  • one aspect of the present invention is a renin-angiotensin system-suppressing composition containing a predetermined cyclic dipeptide or a salt thereof as an active ingredient, which has an angiotensin converting enzyme inhibitory action.
  • Another embodiment of the present invention is a composition for inhibiting renin-angiotensin system containing a predetermined cyclic dipeptide or a salt thereof as an active ingredient, and an angiotensin II receptor (AT-1 or AT-2) The composition having an antagonistic action.
  • the renin-angiotensin system inhibiting composition of the present invention can also be an angiotensin converting enzyme inhibiting composition and / or angiotensin II receptor (AT-1 or AT-2) antagonistic composition.
  • cyclic dipeptide or a salt thereof contained in the composition of the present invention can suppress blood pressure increase, blood pressure decrease, protect renal function, and prevent or improve stroke or heart disease through suppression of the renin-angiotensin system. it can. Therefore, still another embodiment of the present invention is a renin-angiotensin-based composition for suppressing renin-angiotensin system containing a predetermined cyclic dipeptide or a salt thereof as an active ingredient, for suppressing blood pressure increase, for decreasing blood pressure, for renal function Said composition for protection, or prevention or amelioration of stroke or heart disease.
  • the renin-angiotensin system-suppressing composition of the present invention is a composition for suppressing blood pressure elevation, a composition for reducing blood pressure, a composition for protecting renal function, or a composition for preventing or improving stroke or heart disease. It can be a thing.
  • composition of the present invention is also useful for treatment and / or prevention of hypertension and the like in relation to an increase in blood pressure.
  • Stroke includes cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage and the like, and heart diseases include angina pectoris, myocardial infarction, cardiac hypertrophy, heart failure and the like.
  • the renin-angiotensin system-suppressing composition of the present invention includes, for example, a solvent, a dispersing agent, an emulsifier, a buffering agent, a stabilizer, an excipient, a binder, a disintegration, if necessary, in the raw material containing the cyclic dipeptide or a salt thereof
  • a solid agent such as a tablet, granule, powder, powder, or capsule, or a liquid agent such as a normal solution, suspension, or emulsion.
  • after preparing the form (for example, powder form and granule form) which can be mix
  • the renin-angiotensin system inhibiting composition of the present invention can be provided in the form of an agent as an example, but is not limited to this form.
  • the agent can be provided as a composition as it is or as a composition containing the agent.
  • the composition of the present invention include, but are not limited to, a pharmaceutical composition, a food / beverage product composition, a food composition, a beverage composition, a cosmetic composition, and the like.
  • Non-limiting examples of food compositions include functional foods, health supplements, functional nutrition foods, special foods, foods for specified health use, dietary supplements, diet foods, health foods, supplements, food additives, etc. Can be mentioned.
  • the renin-angiotensin composition-suppressing composition of the present invention can be applied to any therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, it does not belong to pharmaceuticals, quasi-drugs, cosmetics, etc. or the Pharmaceutical Affairs Law, but it has an effect of suppressing an increase in blood pressure, an effect of slowing an increase in blood pressure, an effect of preventing hypertension, or Examples thereof include use as a composition that explicitly or implicitly promotes the effect of improving hypertension and the like.
  • the present invention relates to the renin-angiotensin system-suppressing composition, which is labeled with the function exhibited by the renin-angiotensin system suppression.
  • Such display or functional display is not particularly limited. For example, “expect blood pressure reduction”, “suppress blood pressure increase”, “slow blood pressure increase”, “prevent hypertension”. , “Helps to improve hypertension”, “protects renal function”, “improves renal function” and the like, or a display or functional display that can be equated with these.
  • indications such as the indication and the functionality indication may be attached to the composition itself, or may be attached to a container or packaging of the composition.
  • the renin-angiotensin system inhibiting composition of the present invention can be taken by an appropriate method according to the form.
  • the intake method is not particularly limited as long as the cyclic dipeptide of the present invention or a salt thereof can be transferred into the circulating blood.
  • oral solid preparations such as tablets, coated tablets, granules, powders, or capsules
  • oral liquid preparations such as oral liquids, syrups, injections, external preparations, suppositories, or transdermal absorption agents, etc.
  • the present invention is not limited thereto.
  • “ingestion” is used to include all aspects such as ingestion, taking, or drinking.
  • the application amount of the renin-angiotensin system-suppressing composition of the present invention is set in a timely manner according to the form, administration method, purpose of use, and age, weight, and symptoms of the patient or animal subject to administration, and is not constant.
  • the effective human intake of the composition of the present invention is not constant, for example, the weight of the cyclic dipeptide or salt thereof as the active ingredient is preferably 10 mg or more, more preferably 100 mg per day for a human body weight of 50 kg. That's it.
  • administration may be performed once or several times within one day within a desired dose range. The administration period is also arbitrary.
  • the effective human intake of the composition of the present invention refers to the intake of the renin-angiotensin system-suppressing composition of the present invention showing an effective effect in humans, and the cyclic dipeptide contained in the composition
  • the type is not particularly limited.
  • the application target of the renin-angiotensin system inhibiting composition of the present invention is preferably human, but domestic animals such as cattle, horses and goats, pet animals such as dogs, cats and rabbits, or mice, rats and guinea pigs. Or a laboratory animal such as a monkey.
  • a cyclic dipeptide or a salt thereof for inhibiting the renin-angiotensin system
  • One embodiment of the present invention is the use of a specific cyclic dipeptide or a salt thereof having an amino acid as a constituent unit for inhibiting the renin-angiotensin system.
  • cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr) )], Cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucine lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl asparagine [Cyclo ( Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalyl serine (Cyclo (Val-Ser)), cycloisoleucil serine (Cyclo (Ile-Ser
  • Uses of the present invention include, for example, for inhibiting angiotensin converting enzyme, for inhibiting binding of angiotensin II to its receptor (AT-1 or AT-2), and / or for suppressing an increase in blood pressure.
  • This includes, but is not limited to, the use of the cyclic dipeptides or salts thereof.
  • the use is a use in a human or non-human animal, and may be a therapeutic use or a non-therapeutic use.
  • “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by treatment.
  • Method for inhibiting renin-angiotensin system is a method for inhibiting the renin-angiotensin system using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient.
  • the method is preferably cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl Asparagine (Cyclo (Trp-Asn)), Cyclolysyl lysine (Cyclo (Lys-Lys)), Cyclovalylserine (Cyclo (Val-Ser)), Cycloisoleucine serine (Cyclo (Ile-S
  • Another aspect related to the method includes a method for inhibiting the renin-angiotensin system, comprising administering to a subject in need of inhibition of the renin-angiotensin system a therapeutically effective amount of a specific cyclic dipeptide or a salt thereof as an active ingredient. It is.
  • cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr) )], Cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucine lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl asparagine [Cyclo ( Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalyl serine (Cyclo (Val-Ser)), cycloisoleucil serine (Cyclo (Ile-Ser
  • the subject requiring renin-angiotensin system inhibition is the same as the application subject of the renin-angiotensin system inhibiting composition of the present invention.
  • the therapeutically effective amount means that when the renin-angiotensin system-suppressing composition of the present invention is administered to the above-mentioned subject, the renin-angiotensin system is suppressed as compared with a non-administered subject. It is the amount.
  • the specific effective amount is appropriately set depending on the administration form, administration method, purpose of use, age, weight, symptom, etc. of the subject and is not constant.
  • the specific cyclic dipeptide or a salt thereof may be administered as it is or as a composition containing the specific cyclic dipeptide or a salt thereof so that the therapeutically effective amount is obtained.
  • Example 1 Activity inhibitory effect on angiotensin I converting enzyme activity
  • the inhibitory effect of cyclic dipeptide preparations on angiotensin I converting enzyme activity was examined. Specifically, with respect to chemically synthesized cyclic dipeptide preparations, ACE Kit-WST (Dojindo Laboratories Co., Ltd.) was used, and angiotensin I converting enzyme inhibitory activity of various cyclic dipeptides according to the instructions attached to the kit. It was measured. The cyclic dipeptide was examined for each concentration of 50 ⁇ M and 500 ⁇ M, and the inhibitory activity was evaluated as the residual activity of angiotensin I converting enzyme calculated using the following formula 1. As control, what added distilled water instead of cyclic dipeptide aqueous solution was used.
  • Residual activity (%) (450 nm absorbance in cyclic dipeptide addition group / 450 nm absorbance in control) ⁇ 100
  • Residual activity (%) (450 nm absorbance in cyclic dipeptide addition group / 450 nm absorbance in control) ⁇ 100
  • the evaluation results of various cyclic dipeptides are shown in Table 1 below.
  • Example 2 Antagonism of angiotensin II receptor (AT-1 ) To examine the antagonistic action of cyclic dipeptide preparations on angiotensin II receptor (ie, inhibition of binding of angiotensin II to angiotensin II receptor), binding to angiotensin II receptor The assay was performed. Specifically, using human recombinant angiotensin II type 1 receptor (AT-1) expressing HEK-293 cells, to this was added 3 nM angiotensin II and various concentrations of chemically synthesized cyclic dipeptide preparations, Changes in intracellular calcium ion concentration due to calcium ion influx were measured. The intracellular calcium ion concentration was quantified by fluorometric analysis.
  • AT-1 human recombinant angiotensin II type 1 receptor
  • FIG. Comparison of blood kinetics during administration of cyclic dipeptide and linear dipeptide Measures plasma concentration after oral administration of 10 mg / kg of cyclo (Tyr-Gly), a cyclic dipeptide having a renin-angiotensin system inhibitory effect, to mice The blood dynamics were confirmed. As comparison subjects, blood kinetics after administration of an equal amount of linear dipeptide Tyr-Gly (10 mg / kg) as a weight per kg body weight were also examined.
  • BALB / c mice male, 6 weeks old were purchased from CLEA Japan, and acclimated for about 1 week before being used for the test.
  • Cyclo (Tyr-Gly) (Kobe Natural Products Chemicals) or linear dipeptide Tyr-Gly (BACHEM) is dissolved in distilled water, and each dose is 10 mg / kg using a syringe and a sonde.
  • Capture, Terumo Capture, Terumo
  • the present invention provides a composition for renin-angiotensin system inhibition containing a specific cyclic dipeptide or a salt thereof as an active ingredient. Since the present invention provides a new safe and effective means that contributes to suppression of blood pressure increase, etc., the industrial applicability is high.

Abstract

Provided are: a composition for inhibiting the renin-angiotensin system; a use of said composition as a substance for inhibiting the renin-angiotensin system; and a method for inhibiting the renin-angiotensin system. It has been discovered that a specific cyclic dipeptide or a salt thereof exhibits renin-angiotensin-system inhibiting action. The present invention provides a novel and effective means for contributing to inhibiting blood pressure elevation.

Description

レニン－アンジオテンシン系抑制用組成物Composition for inhibiting renin-angiotensin system
　本発明は、レニン－アンジオテンシン系抑制用組成物に関する。さらに詳しくは、アミノ酸を構成単位とする特定の環状ジペプチド又はその塩を有効成分とするレニン－アンジオテンシン系抑制用組成物、レニン－アンジオテンシン系を抑制するための特定の環状ジペプチド又はその塩の使用、及びレニン－アンジオテンシン系を抑制する方法に関する。 The present invention relates to a composition for inhibiting a renin-angiotensin system. More specifically, a composition for inhibiting a renin-angiotensin system comprising a specific cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient, use of a specific cyclic dipeptide or a salt thereof for inhibiting the renin-angiotensin system, And a method for inhibiting the renin-angiotensin system.
　レニン－アンジオテンシン系は、生体において血圧調節作用や体液・電解質のホメオスタシス維持に関わり、高血圧症の発症に深く関与していることが知られている。レニン－アンジオテンシン系においては、末梢毛細血管収縮作用を有し、交感神経及び副腎を刺激してカテコールアミンの放出を促進するアンジオテンシンＩＩが高い血圧上昇作用を示す。アンジオテンシンＩＩは副腎皮質ホルモンのアルドステロンの分泌も促進するため、ナトリウムの再吸収促進及び循環血流量の増大というメカニズムによっても血圧を上昇させる。 The renin-angiotensin system is known to be involved in the regulation of blood pressure and the maintenance of homeostasis of body fluids and electrolytes in the body and is deeply involved in the development of hypertension. In the renin-angiotensin system, angiotensin II, which has peripheral capillary contraction action and stimulates sympathetic nerves and adrenal glands to promote the release of catecholamine, exhibits a high blood pressure raising action. Angiotensin II also promotes the secretion of the adrenocortical hormone aldosterone, and therefore increases blood pressure through the mechanisms of promoting sodium reabsorption and increasing circulating blood flow.
　アンジオテンシンＩＩの産生には、血管内皮細胞膜などに存在するアンジオテンシン変換酵素（アンジオテンシンＩ変換酵素ともいう）が重要な役割を果たしている。そのため、アンジオテンシン変換酵素の活性を阻害するカプトプリルやエナラプリルなどが、高血圧治療薬として従来利用されている。アンジオテンシン変換酵素はアンジオテンシンＩＩを産生するほか、血管拡張作用を持つブラジキニンを分解する作用もあるため、アンジオテンシン変換酵素阻害剤はブラジキニン分解阻害作用というメカニズムによっても血圧降下作用が期待できる。 In production of angiotensin II, angiotensin converting enzyme (also referred to as angiotensin I converting enzyme) present in the vascular endothelial cell membrane plays an important role. Therefore, captopril, enalapril, and the like that inhibit the activity of angiotensin converting enzyme are conventionally used as antihypertensive drugs. Since angiotensin converting enzyme produces angiotensin II and also has an action of degrading bradykinin having a vasodilating action, an angiotensin converting enzyme inhibitor can be expected to have a blood pressure lowering action also by a mechanism of bradykinin degradation inhibiting action.
　アンジオテンシン変換酵素の阻害については、食品タンパク質由来の直鎖状ペプチドも有用であることが知られている。そのアンジオテンシン変換酵素阻害作用やそれに伴う血圧上昇抑制作用はこれまでに数多く報告されており、例えばゴマペプチド（ロイシン－バリン－チロシン（ＬＶＹ））などを関与成分として添加した特定保健用食品が数多く実用化されている（非特許文献１）。 For the inhibition of angiotensin converting enzyme, it is known that linear peptides derived from food proteins are also useful. There have been many reports on its angiotensin converting enzyme inhibitory effect and blood pressure elevation-suppressing effect associated therewith. For example, many specific health foods containing sesame peptide (leucine-valine-tyrosine (LVY)) as a relevant component are put to practical use. (Non-Patent Document 1).
　食品タンパク質由来のペプチドの中では、アミノ酸が二つ結合した「ジペプチド」も機能性物質として注目されている。ジペプチドには、単体アミノ酸にない物理的、化学的性質や新たな機能を付加することが可能であり、単体アミノ酸以上の応用範囲を有するものとして期待されている。アンジオテンシン変換酵素の阻害に関しては、魚介類由来の特定の直鎖状ジペプチドが有用であることがこれまでに開示されている（特許文献１）。 Among peptides derived from food proteins, “dipeptides” in which two amino acids are combined are also attracting attention as functional substances. Dipeptides can be added with physical and chemical properties and new functions not found in single amino acids, and are expected to have a range of applications beyond single amino acids. Regarding the inhibition of angiotensin converting enzyme, it has been disclosed so far that specific linear dipeptides derived from seafood are useful (Patent Document 1).
　レニン－アンジオテンシン系の抑制には、アンジオテンシンＩＩの産生抑制のほかに、アンジオテンシンＩＩのアンジオテンシンＩＩ受容体への結合阻害も有用である。アンジオテンシンＩＩ受容体にはＡＴ－１とＡＴ－２の２種類のサブタイプが存在している。このうちＡＴ－１は、血管平滑筋、肺、肝臓、腎臓、副腎、卵巣、脾臓、脳などに分布しており、血管収縮や動脈硬化に関与している。 In addition to inhibiting the production of angiotensin II, inhibition of the binding of angiotensin II to the angiotensin II receptor is also useful for inhibiting the renin-angiotensin system. There are two subtypes of angiotensin II receptor, AT-1 and AT-2. Among them, AT-1 is distributed in vascular smooth muscle, lung, liver, kidney, adrenal gland, ovary, spleen, brain and the like, and is involved in vasoconstriction and arteriosclerosis.
　アンジオテンシンＩＩのその受容体への結合阻害にはアンジオテンシンＩＩ受容体（ＡＴ－１）拮抗剤が用いられており、これは特にレニン依存性の高血圧治療に有効であり、優れた臓器保護効果を有している。従来使用されている薬剤としては、ロサルタン、カンデサルタン、バルサルタン、テルミサルタン、オルメサルタン、イルベサルタン等が挙げられる。また、ペプチドに関しては、アラニン－ロイシン－プロリン－メチオニン（ＡＬＰＭ）のテトラペプチドが有用であることが開示されている（特許文献２）。 Angiotensin II receptor (AT-1) antagonists are used to inhibit the binding of angiotensin II to its receptor, which is particularly effective in the treatment of renin-dependent hypertension and has an excellent organ protective effect. is doing. Examples of conventionally used drugs include losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan, and the like. Regarding peptides, it is disclosed that a tetrapeptide of alanine-leucine-proline-methionine (ALPM) is useful (Patent Document 2).
　近年では、アンジオテンシンＩＩ受容体（ＡＴ－１）拮抗薬が血圧調節作用のみならず、脳卒中、心筋梗塞、心臓発作などの心血管イベントの発症抑制や蛋白尿の減少など腎保護効果をもたらすことが大規模臨床試験によって証明されている。また、アンジオテンシン変換酵素阻害薬に関しても、臓器保護作用が証明されている。 In recent years, angiotensin II receptor (AT-1) antagonists may not only regulate blood pressure, but also have renal protective effects such as suppression of the onset of cardiovascular events such as stroke, myocardial infarction and heart attack, and reduction of proteinuria. Proven in large clinical trials. In addition, an angiotensin converting enzyme inhibitor has been proven to protect organs.
　上述した通り、レニン－アンジオテンシン系の抑制には種々の医薬品が従来使用されているが、一方ではそれらの副作用が懸念されるところである。この点では、食品タンパク質由来の直鎖状ペプチドは有効であるように考えられる。しかしながら、直鎖状ジペプチドは極性基であるアミノ基とカルボキシル基が末端に露出しているため、脂溶性に欠けるという問題点が存在する。そのため、直鎖状ジペプチドは、植物油やオリーブ油、魚油、米胚芽油といった油性基材への高濃度での混合が難しい場合がある。また、直鎖状ジペプチドは、消化管に分泌されるカルボキシペプチダーゼやアミノペプチダーゼなどの各種ペプチダーゼの作用によって遊離アミノ酸に分解されることがあり（非特許文献２）、この特性によって体内への吸収性が低くなることも考えられる。以上の点から、効果の高いレニン－アンジオテンシン系抑制剤の中でも、より副作用が少なく、油性基材への適用も可能であり、更には体内への吸収性にも優れているものが望ましいと考えられる。 As described above, various drugs have been conventionally used to suppress the renin-angiotensin system, but on the other hand, there are concerns about their side effects. In this respect, linear peptides derived from food proteins appear to be effective. However, the linear dipeptide has a problem that it lacks fat solubility because the amino group and carboxyl group, which are polar groups, are exposed at the terminal. Therefore, it may be difficult to mix a linear dipeptide at a high concentration into an oily base material such as vegetable oil, olive oil, fish oil, or rice germ oil. In addition, linear dipeptides may be decomposed into free amino acids by the action of various peptidases such as carboxypeptidase and aminopeptidase secreted into the digestive tract (Non-patent Document 2). It is conceivable that becomes lower. In view of the above, among renin-angiotensin inhibitors that are highly effective, it is desirable that they have fewer side effects, can be applied to oily base materials, and have excellent absorbability into the body. It is done.
特開２００３－２４０１２号公報Japanese Patent Laid-Open No. 2003-24012 特開２００５－３５０４４３号公報JP-A-2005-350443
　本発明の課題は、安全性が高く、製剤化における使用性に優れており、更には体内への高い吸収性が期待できるレニン－アンジオテンシン系抑制用組成物を提供することにある。また、本発明の課題は、レニン－アンジオテンシン系を抑制するための当該組成物の使用、及びレニン－アンジオテンシン系を抑制する方法等を提供することにある。 An object of the present invention is to provide a renin-angiotensin-based composition for suppressing renin-angiotensin that has high safety, is excellent in usability in formulation, and can be expected to be highly absorbed into the body. Another object of the present invention is to provide a use of the composition for inhibiting the renin-angiotensin system, a method for inhibiting the renin-angiotensin system, and the like.
　本発明者らは、上記課題について鋭意検討した結果、環状ジペプチドの利用に着目した。環状ジペプチドは、直鎖状ジペプチドの末端に存在するアミノ基とカルボキシル基とが脱水縮合することにより生成した環状構造を有するジペプチドであり、近年ではその様々な生理活性が注目を受けている。本発明者らは、天然アミノ酸の組合せからなる１００種類以上にも及ぶ多数の環状ジペプチドについて鋭意検討し、その中から特定の環状ジペプチドがアンジオテンシン変換酵素阻害作用及び／又はアンジオテンシンＩＩ受容体拮抗作用を有することを初めて見出した。かかる知見に基づき、本発明者らは本発明を完成するに至った。 As a result of intensive studies on the above problems, the present inventors have focused on the use of cyclic dipeptides. A cyclic dipeptide is a dipeptide having a cyclic structure formed by dehydration condensation of an amino group and a carboxyl group present at the end of a linear dipeptide. In recent years, various physiological activities have received attention. The present inventors have diligently studied over 100 kinds of cyclic dipeptides composed of combinations of natural amino acids. Among them, specific cyclic dipeptides have angiotensin converting enzyme inhibitory action and / or angiotensin II receptor antagonistic action. Found for the first time to have. Based on this finding, the present inventors have completed the present invention.
　即ち、本発明は以下に関するが、これらに限定されない。
（１）アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として含有するレニン－アンジオテンシン系抑制用組成物であって、
　前記環状ジペプチド又はその塩が、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記レニン－アンジオテンシン系抑制用組成物。
（２）アンジオテンシン変換酵素阻害作用を有する、（１）に記載のレニン－アンジオテンシン系抑制用組成物であって、
　環状ジペプチド又はその塩が、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、及びシクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記レニン－アンジオテンシン系抑制用組成物。
（３）アンジオテンシンＩＩ受容体拮抗作用を有する、（１）に記載のレニン－アンジオテンシン系抑制用組成物であって、
　環状ジペプチド又はその塩が、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、シクロバリルバリン〔Cyclo(Val-Val)〕、及びシクログルタミルチロシン〔Cyclo(Glu-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記レニン－アンジオテンシン系抑制用組成物。
（４）血圧上昇抑制用、血圧降下用、腎機能保護用、又は脳卒中若しくは心疾患の予防若しくは改善用である、（１）～（３）のいずれかに記載のレニン－アンジオテンシン系抑制用組成物。
（５）環状ジペプチド又はその塩が動植物由来ペプチドから得られるものである、（１）～（４）のいずれかに記載のレニン－アンジオテンシン系抑制用組成物。
（６）レニン－アンジオテンシン系の抑制により発揮される機能の表示を付した、（１）～（５）のいずれかに記載のレニン－アンジオテンシン系抑制用組成物。
（７）機能の表示が、「血圧低下を期待する」、「血圧の上昇を抑制する」、「血圧の上昇を緩やかにする」、「高血圧症を予防する」、「高血圧症の改善に役立つ」、「腎機能を保護する」、及び「腎機能を改善する」からなる群から選択されるものである、（６）に記載のレニン－アンジオテンシン系抑制用組成物。
（８）前記組成物が剤である、（１）～（７）のいずれかに記載のレニン－アンジオテンシン系抑制用組成物。
（９）レニン－アンジオテンシン系を抑制するための、アミノ酸を構成単位とする環状ジペプチド又はその塩の使用であって、
　前記環状ジペプチド又はその塩が、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記使用。
（１０）アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として使用する、レニン－アンジオテンシン系を抑制する方法であって、
　前記環状ジペプチド又はその塩が、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記方法。 That is, the present invention relates to the following, but is not limited thereto.
(1) A renin-angiotensin system-suppressing composition comprising a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cycloisoleucine serine (Cyclo (Ile-Ser)), cyclo Arginyltyrosine [Cyclo (Arg-Tyr)], Cycloarginylphenylalanine [Cyclo (Arg-Phe)], Cyclolysylphenylalanine [Cyclo (Lys-Phe)], Cycloasparaginyllysine [Cyclo (Asn-Lys)] , Cyclolysyl Bali (Cyclo (Lys-Val)), cycloseryltyrosine (Cyclo (Ser-Tyr)), cycloaspartylglutamic acid (Cyclo (Asp-Glu)), cyclohistidylisoleucine (Cyclo (His-Ile)), cycloaralyl Nylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloalanyl leucine (Cyclo (Ala-Leu)), cycloisoleuyl proline (Cyclo (Ile-Pro)), Cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln-Phe)) Cyclothreonyl valine [Cyclo (Thr-Val)], cycloaspartyl valine [Cyclo (Asp-Val)], cyclomethionyl arginine [Cyclo (Met-Arg)], cycloaspartyl leucine [Cyclo (Asp-Leu)] )], Cycloisoleucylthreonine (Cyclo (Ile-Thr)), cyclo Lanylmethionine (Cyclo (Ala-Met)), Cyclolysylproline (Cyclo (Lys-Pro)), Cycloseryltryptophan (Cyclo (Ser-Trp)), Cycloleusyltryptophan (Cyclo (Leu-Trp)), and The renin-angiotensin system-suppressing composition comprising one or more selected from the group consisting of cyclovalyl valine [Cyclo (Val-Val)].
(2) The renin-angiotensin system inhibiting composition according to (1), which has an angiotensin converting enzyme inhibitory action,
Cyclic dipeptide or a salt thereof may be cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl Asparagine (Cyclo (Trp-Asn)), Cyclolysyl lysine (Cyclo (Lys-Lys)), Cyclovalylserine (Cyclo (Val-Ser)), Cycloisoleucine serine (Cyclo (Ile-Ser)), and Cyclo The renin-angiotensin system-suppressing composition comprising one or more selected from the group consisting of arginyltyrosine [Cyclo (Arg-Tyr)].
(3) The renin-angiotensin system inhibiting composition according to (1), which has an angiotensin II receptor antagonistic action,
Cyclic dipeptide or a salt thereof may be cycloarginylphenylalanine [Cyclo (Arg-Phe)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloasparaginyllysine [Cyclo (Asn-Lys)], cyclolysylvaline [ Cyclo (Lys-Val)], cycloseryltyrosine [Cyclo (Ser-Tyr)], cycloaspartylglutamic acid [Cyclo (Asp-Glu)], cyclohistidylisoleucine [Cyclo (His-Ile)], cycloalanyl Glutamic acid [Cyclo (Ala-Glu)], cyclovalylglycine [Cyclo (Val-Gly)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyl leucine [Cyclo (Ala-Leu)], cycloisoleucine Sylproline (Cyclo (Ile-Pro)), cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cyclo Glutaminylphenylalanine Cyclo (Gln-Phe)], cyclothreonyl valine (Cyclo (Thr-Val)), cycloaspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg)), cycloaspartyl Leucine (Cyclo (Asp-Leu)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloalanyl methionine (Cyclo (Ala-Met)), cycloaspartyl phenylalanine (Cyclo (Asp-Phe)), Cyclolysylproline (Cyclo (Lys-Pro)), cycloseryltryptophan (Cyclo (Ser-Trp)), cycloleucyltryptophan (Cyclo (Leu-Trp)), cyclovalylvaline (Cyclo (Val-Val)), and The renin-angiotensin system-suppressing composition comprising one or more selected from the group consisting of cycloglutamyltyrosine [Cyclo (Glu-Tyr)].
(4) The renin-angiotensin system-suppressing composition according to any one of (1) to (3), which is used for suppressing blood pressure increase, for decreasing blood pressure, for protecting renal function, or for preventing or improving stroke or heart disease. object.
(5) The renin-angiotensin system inhibiting composition according to any one of (1) to (4), wherein the cyclic dipeptide or a salt thereof is obtained from an animal or plant derived peptide.
(6) The composition for inhibiting renin-angiotensin system according to any one of (1) to (5), which is labeled with a function exhibited by inhibiting the renin-angiotensin system.
(7) Function indications are “expect blood pressure drop”, “suppress blood pressure rise”, “moderate blood pressure rise”, “prevent hypertension”, “help to improve hypertension The composition for inhibiting a renin-angiotensin system according to (6), which is selected from the group consisting of “protecting renal function” and “improves renal function”.
(8) The renin-angiotensin system inhibiting composition according to any one of (1) to (7), wherein the composition is an agent.
(9) Use of a cyclic dipeptide having an amino acid as a structural unit or a salt thereof for suppressing the renin-angiotensin system,
The cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cycloisoleucine serine (Cyclo (Ile-Ser)), cyclo Arginyltyrosine [Cyclo (Arg-Tyr)], Cycloarginylphenylalanine [Cyclo (Arg-Phe)], Cyclolysylphenylalanine [Cyclo (Lys-Phe)], Cycloasparaginyllysine [Cyclo (Asn-Lys)] , Cyclolysyl Bali (Cyclo (Lys-Val)), cycloseryltyrosine (Cyclo (Ser-Tyr)), cycloaspartylglutamic acid (Cyclo (Asp-Glu)), cyclohistidylisoleucine (Cyclo (His-Ile)), cycloaralyl Nylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloalanyl leucine (Cyclo (Ala-Leu)), cycloisoleuyl proline (Cyclo (Ile-Pro)), Cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln-Phe)) Cyclothreonyl valine [Cyclo (Thr-Val)], cycloaspartyl valine [Cyclo (Asp-Val)], cyclomethionyl arginine [Cyclo (Met-Arg)], cycloaspartyl leucine [Cyclo (Asp-Leu)] )], Cycloisoleucylthreonine (Cyclo (Ile-Thr)), cyclo Lanylmethionine (Cyclo (Ala-Met)), Cyclolysylproline (Cyclo (Lys-Pro)), Cycloseryltryptophan (Cyclo (Ser-Trp)), Cycloleusyltryptophan (Cyclo (Leu-Trp)), and The use as described above, which comprises one or more selected from the group consisting of cyclovalylvaline [Cyclo (Val-Val)].
(10) A method for inhibiting the renin-angiotensin system, comprising using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cycloisoleucine serine (Cyclo (Ile-Ser)), cyclo Arginyltyrosine [Cyclo (Arg-Tyr)], Cycloarginylphenylalanine [Cyclo (Arg-Phe)], Cyclolysylphenylalanine [Cyclo (Lys-Phe)], Cycloasparaginyllysine [Cyclo (Asn-Lys)] , Cyclolysyl Bali (Cyclo (Lys-Val)), cycloseryltyrosine (Cyclo (Ser-Tyr)), cycloaspartylglutamic acid (Cyclo (Asp-Glu)), cyclohistidylisoleucine (Cyclo (His-Ile)), cycloaralyl Nylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloalanyl leucine (Cyclo (Ala-Leu)), cycloisoleuyl proline (Cyclo (Ile-Pro)), Cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln-Phe)) Cyclothreonyl valine [Cyclo (Thr-Val)], cycloaspartyl valine [Cyclo (Asp-Val)], cyclomethionyl arginine [Cyclo (Met-Arg)], cycloaspartyl leucine [Cyclo (Asp-Leu)] )], Cycloisoleucylthreonine (Cyclo (Ile-Thr)), cyclo Lanylmethionine (Cyclo (Ala-Met)), Cyclolysylproline (Cyclo (Lys-Pro)), Cycloseryltryptophan (Cyclo (Ser-Trp)), Cycloleusyltryptophan (Cyclo (Leu-Trp)), and The method as described above, which comprises one or more selected from the group consisting of cyclovalylvaline [Cyclo (Val-Val)].
　本発明によって、レニン－アンジオテンシン系の優れた抑制効果を有する組成物を提供することができる。また、本発明の組成物はアンジオテンシン変換酵素阻害作用及び／又はアンジオテンシンＩＩ受容体拮抗作用を有することから、アンジオテンシン変換酵素阻害用組成物及び／又はアンジオテンシンＩＩ受容体拮抗用組成物としても有用である。そして、本発明の組成物を利用すれば、メタボリックシンドローム診断の副次項目に挙げられるような高血圧に対して血圧降下作用が得られ、更には、脳卒中、心筋梗塞、心臓発作などの心血管イベントの発症抑制や、蛋白尿の減少などの腎保護効果も得られる可能性がある。 According to the present invention, a composition having an excellent inhibitory effect on the renin-angiotensin system can be provided. In addition, since the composition of the present invention has an angiotensin converting enzyme inhibitory action and / or angiotensin II receptor antagonistic action, it is useful as an angiotensin converting enzyme inhibitory composition and / or angiotensin II receptor antagonistic composition. . By using the composition of the present invention, blood pressure lowering action can be obtained for hypertension as listed in the sub-item of metabolic syndrome diagnosis, and further, cardiovascular events such as stroke, myocardial infarction, heart attack, etc. There is also a possibility that a renal protective effect such as suppression of onset and decrease of proteinuria can be obtained.
　本発明の組成物に有効成分として含まれる環状ジペプチド又はその塩は、食品タンパク質由来ペプチドの熱処理物にも含まれていることから安全性は高く、副作用は従来の医薬品に比して極めて少ないと考えられる。また、環状ジペプチドは直鎖状ジペプチドと比較して親油性に優れており、油性基材への高濃度充填も十分に可能である。そのため、本発明の組成物は、製剤化における使用性に優れているといえる。さらに、環状ジペプチドは脂溶性に富み、且つ単なるペプチド結合のみで構成されるジペプチドではないため、消化管に分泌される各種ペプチド分解酵素の作用に対して耐性を有することが考えられ、高い消化管吸収性も期待できる。 The cyclic dipeptide or salt thereof contained as an active ingredient in the composition of the present invention is high in safety because it is also contained in a heat-treated food protein-derived peptide, and side effects are extremely small compared to conventional pharmaceuticals. Conceivable. In addition, the cyclic dipeptide is excellent in lipophilicity as compared with the linear dipeptide, and high concentration filling into the oily base material is also possible. Therefore, it can be said that the composition of this invention is excellent in the usability in formulation. Furthermore, since cyclic dipeptides are rich in fat solubility and are not dipeptides composed solely of peptide bonds, it is considered that they are resistant to the action of various peptide-degrading enzymes secreted into the digestive tract. Absorbability can also be expected.
図１は、各種ジペプチドの経口投与後の血漿中濃度を示す図である。FIG. 1 is a graph showing plasma concentrations of various dipeptides after oral administration.
　１．レニン－アンジオテンシン系及びレニン－アンジオテンシン系抑制
　本明細書において「レニン－アンジオテンシン系」とは、レニン及びアンジオテンシノーゲンの作用に基づいて血圧調節を司る系をいう。レニンは、腎臓から分泌されるタンパク質分解酵素であり、アンジオテンシノーゲンを基質としてこれに作用してアンジオテンシンＩを生成する。このアンジオテンシンＩがアンジオテンシン変換酵素（本明細書では、「アンジオテンシンＩ変換酵素」とも称する）の作用でアンジオテンシンＩＩに変化して、このアンジオテンシンＩＩが血圧上昇をもたらす。 1. Renin-angiotensin system and renin-angiotensin system inhibition As used herein, “renin-angiotensin system” refers to a system that regulates blood pressure based on the action of renin and angiotensinogen. Renin is a proteolytic enzyme secreted from the kidney and acts on angiotensinogen as a substrate to produce angiotensin I. This angiotensin I is converted into angiotensin II by the action of an angiotensin converting enzyme (also referred to herein as “angiotensin I converting enzyme”), and this angiotensin II causes an increase in blood pressure.
　本明細書において「レニン－アンジオテンシン系抑制」とは、上述したレニン－アンジオテンシン系を血圧上昇抑制、血圧降下、腎機能保護、又は脳卒中若しくは心疾患の予防若しくは改善のために抑制することを意味する。この「抑制」には、レニン－アンジオテンシン系の抑制に関連する各種因子のあらゆる作用機序が包含される。その一つの具体例としては、アンジオテンシン変換酵素の阻害が挙げられる。アンジオテンシン変換酵素の阻害活性は、公知の方法に従って測定することができ、例えば、合成基質Hippuryl-His-Leuに作用して得られる馬尿酸を酢酸エチルで溶媒抽出後、濃縮乾固し、再溶解して２２８ｎｍの吸光度を測定することで算出される。また、アンジオテンシン変換酵素の阻害活性は、市販のキット等を用いて測定することもできる。 As used herein, “suppression of the renin-angiotensin system” means suppression of the above-described renin-angiotensin system for the suppression of blood pressure increase, blood pressure decrease, renal function protection, or prevention or improvement of stroke or heart disease. . This “inhibition” encompasses all mechanisms of action of various factors related to the renin-angiotensin system inhibition. One specific example is inhibition of angiotensin converting enzyme. The inhibitory activity of angiotensin converting enzyme can be measured according to known methods. For example, hippuric acid obtained by acting on the synthetic substrate Hippuryl-His-Leu is extracted with ethyl acetate, concentrated to dryness, and re-dissolved. And the absorbance at 228 nm is measured. Moreover, the inhibitory activity of an angiotensin converting enzyme can also be measured using a commercially available kit or the like.
　レニン－アンジオテンシン系抑制の別の具体例としては、アンジオテンシンＩＩのアンジオテンシンＩＩ受容体（ＡＴ－１又はＡＴ－２）への結合阻害が挙げられる。アンジオテンシンＩＩのその受容体への結合阻害は、アンジオテンシンＩＩ受容体拮抗作用（即ち、アンジオテンシンＩＩと拮抗してアンジオテンシンＩＩのアンジオテンシンＩＩ受容体への結合を阻害する作用）を有する物質を用いて対処することが可能である。アンジオテンシンＩＩ受容体拮抗作用については、公知の方法に従って評価することができ、例えば、アンジオテンシンＩＩ受容体を発現した細胞を用いて、アンジオテンシンＩＩを添加したときの細胞内カルシウムイオン濃度の変化を測定し、試料が存在する場合と存在しない場合との測定値を比較して評価することができる。より具体的には、試料が存在しない場合の測定値に対して試料が存在する測定値の方が低い（即ち、細胞内カルシウムイオン濃度の変化が小さい）ほど、アンジオテンシンＩＩ受容体拮抗作用は大きいと評価することができる。 Another specific example of renin-angiotensin system inhibition includes inhibition of binding of angiotensin II to an angiotensin II receptor (AT-1 or AT-2). Inhibition of binding of angiotensin II to its receptor is addressed using a substance having an angiotensin II receptor antagonism (ie, an action that antagonizes angiotensin II and inhibits angiotensin II binding to the angiotensin II receptor). It is possible. Angiotensin II receptor antagonism can be evaluated according to a known method. For example, using cells expressing angiotensin II receptor, changes in intracellular calcium ion concentration when angiotensin II is added are measured. Evaluation can be made by comparing measured values in the presence and absence of the sample. More specifically, the angiotensin II receptor antagonistic action is greater as the measured value in the sample is lower than the measured value in the absence of the sample (ie, the change in intracellular calcium ion concentration is smaller). Can be evaluated.
　２．環状ジペプチド
　本明細書において「環状ジペプチド」とは、アミノ酸を構成単位とすることを特徴とし、アミノ酸のアミノ基とカルボキシル基とが脱水縮合することにより生成したジケトピペラジン構造を有する環状ジペプチドのことをいう。そのため、環状ジペプチドは、鎖状のジペプチドとは区別される。なお、本明細書において、環状ジペプチド又はその塩をまとめて、単に、環状ジペプチドと称する場合がある。また、本明細書において、環状ジペプチドのアミノ酸構成が同じであれば、それらの記載順序はいずれが先でも構わず、例えば、〔Cyclo(Met-Arg)〕と〔Cyclo(Arg-Met)〕とは同じ環状ジペプチドを表すものである。 2. Cyclic dipeptide In this specification, “cyclic dipeptide” refers to a cyclic dipeptide having a diketopiperazine structure formed by dehydration condensation of an amino group and a carboxyl group of an amino acid. Say. Therefore, the cyclic dipeptide is distinguished from the chain dipeptide. In addition, in this specification, cyclic dipeptide or its salt may be collectively called a cyclic dipeptide. Further, in this specification, as long as the cyclic dipeptides have the same amino acid configuration, any order thereof may be used, for example, [Cyclo (Met-Arg)] and [Cyclo (Arg-Met)] and Represent the same cyclic dipeptide.
　環状ジペプチドではアミド結合を介して二個のアミノ酸の末端部分が結合しているため（即ち、環状ジペプチドは、アミノ末端とカルボキシ末端とがアミド結合することによって形成される環状構造を有しているため）、分子末端部分に極性基であるカルボキシル基やアミノ基が露出している直鎖状ジペプチド（特に、同種のアミノ酸組成からなる直鎖状ジペプチド）と比較して環状ジペプチドは脂溶性が高いという特徴を有する。そのため、環状ジペプチドは直鎖状のジペプチドと比較して、消化管透過性や膜透過性に優れる。このことは、過去に報告されているラット反転腸管を用いた化合物透過試験の結果からも明らかである（J. Pharmacol, 1998, 50: 167-172）。また環状ジペプチドは、その特異的な構造から各種ペプチダーゼに対する耐性も高まると考えられる。 In cyclic dipeptides, the terminal portions of two amino acids are linked via an amide bond (that is, the cyclic dipeptide has a cyclic structure formed by the amide bond between the amino terminus and the carboxy terminus. Therefore, cyclic dipeptides are more lipophilic than linear dipeptides with polar carboxyl groups or amino groups exposed at the molecular end (particularly linear dipeptides of the same amino acid composition). It has the characteristics. Therefore, cyclic dipeptides are superior in gastrointestinal permeability and membrane permeability compared to linear dipeptides. This is also clear from the results of compound permeation tests using rat inverted intestinal tracts reported in the past (J. Pharmacol, 1998, 50: 167-172). Cyclic dipeptides are also considered to have increased resistance to various peptidases due to their specific structure.
　本発明において有効成分として含有される環状ジペプチド又はその塩は、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上のものである。環状ジペプチド又はその塩の数は特に限定されないが、本発明では、上述した環状ジペプチド又はその塩から選択される２つ以上を有効成分とすることが好ましい。 Cyclic dipeptide or a salt thereof contained as an active ingredient in the present invention includes cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyl lysine [Cyclo (Ala- Lys)], cycloglutamyl tyrosine (Cyclo (Glu-Tyr)), cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine (Cyclo (Glu-Tyr)) -His)], cyclotryptophanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cycloisoleucine serine (Cyclo (Ile-Ser)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloasparaginylyl Syn (Cyclo (Asn-Lys)), Cyclolysyl valine (Cyclo (Lys-Val)), Cycloceryl tyrosine (Cyclo (Ser-Tyr)), Cycloaspartyl glutamic acid (Cyclo (Asp-Glu)), Cyclohisti Diisoleucine (Cyclo (His-Ile)), cycloalanylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloalanylleucine (Cyclo (Ala-Leu)), cyclo Isoleucil proline (Cyclo (Ile-Pro)), cycloglutamyl valine (Cyclo (Glu-Val)), cycloalanyl tyrosine (Cyclo (Ala-Tyr)), cycloglycyl tyrosine (Cyclo (Gly-Tyr)) Cycloglutaminylphenylalanine (Cyclo (Gln-Phe)), cyclothreonyl valine (Cyclo (Thr-Val)), cycloaspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg) )], Cycloaspartyl leucine [Cyclo (Asp-Leu)], cycloisoleucine Silthreonine [Cyclo (Ile-Thr)], Cycloalanylmethionine [Cyclo (Ala-Met)], Cyclolysylproline [Cyclo (Lys-Pro)], Cycloseryltryptophan [Cyclo (Ser-Trp)], Cycloleu One or more selected from the group consisting of syltryptophan [Cyclo (Leu-Trp)] and cyclovalylvaline [Cyclo (Val-Val)]. Although the number of cyclic dipeptide or its salt is not specifically limited, In this invention, it is preferable to use as an active ingredient two or more selected from the cyclic dipeptide or its salt mentioned above.
　本発明では、アンジオテンシン変換酵素阻害効果の観点から、有効成分として含有される環状ジペプチド又はその塩は、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、及びシクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕からなる群から選択される１つ又は２つ以上のものであることが好ましく、前記環状ジペプチド又はその塩から選択される３つ以上を有効成分とすることがより好ましい。また、前記環状ジペプチド又はその塩の中では、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、及びシクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕からなる群から選択される１つ又は２つ以上が好ましく、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、及び／又はシクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕がより好ましい。 In the present invention, from the viewpoint of angiotensin converting enzyme inhibitory effect, the cyclic dipeptide or salt thereof contained as an active ingredient is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)]. Cycloalanyl lysine (Cyclo (Ala-Lys)), cycloglutamyl tyrosine (Cyclo (Glu-Tyr)), cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys) )], Cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl asparagine [Cyclo (Trp-Asn)], cyclolysyl lysine [Cyclo (Lys-Lys)], cyclovalylserine [Cyclo (Val-Ser )], Cycloisoleucylserine [Cyclo (Ile-Ser)], and cycloarginyltyrosine [Cyclo (Arg-Tyr)], preferably one or two or more selected from the group consisting of , Serial and more preferably in a cyclic dipeptide or three or more active ingredients selected from a salt thereof. Among the cyclic dipeptides or salts thereof, cycloisoleucine serine [Cyclo (Ile-Ser)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)] 1 or 2 or more selected from the group consisting of cyclolysyllysine [Cyclo (Lys-Lys)] and cycloarginyltyrosine [Cyclo (Arg-Tyr)] is preferred, and cycloisoleucylserine [Cyclo ( Ile-Ser)] and / or cycloarginyl tyrosine [Cyclo (Arg-Tyr)].
　また、本発明では、アンジオテンシンＩＩ受容体拮抗効果の観点から、有効成分として含有される環状ジペプチド又はその塩は、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、シクロバリルバリン〔Cyclo(Val-Val)〕、及びシクログルタミルチロシン〔Cyclo(Glu-Tyr)〕からなる群から選択される１つ又は２つ以上のものであることが好ましく、前記環状ジペプチド又はその塩から選択される３つ以上を有効成分とすることがより好ましい。また、前記環状ジペプチド又はその塩の中では、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロバリルバリン〔Cyclo(Val-Val)〕、及びシクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕からなる群から選択される１つ又は２つ以上が好ましく、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、及び／又はシクロバリルバリン〔Cyclo(Val-Val)〕がより好ましい。 In the present invention, from the viewpoint of angiotensin II receptor antagonistic effect, the cyclic dipeptide or salt thereof contained as an active ingredient is cycloarginylphenylalanine [Cyclo (Arg-Phe)], cyclolysylphenylalanine [Cyclo (Lys- Phe)], cycloasparaginyl lysine (Cyclo (Asn-Lys)), cyclolysyl valine (Cyclo (Lys-Val)), cycloseryl tyrosine (Cyclo (Ser-Tyr)), cycloaspartyl glutamic acid (Cyclo (Asp -Glu)], cyclohistidylisoleucine (Cyclo (His-Ile)), cycloalanylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloglutamylphenylalanine (Cyclo ( Glu-Phe)], cycloalanyl leucine (Cyclo (Ala-Leu)), cycloisoleucil proline (Cyclo (Ile-Pro)), cycloglutamyl valine (Cyclo (Glu-Val)), cycloalanyl tyros (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln-Phe)), cyclothreonyl valine (Cyclo (Thr-Val)), cyclo Aspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg)), cycloaspartyl leucine (Cyclo (Asp-Leu)), cycloisoleucil threonine (Cyclo (Ile-Thr)) ), Cycloalanylmethionine [Cyclo (Ala-Met)], cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cyclolysylproline [Cyclo (Lys-Pro)], cycloseryltryptophan [Cyclo (Ser-Trp)] ], Cycloleucyltryptophan [Cyclo (Leu-Trp)], cyclovalylvaline [Cyclo (Val-Val)], and cycloglutamyltyrosine [Cyclo (Glu-Tyr)]. Preferably, the ring More preferably, three or more selected from dipeptides or salts thereof are used as active ingredients. Among the cyclic dipeptides or salts thereof, cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartylglutamic acid [Cyclo (Asp-Glu)], cyclovalylvaline [Cyclo (Val-Val)], and One or two or more selected from the group consisting of cycloasparaginyl lysine [Cyclo (Asn-Lys)] is preferred, and cycloglutamyltyrosine [Cyclo (Glu-Tyr)] and / or cyclovalylvaline [Cyclo ( Val-Val)] is more preferable.
　本明細書において「環状ジペプチドの塩」とは、前記環状ジペプチドの薬理学的に許容される任意の塩（無機塩及び有機塩を含む）をいい、例えば、前記環状ジペプチドのナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩、塩酸塩、硫酸塩、硝酸塩、燐酸塩、有機酸塩（酢酸塩、クエン酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、乳酸塩、コハク酸塩、フマル酸塩、プロピオン酸塩、蟻酸塩、安息香酸塩、ピクリン酸塩、ベンゼンスルホン酸塩、トリフルオロ酢酸塩等）等が挙げられるが、これらに限定されない。環状ジペプチドの塩は、当該分野で公知の任意の方法により、当業者によって容易に調製され得る。 As used herein, the term “cyclic dipeptide salt” refers to any pharmacologically acceptable salt (including inorganic salts and organic salts) of the cyclic dipeptide, such as sodium salt and potassium salt of the cyclic dipeptide. , Calcium salt, magnesium salt, ammonium salt, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate , Fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, and the like), but are not limited thereto. Cyclic dipeptide salts can be readily prepared by those skilled in the art by any method known in the art.
　本発明で用いる環状ジペプチドは、当該分野で公知の方法に従って調製することができる。例えば、化学合成法や酵素法、微生物発酵法により製造されてもよく、直鎖状ペプチドを脱水及び環化させることにより合成されてもよく、特開２００３－２５２８９６号公報やJournal of Peptide Science, 10, 737-737, 2004に記載の方法に従って調製することもできる。例えば、動植物由来タンパク質を含む原料に酵素処理や熱処理を施して得られる動植物由来ペプチドを、さらに高温加熱処理することで、環状ジペプチドを豊富に含む動植物由来ペプチド熱処理物を得ることができる。これらの点から、本発明で用いる環状ジペプチド又はその塩は、化学的又は生物的に合成されるものであってもよいし、或いは動植物由来ペプチドから得られるものであってもよい。 The cyclic dipeptide used in the present invention can be prepared according to a method known in the art. For example, it may be produced by a chemical synthesis method, an enzymatic method, or a microbial fermentation method, or may be synthesized by dehydration and cyclization of a linear peptide. JP 2003-252896 A, Journal of Peptide や Science, 10, 737-737, 2004. For example, an animal and plant derived peptide heat-treated product rich in cyclic dipeptide can be obtained by further heat-treating an animal and plant derived peptide obtained by subjecting a raw material containing animal and plant derived protein to enzyme treatment or heat treatment. From these points, the cyclic dipeptide or salt thereof used in the present invention may be chemically or biologically synthesized, or may be obtained from an animal or plant derived peptide.
　３．動植物由来ペプチド
　本明細書における「動植物由来ペプチド」は特に限定されないが、例えば、大豆ペプチド、茶ペプチド、麦芽ペプチド、乳ペプチド、プラセンタペプチド、コラーゲンペプチド等を用いることができる。動植物由来のタンパク質又はタンパク質を含む原料から動植物由来ペプチドを調製して用いてもよいが、市販品を用いてもよい。 3. Animal and Plant Derived Peptide “Animal and Plant Derived Peptide” in the present specification is not particularly limited. For example, soybean peptide, tea peptide, malt peptide, milk peptide, placenta peptide, collagen peptide and the like can be used. Animal and plant-derived peptides may be prepared and used from animal or plant-derived proteins or raw materials containing proteins, but commercially available products may also be used.
　３－１．大豆ペプチド
　本明細書でいう「大豆ペプチド」とは、大豆タンパク質に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる低分子ペプチドをいう。原料となる大豆（学名：Glycine max）は品種や産地などの制限なく用いることができ、粉砕品などの加工品段階のものを用いることもできる。 3-1. Soybean peptide As used herein, “soybean peptide” refers to a low molecular weight peptide obtained by subjecting soy protein to enzyme treatment or heat treatment to lower the molecular weight of the protein. Soybeans (scientific name: Glycine max) used as a raw material can be used without restriction of varieties and production areas, and can also be used in processed products such as pulverized products.
　３－２．茶ペプチド
　本明細書でいう「茶ペプチド」とは、茶（茶葉や茶殻を含む）抽出物に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる茶由来の低分子ペプチドをいう。抽出原料となる茶葉としては、茶樹（学名：Camellia sinensis）を用いて製造された茶葉の葉、茎など、抽出して飲用可能な部位を使用することができる。また、その形態も大葉、粉状など制限されない。茶葉の収穫期についても、所望する香味に合わせて適宜選択できる。 3-2. Tea peptide As used herein, “tea peptide” refers to a low molecular weight peptide derived from tea obtained by subjecting a tea (including tea leaves or tea husk) extract to enzyme treatment or heat treatment to lower the protein. . As a tea leaf used as an extraction raw material, a tea leaf (scientific name: Camellia sinensis) manufactured tea leaf leaf, stem, etc. that can be extracted and used can be used. Also, the form is not limited to large leaves or powders. The harvest time of tea leaves can also be selected appropriately according to the desired flavor.
　３－３．麦芽ペプチド
　本明細書でいう「麦芽ペプチド」とは、麦芽又はその粉砕物から得られる抽出物に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる麦芽由来の低分子ペプチドをいう。原料となる麦芽ペプチドは、品種や産地などの制限なく用いることができるが、特に大麦の種子を発芽させた大麦麦芽が好適に用いられる。本明細書においては、大麦麦芽を単に「麦芽」と表記することもある。 3-3. Malt peptide As used herein, the term “malt peptide” refers to a malt-derived low molecular weight peptide obtained by subjecting an extract obtained from malt or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of the protein. . Although the malt peptide used as a raw material can be used without restriction of varieties and production areas, barley malt obtained by germinating barley seeds is particularly preferably used. In the present specification, barley malt may be simply referred to as “malt”.
　３－４．乳ペプチド
　本明細書でいう「乳ペプチド」とは、天然の乳由来の成分である乳蛋白質をアミノ酸が少なくとも数個結合した分子に分解したものである。より具体的には、ホエイ（乳清タンパク質）又はカゼイン等の乳蛋白質をプロテナーゼ等の酵素により加水分解し、これを濾過して得られる濾液を殺菌及び／又は濃縮して乾燥することにより得られるホエイペプチド、カゼインペプチド等が挙げられる。 3-4. Milk peptide As used herein, “milk peptide” is a product obtained by decomposing milk protein, which is a component derived from natural milk, into a molecule in which at least several amino acids are bound. More specifically, it is obtained by hydrolyzing milk protein such as whey (whey protein) or casein with an enzyme such as proteinase, and filtering and sterilizing and / or concentrating and drying the filtrate. Examples include whey peptides and casein peptides.
　３－５．プラセンタペプチド
　プラセンタとは哺乳類の胎盤のことであり、その優れた機能性から、近年、健康食品、化粧品、医薬品素材として用いられている。本明細書において「プラセンタペプチド」とは、プラセンタを酵素処理、又は亜臨界処理により可溶化、低分子化したものをいう。また、本来の意味とは異なるが、植物の胎座から得られる抽出物が胎盤由来のプラセンタと同等の生理学的効果を有するものとして健康食品、化粧品等に利用されており、これらは植物プラセンタと呼ばれる。本明細書における「プラセンタペプチド」には、植物プラセンタに酵素処理、又は亜臨界処理等を施し、可溶化、低分子化したものも含まれる。 3-5. The placenta peptide placenta is the placenta of mammals and has been used as a health food, cosmetics, and pharmaceutical material in recent years because of its excellent functionality. In the present specification, “placenta peptide” refers to a placenta that has been solubilized and reduced in molecular weight by enzyme treatment or subcritical treatment. In addition, although different from the original meaning, extracts obtained from plant placenta are used in health foods, cosmetics, etc. as having a physiological effect equivalent to placenta derived from placenta. be called. The “placenta peptide” in the present specification includes those obtained by subjecting plant placenta to enzyme treatment or subcritical treatment, solubilization and low molecular weight.
　３－６．コラーゲンペプチド
　本明細書でいう「コラーゲンペプチド」とは、コラーゲン又はその粉砕物を酵素処理や熱処理を施し、コラーゲンを低分子化することによって得られる低分子ペプチドをいう。コラーゲンは動物の結合組織の主要なタンパク質であり、ヒトを含めた哺乳類の身体に最も大量に含まれるタンパク質である。 3-6. Collagen peptide As used herein, the term “collagen peptide” refers to a low molecular peptide obtained by subjecting collagen or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of collagen. Collagen is a major protein in animal connective tissue and is the most abundant protein in mammalian bodies including humans.
　４．動植物由来ペプチド熱処理物
　上述した通り、動植物由来ペプチドを高温加熱処理することで、環状ジペプチドを豊富に含む動植物由来ペプチド熱処理物を得ることができる。本明細書において「高温加熱処理」とは、１００℃以上の温度かつ大気圧を超える圧力下で一定時間処理することを意味する。高温高圧処理装置としては、耐圧性抽出装置や圧力鍋、オートクレーブなどを条件に合わせて用いることができる。 4). As described above animal and plant derived peptides Cook, by high-temperature heat treatment plants and animals derived peptides, it is possible to obtain plants and animals derived peptides heat treatment comprising a cyclic dipeptide rich. In this specification, “high temperature heat treatment” means that the treatment is performed for a certain period of time at a temperature of 100 ° C. or higher and a pressure exceeding atmospheric pressure. As the high-temperature and high-pressure treatment device, a pressure-resistant extraction device, a pressure cooker, an autoclave, or the like can be used according to conditions.
　高温加熱処理における温度は、１００℃以上である限り特に限定されないが、好ましくは１００℃～１７０℃、より好ましくは１１０℃～１５０℃、さらにより好ましくは１２０℃～１４０℃である。なお、この温度は、加熱装置として耐圧性抽出装置を用いた場合には抽出カラムの出口温度を測定した値を示し、加熱装置としてオートクレーブを用いた場合には、圧力容器内の中心温度の温度を測定した値を示す。 The temperature in the high-temperature heat treatment is not particularly limited as long as it is 100 ° C or higher, but is preferably 100 ° C to 170 ° C, more preferably 110 ° C to 150 ° C, and still more preferably 120 ° C to 140 ° C. In addition, this temperature shows the value which measured the exit temperature of the extraction column, when using a pressure-resistant extraction apparatus as a heating apparatus, and when using an autoclave as a heating apparatus, it is the temperature of the center temperature in a pressure vessel. The measured value is shown.
　高温加熱処理における圧力は、大気圧を超える圧力である限り特に限定されないが、好ましくは０．１０１ＭＰａ～０．７９ＭＰａ、より好ましくは０．１０１ＭＰａ～０．６０ＭＰａ、さらにより好ましくは０．１０１ＭＰａ～０．４８ＭＰａである。 The pressure in the high-temperature heat treatment is not particularly limited as long as it is a pressure exceeding atmospheric pressure, but is preferably 0.101 MPa to 0.79 MPa, more preferably 0.101 MPa to 0.60 MPa, and even more preferably 0.101 MPa to 0. 48 MPa.
　高温加熱処理時間は、環状ジペプチドを含む処理物が得られる限り特に限定されないが、好ましくは１５分～６００分程度、より好ましくは３０分～５００分程度、さらにより好ましくは６０分～３００分程度である。 The high-temperature heat treatment time is not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but is preferably about 15 minutes to 600 minutes, more preferably about 30 minutes to 500 minutes, and even more preferably about 60 minutes to 300 minutes. It is.
　また、動植物由来ペプチドの高温加熱処理条件は、環状ジペプチドを含む処理物が得られる限り特に限定されないが、好ましくは［温度：圧力：時間］が［１００℃～１７０℃：０．１０１ＭＰａ～０．７９ＭＰａ：１５分～６００分］、より好ましくは［１１０℃～１５０℃：０．１０１ＭＰａ～０．６０ＭＰａ：３０分～５００分］、さらにより好ましくは［１２０℃～１４０℃：０．１０１ＭＰａ～０．４８ＭＰａ：６０分～３００分］である。 In addition, the high-temperature heat treatment conditions for the animal and plant derived peptides are not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but preferably [temperature: pressure: time] is [100 ° C. to 170 ° C .: 0.101 MPa to 0.001. 79 MPa: 15 minutes to 600 minutes], more preferably [110 ° C. to 150 ° C .: 0.101 MPa to 0.60 MPa: 30 minutes to 500 minutes], even more preferably [120 ° C. to 140 ° C .: 0.101 MPa to 0 48 MPa: 60 minutes to 300 minutes].
　なお、得られた動植物由来ペプチド熱処理物に対して、所望により、濾過、遠心分離、濃縮、限外濾過、凍結乾燥、粉末化等の処理を行ってもよい。また、動植物由来ペプチド熱処理物中の特定の環状ジペプチドが所望の含有量に満たなければ、不足する特定の環状ジペプチドについては他の動植物由来ペプチドや市販品、合成品を用いて適宜追加することもできる。 In addition, you may perform processes, such as filtration, centrifugation, concentration, ultrafiltration, lyophilization | freeze-drying, and powdering, with respect to the obtained heat-processed peptide derived from animals and plants. In addition, if the specific cyclic dipeptide in the heat-treated product of animal and plant derived peptides does not satisfy the desired content, the specific cyclic dipeptide that is deficient may be appropriately added using other animal or plant derived peptides, commercial products, or synthetic products. it can.
　５．レニン－アンジオテンシン系抑制用組成物
　５－１．環状ジペプチド含有レニン－アンジオテンシン系抑制用組成物
　本発明の一態様は、特定の環状ジペプチド又はその塩を有効成分とするレニン－アンジオテンシン系抑制用組成物である。 5). 5. Renin-angiotensin system inhibiting composition 5-1. Cyclic Dipeptide-Containing Renin-Angiotensin System Inhibiting Composition One embodiment of the present invention is a renin-angiotensin system inhibiting composition containing a specific cyclic dipeptide or a salt thereof as an active ingredient.
　本発明のレニン－アンジオテンシン系抑制用組成物は、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として含むものである。本発明のレニン－アンジオテンシン系抑制用組成物に含まれる環状ジペプチド又はその塩の数は特に限定されないが、本発明では、上述した環状ジペプチド又はその塩から選択される３つ以上が含まれることが好ましい。 The composition for inhibiting renin-angiotensin system of the present invention comprises cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)]. Cycloglutamyl tyrosine [Cyclo (Glu-Tyr)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucine lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)] ], Cyclotryptophanyl asparagine [Cyclo (Trp-Asn)], cyclolysyl lysine [Cyclo (Lys-Lys)], cyclovalylserine [Cyclo (Val-Ser)], cycloisoleucine serine [Cyclo (Ile- Ser)), cycloarginyl tyrosine (Cyclo (Arg-Tyr)], cycloarginylphenylalanine (Cyclo (Arg-Phe)), cyclolysylphenylalanine (Cyclo (Lys-Phe)), cycloasparaginyl lysine (Cyclo ( Asn-Lys) Cyclolysyl valine [Cyclo (Lys-Val)], cycloseryltyrosine [Cyclo (Ser-Tyr)], cycloaspartyl glutamic acid [Cyclo (Asp-Glu)], cyclohistidylisoleucine [Cyclo (His-Ile)] ), Cycloalanylglutamic acid [Cyclo (Ala-Glu)], cyclovalylglycine [Cyclo (Val-Gly)], cycloalanylleucine [Cyclo (Ala-Leu)], cycloisoleucylproline [Cyclo (Ile- Pro)), cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln -Phe)], cyclothreonyl valine (Cyclo (Thr-Val)), cycloaspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg)), cycloaspartyl leucine (Cyclo (Asp-Leu)], cycloisoleucil threonine [ Cyclo (Ile-Thr)], cycloalanyl methionine (Cyclo (Ala-Met)), cyclolysyl proline (Cyclo (Lys-Pro)), cycloseryl tryptophan (Cyclo (Ser-Trp)), cycloleucyl tryptophan [ Cyclo (Leu-Trp)] and cyclovalylvaline [Cyclo (Val-Val)] are included as an active ingredient, or one or more cyclic dipeptides or salts thereof selected from the group consisting of. The number of cyclic dipeptides or salts thereof contained in the renin-angiotensin system inhibiting composition of the present invention is not particularly limited, but the present invention may include three or more selected from the above-mentioned cyclic dipeptides or salts thereof. preferable.
　本発明のレニン－アンジオテンシン系抑制用組成物は、アンジオテンシン変換酵素阻害効果の観点から、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、及びシクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として含むものである。本発明の組成物は、好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を有効成分として含むものである。前記環状ジペプチド又はその塩の中では、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、及びシクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕からなる群から選択される１つ又は２つ以上が好ましく、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、及び／又はシクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕がより好ましい。 The composition for inhibiting renin-angiotensin system of the present invention comprises cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyl from the viewpoint of angiotensin converting enzyme inhibitory effect. Lysine (Cyclo (Ala-Lys)), cycloglutamyl tyrosine (Cyclo (Glu-Tyr)), cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleuyl lysine (Cyclo (Ile-Lys)), cyclo Glutamylhistidine (Cyclo (Glu-His)), cyclotryptophanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cyclo One or more cyclic dipeptides selected from the group consisting of isoleucylserine [Cyclo (Ile-Ser)] and cycloarginyltyrosine [Cyclo (Arg-Tyr)] or salts thereof as active ingredients Is Dressings. The composition of the present invention preferably contains three or more selected from the cyclic dipeptides or salts thereof as active ingredients. Among the cyclic dipeptides or salts thereof, cycloisoleucine serine [Cyclo (Ile-Ser)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclo One or more selected from the group consisting of lysyl lysine [Cyclo (Lys-Lys)] and cycloarginyl tyrosine [Cyclo (Arg-Tyr)] are preferred, and cycloisoleucine serine [Cyclo (Ile- Ser)] and / or cycloarginyl tyrosine [Cyclo (Arg-Tyr)].
　また、本発明のレニン－アンジオテンシン系抑制用組成物は、アンジオテンシンＩＩ受容体拮抗効果の観点から、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、シクロバリルバリン〔Cyclo(Val-Val)〕、及びシクログルタミルチロシン〔Cyclo(Glu-Tyr)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として含むものである。本発明の組成物は、好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を有効成分として含むものである。前記環状ジペプチド又はその塩の中では、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロバリルバリン〔Cyclo(Val-Val)〕、及びシクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕からなる群から選択される１つ又は２つ以上が好ましく、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、及び／又はシクロバリルバリン〔Cyclo(Val-Val)〕がより好ましい。 In addition, the renin-angiotensin system inhibiting composition of the present invention, from the viewpoint of angiotensin II receptor antagonistic effect, cycloarginylphenylalanine [Cyclo (Arg-Phe)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], Cycloasparaginyl lysine (Cyclo (Asn-Lys)), cyclolysyl valine (Cyclo (Lys-Val)), cycloseryltyrosine (Cyclo (Ser-Tyr)), cycloaspartyl glutamic acid (Cyclo (Asp-Glu)) Cyclohistidylisoleucine (Cyclo (His-Ile)), cycloalanyl glutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloglutamylphenylalanine (Cyclo (Glu-Phe)) ], Cycloalanyl leucine [Cyclo (Ala-Leu)], cycloisoleucylproline [Cyclo (Ile-Pro)], cycloglutamylvaline [Cyclo (Glu-Val)], cycloalanyl tyrosine [Cyclo (Ala- Tyr) ), Cycloglycyltyrosine [Cyclo (Gly-Tyr)], cycloglutaminylphenylalanine [Cyclo (Gln-Phe)], cyclothreonyl valine [Cyclo (Thr-Val)], cycloaspartyl valine [Cyclo (Asp- Val)], cyclomethionyl arginine (Cyclo (Met-Arg)), cycloaspartyl leucine (Cyclo (Asp-Leu)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloalanyl methionine (Cyclo (Ala-Met)], cycloaspartylphenylalanine (Cyclo (Asp-Phe)), cyclolysylproline (Cyclo (Lys-Pro)), cycloseryltryptophan (Cyclo (Ser-Trp)), cycloleucyltryptophan (Cyclo (Leu-Trp)], cyclovalylvaline [Cyclo (Val-Val)], and cycloglutamyltyrosine [Cyclo (Glu-Tyr)], or one or more cyclic dipeptides or salts thereof Containing as an active ingredient It is. The composition of the present invention preferably contains three or more selected from the cyclic dipeptides or salts thereof as active ingredients. Among the cyclic dipeptides or salts thereof, cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartylglutamic acid [Cyclo (Asp-Glu)], cyclovalylvaline [Cyclo (Val-Val)], and cycloaspara One or two or more selected from the group consisting of ginyllysine [Cyclo (Asn-Lys)] are preferred, and cycloglutamyltyrosine [Cyclo (Glu-Tyr)] and / or cyclovalylvaline [Cyclo (Val- Val)] is more preferable.
　本発明のレニン－アンジオテンシン系抑制用組成物における環状ジペプチド又はその塩の含有量は、その投与形態、投与方法などを考慮し、本発明の所望の効果が得られるような量であればよく、特に限定されるものではない。例えば、動植物由来ペプチドを原料として用いる場合、本発明の組成物における環状ジペプチド又はその塩の含有量の総量は、１．０×１０ｐｐｍ／Ｂｒｉｘ以上、好ましくは１．０×１０2ｐｐｍ／Ｂｒｉｘ以上であり、５．０×１０3ｐｐｍ／Ｂｒｉｘ以下、好ましくは３．０×１０3ｐｐｍ／Ｂｒｉｘ以下である。また、本発明のレニン－アンジオテンシン系抑制用組成物におけるシクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、シクロバリルバリン〔Cyclo(Val-Val)〕、又はそれぞれに対応する塩の含有量としては、１．０ｐｐｍ／Ｂｒｉｘ以上、好ましくは１．０×１０ｐｐｍ／Ｂｒｉｘ以上であり、５．０×１０3ｐｐｍ／Ｂｒｉｘ以下、好ましくは３．０×１０3ｐｐｍ／Ｂｒｉｘ以下である。前記の含有量は、合成品又は精製品の環状ジペプチド又はその塩を用いた場合にも適用可能である。本発明において、環状ジペプチド又はその塩の含有量は上記の通りＢｒｉｘ（ブリックス）あたりの量で表される。本明細書において「Ｂｒｉｘあたりの量」は、２０℃のショ糖溶液（ショ糖のみを溶質として含む水溶液）の質量百分率に相当する値で定められる量を意味する。なお、特に断りがない限り、本明細書において用いる「ｐｐｍ」は、重量／容量（ｗ／ｖ）のｐｐｍを意味し、１．０ｐｐｍ／Ｂｒｉｘは溶媒の比重が１の場合、０．１ｍｇ／ｍＬと換算され、０．０１重量％と換算されるものである。 The content of the cyclic dipeptide or the salt thereof in the renin-angiotensin system inhibiting composition of the present invention may be an amount that can achieve the desired effect of the present invention in consideration of its administration form, administration method, etc. It is not particularly limited. For example, when animal or plant-derived peptides are used as raw materials, the total content of cyclic dipeptides or salts thereof in the composition of the present invention is 1.0 × 10 ppm / Brix or more, preferably 1.0 × 10 2 ppm / Brix or more. 5.0 × 10 3 ppm / Brix or less, preferably 3.0 × 10 3 ppm / Brix or less. Further, cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyl lysine [Cyclo (Ala-Lys)] in the renin-angiotensin system inhibiting composition of the present invention. ), Cycloglutamyl tyrosine [Cyclo (Glu-Tyr)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucine lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)] )], Cyclotryptophanyl asparagine [Cyclo (Trp-Asn)], cyclolysyl lysine [Cyclo (Lys-Lys)], cyclovalylserine [Cyclo (Val-Ser)], cycloisoleuyl serine [Cyclo (Ile -Ser)], cycloarginyltyrosine (Cyclo (Arg-Tyr)), cycloarginylphenylalanine (Cyclo (Arg-Phe)), cyclolysylphenylalanine (Cyclo (Lys-Phe)), cycloasparaginyl lysine (Cyc lo (Asn-Lys)], cyclolysyl valine [Cyclo (Lys-Val)], cycloseryltyrosine [Cyclo (Ser-Tyr)], cycloaspartyl glutamic acid [Cyclo (Asp-Glu)], cyclohistidylisoleucine (Cyclo (His-Ile)), cycloalanylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloalanylleucine (Cyclo (Ala-Leu)), cycloisoleucine Sylproline (Cyclo (Ile-Pro)), cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cyclo Glutaminylphenylalanine (Cyclo (Gln-Phe)), cyclothreonyl valine (Cyclo (Thr-Val)), cycloaspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg)) , Cycloaspartyl leucine (Cyclo (Asp-Leu)), cycloisoleucine Onine (Cyclo (Ile-Thr)), Cycloalanylmethionine (Cyclo (Ala-Met)), Cyclolysylproline (Cyclo (Lys-Pro)), Cycloseryltryptophan (Cyclo (Ser-Trp)), Cycloleusyl The content of tryptophan [Cyclo (Leu-Trp)], cyclovalylvaline [Cyclo (Val-Val)], or a salt corresponding to each, is 1.0 ppm / Brix or more, preferably 1.0 × 10 ppm / Brix. It is above, and is 5.0 * 10 < 3 > ppm / Brix or less, Preferably it is 3.0 * 10 < 3 > ppm / Brix or less. The above content can also be applied when a synthetic or purified cyclic dipeptide or a salt thereof is used. In the present invention, the content of the cyclic dipeptide or a salt thereof is represented by the amount per Brix as described above. In this specification, “amount per Brix” means an amount determined by a value corresponding to a mass percentage of a sucrose solution at 20 ° C. (an aqueous solution containing only sucrose as a solute). Unless otherwise specified, “ppm” used in the present specification means ppm of weight / volume (w / v), and 1.0 ppm / Brix is 0.1 mg / wt when the specific gravity of the solvent is 1. Converted to mL and converted to 0.01% by weight.
　環状ジペプチド又はその塩の含有量は、公知の方法に従って測定することができる。例えば、ＬＣ－ＭＳ／ＭＳ又は糖度計を使用することで測定することができる。 The content of the cyclic dipeptide or a salt thereof can be measured according to a known method. For example, it can be measured by using LC-MS / MS or a saccharimeter.
　５－２．作用メカニズム
　上述した通り「レニン－アンジオテンシン系」とは、レニン及びアンジオテンシノーゲンの作用に基づいて血圧が調節される系をいう。当該系には種々の因子が関与しており、その一つとしてアンジオテンシン変換酵素が挙げられる。アンジオテンシン変換酵素は肺毛細血管等に存在しており、アンジオテンシンＩをアンジオテンシンＩＩに変換する作用を有している。これにより変換されたアンジオテンシンＩＩは、副腎皮質に存在する受容体に結合し、副腎皮質からのアルドステロンの合成及び分泌を促進する。このアルドステロンの働きによって腎集合管でのナトリウムの再吸収を促進し、これによって体液量が増加して昇圧作用がもたらされる。そのため、アンジオテンシン変換酵素の阻害はアンジオテンシンＩＩの産生抑制に寄与し、それによって血圧上昇抑制作用や血圧降下作用が得られる。 5-2. Mechanism of Action As described above, the “renin-angiotensin system” refers to a system in which blood pressure is regulated based on the action of renin and angiotensinogen. Various factors are involved in the system, one of which is an angiotensin converting enzyme. Angiotensin converting enzyme is present in pulmonary capillaries and the like, and has an action of converting angiotensin I into angiotensin II. The converted angiotensin II binds to a receptor present in the adrenal cortex and promotes aldosterone synthesis and secretion from the adrenal cortex. The action of aldosterone promotes the reabsorption of sodium in the renal collecting duct, thereby increasing the amount of fluid and causing a pressor action. Therefore, inhibition of angiotensin converting enzyme contributes to suppression of production of angiotensin II, thereby obtaining an antihypertensive action and an antihypertensive action.
　また、レニン－アンジオテンシン系に関与する因子には、上述の内容に関連してアンジオテンシンＩＩ及びアンジオテンシンＩＩ受容体（ＡＴ－１又はＡＴ－２）が挙げられる。上述した通り、アンジオテンシンＩＩはアンジオテンシンＩＩ受容体に結合して、アルドステロンの合成及び分泌を促進し、結果的に昇圧作用をもたらす。そのため、アンジオテンシンＩＩのアンジオテンシンＩＩ受容体への結合を阻害することは、アルドステロンの合成及び分泌の抑制に寄与し、それによって血圧上昇抑制作用や血圧降下作用が得られる。アンジオテンシンＩＩのその受容体への結合阻害は、アンジオテンシンＩＩ受容体拮抗作用（即ち、アンジオテンシンＩＩと拮抗してアンジオテンシンＩＩのアンジオテンシンＩＩ受容体への結合を阻害する作用）を有する物質を用いて対処することが可能である。 In addition, factors involved in the renin-angiotensin system include angiotensin II and angiotensin II receptor (AT-1 or AT-2) in relation to the above contents. As described above, angiotensin II binds to the angiotensin II receptor and promotes aldosterone synthesis and secretion, resulting in a pressor effect. Therefore, inhibiting the binding of angiotensin II to the angiotensin II receptor contributes to suppression of aldosterone synthesis and secretion, thereby obtaining an increase in blood pressure and an effect of lowering blood pressure. Inhibition of binding of angiotensin II to its receptor is addressed using a substance having an angiotensin II receptor antagonism (ie, an action that antagonizes angiotensin II and inhibits angiotensin II binding to the angiotensin II receptor). It is possible.
　５－３．他の成分
　本発明のレニン－アンジオテンシン系抑制用組成物は、その形態に応じて、環状ジペプチド又はその塩の他に、任意の添加剤、通常用いられる任意の成分を含有することができる。これらの添加剤及び／又は成分の例としては、ビタミンＥ、ビタミンＣ等のビタミン類、ミネラル類、栄養成分、香料などの生理活性成分の他、製剤化において配合される賦形剤、結合剤、乳化剤、緊張化剤（等張化剤）、緩衝剤、溶解補助剤、防腐剤、安定化剤、抗酸化剤、着色剤、凝固剤、又はコーティング剤等が挙げられるが、これらに限定されるものではない。 5-3. Other Components The renin-angiotensin system-suppressing composition of the present invention can contain any additive and any commonly used component in addition to the cyclic dipeptide or a salt thereof, depending on the form. Examples of these additives and / or ingredients include vitamins such as vitamin E and vitamin C, bioactive ingredients such as minerals, nutritional ingredients, and fragrances, as well as excipients and binders incorporated in the formulation. , Emulsifiers, tonicity agents (isotonic agents), buffers, solubilizers, preservatives, stabilizers, antioxidants, colorants, coagulants, or coating agents, but are not limited thereto. It is not something.
　５－４．用途
　本発明のレニン－アンジオテンシン系抑制用組成物は、前述の環状ジペプチド又はその塩を有効成分として含有することを特徴としており、当該有効成分がレニン－アンジオテンシン系の抑制効果に寄与し得る。レニン－アンジオテンシン系の抑制には、アンジオテンシン変換酵素の阻害やアンジオテンシンＩＩのその受容体（ＡＴ－１又はＡＴ－２）への結合阻害が含まれ、前述の環状ジペプチド又はその塩は、後述の実施例でも示される通りアンジオテンシン変換酵素の阻害作用やアンジオテンシンＩＩ受容体の拮抗作用を有している。従って、本発明の一態様は、所定の環状ジペプチド又はその塩を有効成分として含有するレニン－アンジオテンシン系抑制用組成物であって、アンジオテンシン変換酵素阻害作用を有する前記組成物である。また、本発明の別の一つの態様は、所定の環状ジペプチド又はその塩を有効成分として含有するレニン－アンジオテンシン系抑制用組成物であって、アンジオテンシンＩＩ受容体（ＡＴ－１又はＡＴ－２）拮抗作用を有する前記組成物である。これらの作用に基づき、本発明のレニン－アンジオテンシン系抑制用組成物は、アンジオテンシン変換酵素阻害用組成物及び／又はアンジオテンシンＩＩ受容体（ＡＴ－１又はＡＴ－２）拮抗用組成物ともなり得る。 5-4. Use The composition for inhibiting renin-angiotensin system of the present invention is characterized by containing the aforementioned cyclic dipeptide or a salt thereof as an active ingredient, and the active ingredient can contribute to the inhibitory effect of renin-angiotensin system. Inhibition of the renin-angiotensin system includes inhibition of angiotensin converting enzyme and inhibition of binding of angiotensin II to its receptor (AT-1 or AT-2). As shown in the examples, it has an inhibitory action on angiotensin converting enzyme and an antagonistic action on angiotensin II receptor. Therefore, one aspect of the present invention is a renin-angiotensin system-suppressing composition containing a predetermined cyclic dipeptide or a salt thereof as an active ingredient, which has an angiotensin converting enzyme inhibitory action. Another embodiment of the present invention is a composition for inhibiting renin-angiotensin system containing a predetermined cyclic dipeptide or a salt thereof as an active ingredient, and an angiotensin II receptor (AT-1 or AT-2) The composition having an antagonistic action. Based on these actions, the renin-angiotensin system inhibiting composition of the present invention can also be an angiotensin converting enzyme inhibiting composition and / or angiotensin II receptor (AT-1 or AT-2) antagonistic composition.
　また、本発明の組成物に含まれる前述の環状ジペプチド又はその塩は、レニン－アンジオテンシン系の抑制を通じて血圧上昇抑制、血圧降下、腎機能保護、及び脳卒中又は心疾患の予防又は改善を行うことができる。そのため、本発明の更なる別の一つの態様は、所定の環状ジペプチド又はその塩を有効成分として含有するレニン－アンジオテンシン系抑制用組成物であって、血圧上昇抑制用、血圧降下用、腎機能保護用、又は脳卒中若しくは心疾患の予防若しくは改善用の前記組成物である。これらの用途に基づき、本発明のレニン－アンジオテンシン系抑制用組成物は、血圧上昇抑制用組成物、血圧降下用組成物、腎機能保護用組成物、又は脳卒中若しくは心疾患の予防若しくは改善用組成物ともなり得る。 In addition, the above-mentioned cyclic dipeptide or a salt thereof contained in the composition of the present invention can suppress blood pressure increase, blood pressure decrease, protect renal function, and prevent or improve stroke or heart disease through suppression of the renin-angiotensin system. it can. Therefore, still another embodiment of the present invention is a renin-angiotensin-based composition for suppressing renin-angiotensin system containing a predetermined cyclic dipeptide or a salt thereof as an active ingredient, for suppressing blood pressure increase, for decreasing blood pressure, for renal function Said composition for protection, or prevention or amelioration of stroke or heart disease. Based on these uses, the renin-angiotensin system-suppressing composition of the present invention is a composition for suppressing blood pressure elevation, a composition for reducing blood pressure, a composition for protecting renal function, or a composition for preventing or improving stroke or heart disease. It can be a thing.
　本発明の組成物はまた、血圧上昇に関連して、高血圧症等の治療及び／又は予防にも有用である。なお、脳卒中においては脳梗塞、脳出血、くも膜下出血等が含まれ、心疾患においては狭心症、心筋梗塞、心肥大、心不全等が含まれる。 The composition of the present invention is also useful for treatment and / or prevention of hypertension and the like in relation to an increase in blood pressure. Stroke includes cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage and the like, and heart diseases include angina pectoris, myocardial infarction, cardiac hypertrophy, heart failure and the like.
　本発明のレニン－アンジオテンシン系抑制用組成物は、例えば、前記環状ジペプチド又はその塩を含有する原料に、所望により溶剤、分散剤、乳化剤、緩衝剤、安定剤、賦形剤、結合剤、崩壊剤、又は滑沢剤等を加えて、公知の方法に従って、錠剤、顆粒剤、散剤、粉末剤、又はカプセル剤等の固形剤や、通常液剤、懸濁剤、又は乳剤等の液剤等に製剤化することができる。これらの組成物はそのまま水等と共に服用することができる。また、容易に配合することが出来る形態（例えば、粉末形態や顆粒形態）に調製後、例えば、医薬品の原材料として用いることができる。 The renin-angiotensin system-suppressing composition of the present invention includes, for example, a solvent, a dispersing agent, an emulsifier, a buffering agent, a stabilizer, an excipient, a binder, a disintegration, if necessary, in the raw material containing the cyclic dipeptide or a salt thereof In accordance with a publicly known method, it is formulated into a solid agent such as a tablet, granule, powder, powder, or capsule, or a liquid agent such as a normal solution, suspension, or emulsion. Can be These compositions can be taken with water or the like as it is. Moreover, after preparing the form (for example, powder form and granule form) which can be mix | blended easily, it can use, for example as a raw material of a pharmaceutical.
　本発明のレニン－アンジオテンシン系抑制用組成物は、一例として、剤の形態で提供することができるが、本形態に限定されるものではない。当該剤をそのまま組成物として、或いは当該剤を含む組成物として提供することもできる。本発明の組成物としては、医薬組成物、飲食品組成物、食品組成物、飲料組成物、化粧用組成物等が挙げられるが、これらに限定されない。食品組成物の限定的でない例として、機能性食品、健康補助食品、栄養機能食品、特別用途食品、特定保健用食品、栄養補助食品、食事療法用食品、健康食品、サプリメント、食品添加剤等が挙げられる。 The renin-angiotensin system inhibiting composition of the present invention can be provided in the form of an agent as an example, but is not limited to this form. The agent can be provided as a composition as it is or as a composition containing the agent. Examples of the composition of the present invention include, but are not limited to, a pharmaceutical composition, a food / beverage product composition, a food composition, a beverage composition, a cosmetic composition, and the like. Non-limiting examples of food compositions include functional foods, health supplements, functional nutrition foods, special foods, foods for specified health use, dietary supplements, diet foods, health foods, supplements, food additives, etc. Can be mentioned.
　本発明のレニン－アンジオテンシン系抑制用組成物は、治療的用途（医療用途）又は非治療用途（非医療用途）のいずれにも適用することができる。具体的には、医薬品、医薬部外品及び化粧料等や薬事法上はこれらに属さないが、血圧の上昇を抑制する効果、血圧の上昇を緩やかにする効果、高血圧症の予防効果、又は高血圧症の改善効果等を明示的又は暗示的に訴求する組成物としての使用が挙げられる。 The renin-angiotensin composition-suppressing composition of the present invention can be applied to any therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, it does not belong to pharmaceuticals, quasi-drugs, cosmetics, etc. or the Pharmaceutical Affairs Law, but it has an effect of suppressing an increase in blood pressure, an effect of slowing an increase in blood pressure, an effect of preventing hypertension, or Examples thereof include use as a composition that explicitly or implicitly promotes the effect of improving hypertension and the like.
　本発明は、別の側面では、レニン－アンジオテンシン系の抑制により発揮される機能の表示を付した、前記レニン－アンジオテンシン系抑制用組成物に関する。このような表示又は機能性表示は特に限定されないが、例えば、「血圧低下を期待する」、「血圧の上昇を抑制する」、「血圧の上昇を緩やかにする」、「高血圧症を予防する」、「高血圧症の改善に役立つ」、「腎機能を保護する」、「腎機能を改善する」等、或いは、これらと同視できる表示又は機能性表示が挙げられる。本明細書において、当該表示及び機能性表示のような表示は、組成物自体に付されてもよいし、組成物の容器又は包装に付されていてもよい。 In another aspect, the present invention relates to the renin-angiotensin system-suppressing composition, which is labeled with the function exhibited by the renin-angiotensin system suppression. Such display or functional display is not particularly limited. For example, “expect blood pressure reduction”, “suppress blood pressure increase”, “slow blood pressure increase”, “prevent hypertension”. , “Helps to improve hypertension”, “protects renal function”, “improves renal function” and the like, or a display or functional display that can be equated with these. In the present specification, indications such as the indication and the functionality indication may be attached to the composition itself, or may be attached to a container or packaging of the composition.
　本発明のレニン－アンジオテンシン系抑制用組成物は、その形態に応じた適当な方法で摂取することができる。摂取方法は、本発明の環状ジペプチド又はその塩が循環血中に移行できるのであれば特に限定はない。例えば、錠剤、被覆錠剤、顆粒剤、散剤、又はカプセル剤等の経口用固形製剤、内服液剤、又はシロップ剤等の経口用液体製剤、注射剤、外用剤、坐剤、又は経皮吸収剤等の非経口用製剤などの形態とすることができるが、これらに限定されない。なお、本明細書において「摂取」とは、摂取、服用、又は飲用等の全態様を含むものとして用いられる。 The renin-angiotensin system inhibiting composition of the present invention can be taken by an appropriate method according to the form. The intake method is not particularly limited as long as the cyclic dipeptide of the present invention or a salt thereof can be transferred into the circulating blood. For example, oral solid preparations such as tablets, coated tablets, granules, powders, or capsules, oral liquid preparations such as oral liquids, syrups, injections, external preparations, suppositories, or transdermal absorption agents, etc. However, the present invention is not limited thereto. In the present specification, “ingestion” is used to include all aspects such as ingestion, taking, or drinking.
　本発明のレニン－アンジオテンシン系抑制用組成物の適用量は、その形態、投与方法、使用目的及び投与対象である患者又は患獣の年齢、体重、症状によって適時設定され、一定ではない。本発明の組成物の有効ヒト摂取量は一定ではないが、例えば、その有効成分である環状ジペプチド又はその塩の重量として、体重５０ｋｇのヒトで一日あたり、好ましくは１０ｍｇ以上、より好ましくは１００ｍｇ以上である。また、投与は所望の投与量範囲内において、１日内において単回又は数回に分けて行ってもよい。投与期間も任意である。なお、本発明の組成物の有効ヒト摂取量とは、ヒトにおいて有効な効果を示す本発明のレニン－アンジオテンシン系抑制用組成物の摂取量のことであり、当該組成物に含まれる環状ジペプチドの種類は特に限定されない。 The application amount of the renin-angiotensin system-suppressing composition of the present invention is set in a timely manner according to the form, administration method, purpose of use, and age, weight, and symptoms of the patient or animal subject to administration, and is not constant. Although the effective human intake of the composition of the present invention is not constant, for example, the weight of the cyclic dipeptide or salt thereof as the active ingredient is preferably 10 mg or more, more preferably 100 mg per day for a human body weight of 50 kg. That's it. Further, administration may be performed once or several times within one day within a desired dose range. The administration period is also arbitrary. The effective human intake of the composition of the present invention refers to the intake of the renin-angiotensin system-suppressing composition of the present invention showing an effective effect in humans, and the cyclic dipeptide contained in the composition The type is not particularly limited.
　本発明のレニン－アンジオテンシン系抑制用組成物の適用対象は、好ましくはヒトであるが、ウシ、ウマ、ヤギ等の家畜動物、イヌ、ネコ、ウサギ等のペット動物、又は、マウス、ラット、モルモット、サル等の実験動物であってもよい。 The application target of the renin-angiotensin system inhibiting composition of the present invention is preferably human, but domestic animals such as cattle, horses and goats, pet animals such as dogs, cats and rabbits, or mice, rats and guinea pigs. Or a laboratory animal such as a monkey.
　６．レニン－アンジオテンシン系を抑制するための環状ジペプチド又はその塩の使用
　本発明の一態様は、アミノ酸を構成単位とする特定の環状ジペプチド又はその塩のレニン－アンジオテンシン系抑制のための使用である。好ましくは、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩のレニン－アンジオテンシン系抑制のための使用である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むもののレニン－アンジオテンシン系抑制のための使用である。 6). Use of a cyclic dipeptide or a salt thereof for inhibiting the renin-angiotensin system One embodiment of the present invention is the use of a specific cyclic dipeptide or a salt thereof having an amino acid as a constituent unit for inhibiting the renin-angiotensin system. Preferably, cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr) )], Cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucine lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl asparagine [Cyclo ( Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalyl serine (Cyclo (Val-Ser)), cycloisoleucil serine (Cyclo (Ile-Ser)), cycloarginyl tyrosine (Cyclo (Arg-Tyr)], cycloarginylphenylalanine (Cyclo (Arg-Phe)), cyclolysylphenylalanine (Cyclo (Lys-Phe)), cycloasparaginyl lysine (Cyclo (Asn-Lys)), cyclolysyl valine [ Cyclo (Lys-Val)), Loceryl tyrosine (Cyclo (Ser-Tyr)), cycloaspartyl glutamic acid (Cyclo (Asp-Glu)), cyclohistidyl isoleucine (Cyclo (His-Ile)), cycloalanyl glutamic acid (Cyclo (Ala-Glu)) ), Cyclovalylglycine [Cyclo (Val-Gly)], cycloalanyl leucine [Cyclo (Ala-Leu)], cycloisoleucylproline [Cyclo (Ile-Pro)], cycloglutamylvaline [Cyclo (Glu-Val)] )], Cycloalanyltyrosine [Cyclo (Ala-Tyr)], cycloglycyltyrosine [Cyclo (Gly-Tyr)], cycloglutaminylphenylalanine [Cyclo (Gln-Phe)], cyclothreonylvaline [Cyclo (Thr -Val)], cycloaspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg)), cycloaspartyl leucine (Cyclo (Asp-Leu)), cycloisoleucil threonine [ Cyclo (Ile-Thr)], cycloalanylmethionine [C yclo (Ala-Met)], cyclolysylproline (Cyclo (Lys-Pro)), cycloseryltryptophan (Cyclo (Ser-Trp)), cycloleucyltryptophan (Cyclo (Leu-Trp)), and cyclovalylvaline [ Use of one or more cyclic dipeptides selected from the group consisting of Cyclo (Val-Val)] or a salt thereof for renin-angiotensin system inhibition. More preferably, use is made of the cyclic dipeptide or a salt thereof containing at least three selected from the cyclic dipeptide or a salt thereof for inhibiting the renin-angiotensin system.
　本発明の使用には、例えば、アンジオテンシン変換酵素の阻害のため、アンジオテンシンＩＩのその受容体（ＡＴ－１又はＡＴ－２）への結合阻害のため、及び／又は血圧上昇を抑制するための、前記環状ジペプチド又はその塩の使用が含まれるが、これらに限定されるものではない。また、当該使用は、ヒト又は非ヒト動物における使用であり、治療的使用であっても非治療的使用であってもよい。ここで、「非治療的」とは、医療行為、即ち、治療による人体への処理行為を含まない概念である。 Uses of the present invention include, for example, for inhibiting angiotensin converting enzyme, for inhibiting binding of angiotensin II to its receptor (AT-1 or AT-2), and / or for suppressing an increase in blood pressure. This includes, but is not limited to, the use of the cyclic dipeptides or salts thereof. In addition, the use is a use in a human or non-human animal, and may be a therapeutic use or a non-therapeutic use. Here, “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by treatment.
　７．レニン－アンジオテンシン系を抑制する方法
　本発明の一態様は、アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として使用する、レニン－アンジオテンシン系を抑制する方法である。当該方法は、好ましくは、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として使用することを含む、レニン－アンジオテンシン系を抑制する方法である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むものを有効成分として使用することを含む、レニン－アンジオテンシン系を抑制する方法である。 7). Method for inhibiting renin-angiotensin system One embodiment of the present invention is a method for inhibiting the renin-angiotensin system using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient. The method is preferably cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl Asparagine (Cyclo (Trp-Asn)), Cyclolysyl lysine (Cyclo (Lys-Lys)), Cyclovalylserine (Cyclo (Val-Ser)), Cycloisoleucine serine (Cyclo (Ile-Ser)), Cycloargy Nyltyrosine (Cyclo (Arg-Tyr)), cycloarginylphenylalanine (Cyclo (Arg-Phe)), cyclolysylphenylalanine (Cyclo (Lys-Phe)), cycloasparaginyl lysine (Cyclo (Asn-Lys)), Cyclolisylvaline (Cyclo (L ys-Val)], cycloseryltyrosine [Cyclo (Ser-Tyr)], cycloaspartylglutamic acid [Cyclo (Asp-Glu)], cyclohistidylisoleucine [Cyclo (His-Ile)], cycloalanylglutamic acid [ Cyclo (Ala-Glu)], cyclovalylglycine (Cyclo (Val-Gly)), cycloalanyl leucine (Cyclo (Ala-Leu)), cycloisoleucil proline (Cyclo (Ile-Pro)), cycloglutamyl valine (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln-Phe)), cyclothreo Nilvaline (Cyclo (Thr-Val)), cycloaspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg)), cycloaspartyl leucine (Cyclo (Asp-Leu)), Cycloisoleuyl threonine (Cyclo (Ile-Thr)), cycloalanyl Thionine [Cyclo (Ala-Met)], Cyclolysylproline [Cyclo (Lys-Pro)], Cycloseryltryptophan [Cyclo (Ser-Trp)], Cycloleusyltryptophan [Cyclo (Leu-Trp)], and Cyclovalyl A method for inhibiting the renin-angiotensin system, comprising using one or more cyclic dipeptides selected from the group consisting of valine [Cyclo (Val-Val)] or a salt thereof as an active ingredient. More preferably, it is a method for suppressing the renin-angiotensin system, comprising using as an active ingredient a substance containing three or more selected from the cyclic dipeptides or salts thereof.
　当該方法に関する別の態様は、レニン－アンジオテンシン系の抑制を必要とする対象に、特定の環状ジペプチド又はその塩を有効成分として治療有効量を投与することを含む、レニン－アンジオテンシン系を抑制する方法である。好ましくは、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として治療有効量を投与することを含む、レニン－アンジオテンシン系を抑制する方法である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むものを有効成分として治療有効量を投与することを含む、レニン－アンジオテンシン系を抑制する方法である。 Another aspect related to the method includes a method for inhibiting the renin-angiotensin system, comprising administering to a subject in need of inhibition of the renin-angiotensin system a therapeutically effective amount of a specific cyclic dipeptide or a salt thereof as an active ingredient. It is. Preferably, cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr) )], Cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucine lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl asparagine [Cyclo ( Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalyl serine (Cyclo (Val-Ser)), cycloisoleucil serine (Cyclo (Ile-Ser)), cycloarginyl tyrosine (Cyclo (Arg-Tyr)], cycloarginylphenylalanine (Cyclo (Arg-Phe)), cyclolysylphenylalanine (Cyclo (Lys-Phe)), cycloasparaginyl lysine (Cyclo (Asn-Lys)), cyclolysyl valine [ Cyclo (Lys-Val)), Loceryl tyrosine (Cyclo (Ser-Tyr)), cycloaspartyl glutamic acid (Cyclo (Asp-Glu)), cyclohistidyl isoleucine (Cyclo (His-Ile)), cycloalanyl glutamic acid (Cyclo (Ala-Glu)) ), Cyclovalylglycine [Cyclo (Val-Gly)], cycloalanyl leucine [Cyclo (Ala-Leu)], cycloisoleucylproline [Cyclo (Ile-Pro)], cycloglutamylvaline [Cyclo (Glu-Val)] )], Cycloalanyltyrosine [Cyclo (Ala-Tyr)], cycloglycyltyrosine [Cyclo (Gly-Tyr)], cycloglutaminylphenylalanine [Cyclo (Gln-Phe)], cyclothreonylvaline [Cyclo (Thr -Val)], cycloaspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg)), cycloaspartyl leucine (Cyclo (Asp-Leu)), cycloisoleucil threonine [ Cyclo (Ile-Thr)], cycloalanylmethionine [C yclo (Ala-Met)], cyclolysylproline (Cyclo (Lys-Pro)), cycloseryltryptophan (Cyclo (Ser-Trp)), cycloleucyltryptophan (Cyclo (Leu-Trp)), and cyclovalylvaline [ Cyclo (Val-Val)] is a method for inhibiting the renin-angiotensin system, comprising administering a therapeutically effective amount of one or more cyclic dipeptides selected from the group consisting of Cyclo (Val-Val) or a salt thereof as an active ingredient . More preferably, it is a method for inhibiting the renin-angiotensin system, comprising administering a therapeutically effective amount using as an active ingredient a substance containing three or more selected from the cyclic dipeptides or salts thereof.
　上記方法において、レニン－アンジオテンシン系の抑制を必要とする対象とは、本発明のレニン－アンジオテンシン系抑制用組成物の前記適用対象と同様である。また、本明細書中において治療有効量とは、本発明のレニン－アンジオテンシン系抑制用組成物を上記対象に投与した場合に、投与していない対象と比較して、レニン－アンジオテンシン系が抑制される量のことである。具体的な有効量としては、投与形態、投与方法、使用目的及び対象の年齢、体重、症状等によって適時設定され一定ではない。 In the above method, the subject requiring renin-angiotensin system inhibition is the same as the application subject of the renin-angiotensin system inhibiting composition of the present invention. In the present specification, the therapeutically effective amount means that when the renin-angiotensin system-suppressing composition of the present invention is administered to the above-mentioned subject, the renin-angiotensin system is suppressed as compared with a non-administered subject. It is the amount. The specific effective amount is appropriately set depending on the administration form, administration method, purpose of use, age, weight, symptom, etc. of the subject and is not constant.
　本発明の方法においては、前記治療有効量となるよう、前記特定の環状ジペプチド又はその塩をそのまま、或いは、特定の環状ジペプチド又はその塩を含有する組成物として投与してもよい。 In the method of the present invention, the specific cyclic dipeptide or a salt thereof may be administered as it is or as a composition containing the specific cyclic dipeptide or a salt thereof so that the therapeutically effective amount is obtained.
　本発明の方法によれば、副作用を生じることなくレニン－アンジオテンシン系を抑制することが可能になる。 According to the method of the present invention, it is possible to suppress the renin-angiotensin system without causing side effects.
　以下、本発明を実施例によりさらに詳しく説明するが、これにより本発明の範囲を限定するものではない。当業者は、本発明の方法を種々変更、修飾して使用することが可能であり、これらも本発明の範囲に含まれる。 Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited thereby. Those skilled in the art can use the method of the present invention with various changes and modifications, and these are also included in the scope of the present invention.
　実施例１．アンジオテンシンＩ変換酵素活性に対する活性阻害効果
　アンジオテンシンＩ変換酵素活性に対する環状ジペプチド標品の阻害効果を調べた。具体的には、化学合成した環状ジペプチド標品について、ＡＣＥ　Ｋｉｔ－ＷＳＴ（（株）同仁化学研究所）を使用し、当該キットに付属の説明書に従って各種環状ジペプチドのアンジオテンシンＩ変換酵素阻害活性を測定した。環状ジペプチドは５０μＭ及び５００μＭの各濃度について検討し、その阻害活性は、下記の式１を用いて算出されたアンジオテンシンＩ変換酵素の残存活性として評価した。コントロールとしては、環状ジペプチド水溶液の代わりに蒸留水を添加したものを用いた。 Example 1. Activity inhibitory effect on angiotensin I converting enzyme activity The inhibitory effect of cyclic dipeptide preparations on angiotensin I converting enzyme activity was examined. Specifically, with respect to chemically synthesized cyclic dipeptide preparations, ACE Kit-WST (Dojindo Laboratories Co., Ltd.) was used, and angiotensin I converting enzyme inhibitory activity of various cyclic dipeptides according to the instructions attached to the kit. It was measured. The cyclic dipeptide was examined for each concentration of 50 μM and 500 μM, and the inhibitory activity was evaluated as the residual activity of angiotensin I converting enzyme calculated using the following formula 1. As control, what added distilled water instead of cyclic dipeptide aqueous solution was used.
　（式１）
残存活性（％）＝（環状ジペプチド添加群における450nm吸光度/コントロールにおける450nm吸光度）×１００
　各種環状ジペプチドの評価結果を下記の表１に示す。 (Formula 1)
Residual activity (%) = (450 nm absorbance in cyclic dipeptide addition group / 450 nm absorbance in control) × 100
The evaluation results of various cyclic dipeptides are shown in Table 1 below.
Figure JPOXMLDOC01-appb-T000001
 　上記の結果から、表１に示した環状ジペプチドはいずれもアンジオテンシンＩ変換酵素の阻害活性を有することが明らかとなった。
Figure JPOXMLDOC01-appb-T000001
 From the above results, it was revealed that all the cyclic dipeptides shown in Table 1 have angiotensin I converting enzyme inhibitory activity.
　実施例２．アンジオテンシンＩＩ受容体（AT-1）に関する拮抗作用
　環状ジペプチド標品のアンジオテンシンII受容体における拮抗作用（即ち、アンジオテンシンIIのアンジオテンシンII受容体への結合阻害作用）を調べるため、アンジオテンシンII受容体に対する結合アッセイを実施した。具体的には、ヒト組み換えアンジオテンシンII 1型受容体（AT-1）発現HEK-293細胞を用い、これに3nMのアンジオテンシンIIと各種濃度の化学合成された環状ジペプチド標品とを添加して、カルシウムイオンの流入による細胞内カルシウムイオン濃度の変化を測定した。なお、細胞内カルシウムイオン濃度は蛍光光度分析により定量した。 Example 2 Antagonism of angiotensin II receptor (AT-1 ) To examine the antagonistic action of cyclic dipeptide preparations on angiotensin II receptor (ie, inhibition of binding of angiotensin II to angiotensin II receptor), binding to angiotensin II receptor The assay was performed. Specifically, using human recombinant angiotensin II type 1 receptor (AT-1) expressing HEK-293 cells, to this was added 3 nM angiotensin II and various concentrations of chemically synthesized cyclic dipeptide preparations, Changes in intracellular calcium ion concentration due to calcium ion influx were measured. The intracellular calcium ion concentration was quantified by fluorometric analysis.
　被験環状ジペプチドの拮抗作用については、環状ジペプチドを添加しない場合の応答率（細胞内カルシウムイオン濃度の変化）を100%とし、これに対して環状ジペプチドを添加したときの応答率(%)を評価した。その結果を表２に示す。 For the antagonistic action of the test cyclic dipeptide, the response rate (change in intracellular calcium ion concentration) when no cyclic dipeptide was added was taken as 100%, and the response rate (%) when a cyclic dipeptide was added was evaluated. did. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
 　上記の結果から、表２に示した環状ジペプチドはいずれもアンジオテンシンII受容体における拮抗作用（即ち、アンジオテンシンIIのアンジオテンシンII受容体への結合阻害作用）を有することが明らかとなった。
Figure JPOXMLDOC01-appb-T000002
 From the above results, it became clear that all of the cyclic dipeptides shown in Table 2 have an antagonistic action at the angiotensin II receptor (that is, an inhibitory action of angiotensin II binding to the angiotensin II receptor).
　実施例３．環状ジペプチド及び直鎖ジペプチド投与時の血中動態の比較
　レニン－アンジオテンシン系抑制作用を有する環状ジペプチドの一種であるCyclo(Tyr-Gly) 10mg/kgをマウスに経口投与した後の血漿中濃度を測定し、血中動態を確認した。比較対象として、体重1kgあたりの重量として等量の直鎖ジペプチドTyr-Gly(10mg/kg)投与後の血中動態を併せて検討した。 Example 3 FIG. Comparison of blood kinetics during administration of cyclic dipeptide and linear dipeptide Measures plasma concentration after oral administration of 10 mg / kg of cyclo (Tyr-Gly), a cyclic dipeptide having a renin-angiotensin system inhibitory effect, to mice The blood dynamics were confirmed. As comparison subjects, blood kinetics after administration of an equal amount of linear dipeptide Tyr-Gly (10 mg / kg) as a weight per kg body weight were also examined.
　日本クレア社よりBALB/cマウス（雄性、６週齢）を購入し、約1週間馴化させた後に試験に供した。Cyclo(Tyr-Gly)（神戸天然物化学社）又は直鎖ジペプチドTyr-Gly（BACHEM社）を蒸留水に溶解し、投与量が10mg/kgとなるようにシリンジ及びゾンデを用いてそれぞれ別のマウス個体に経口投与した。一定時間後に腹部大静脈より血液を回収し、ヘパリンリチウム及び血漿分離剤入り採血容器（キャピジェクト、テルモ社）を用いて速やかに血漿を取得した。取得した血漿のうち20μLを、内部標準物質入り溶液10μL、水10μL、及びアセトニトリル80μLと順に混合し、撹拌及び遠心分離（15,000rpm、10℃、4℃）を行い、タンパク質を除去した。なお、内部標準物質として、Cyclo(Tyr-Gly)の場合はワルファリン、直鎖Tyr-Glyの場合はフェニトインを使用した。遠心後の上清を窒素気流下で蒸発乾固し、アセトニトリル15%水溶液で再溶解してLC-MS/MS分析（質量分析装置：API5000、AB Sciex社）に供した。LC-MS/MS分析は以下の分析条件で実施した。定量解析はブランク血漿試料と標準品水溶液とを用いて作成した検量線データを利用して実施し、投与後各時間における血漿中濃度（ng/mL）を得た。その結果を図１に示す。グラフ中の各時刻における血漿中濃度の値は（平均値）±（標準誤差）（n=4）を示す。 BALB / c mice (male, 6 weeks old) were purchased from CLEA Japan, and acclimated for about 1 week before being used for the test. Cyclo (Tyr-Gly) (Kobe Natural Products Chemicals) or linear dipeptide Tyr-Gly (BACHEM) is dissolved in distilled water, and each dose is 10 mg / kg using a syringe and a sonde. Orally administered to individual mice. After a certain period of time, blood was collected from the abdominal vena cava, and plasma was quickly obtained using a blood collection container (Capture, Terumo) containing lithium heparin and a plasma separating agent. 20 μL of the obtained plasma was mixed with 10 μL of an internal standard substance-containing solution, 10 μL of water, and 80 μL of acetonitrile in this order, followed by stirring and centrifugation (15,000 rpm, 10 ° C., 4 ° C.) to remove proteins. As internal standards, warfarin was used for Cyclo (Tyr-Gly), and phenytoin was used for linear Tyr-Gly. The supernatant after centrifugation was evaporated to dryness under a nitrogen stream, redissolved with a 15% acetonitrile aqueous solution, and subjected to LC-MS / MS analysis (mass spectrometer: API5000, AB Sciex). LC-MS / MS analysis was performed under the following analysis conditions. Quantitative analysis was performed using calibration curve data prepared using a blank plasma sample and a standard aqueous solution, and plasma concentrations (ng / mL) at each time after administration were obtained. The result is shown in FIG. The value of plasma concentration at each time in the graph represents (mean value) ± (standard error) (n = 4).
　＜LC-MS/MSの分析条件＞
[HPLC条件]
　移動相は以下の溶媒を使用し、下記のグラジェント条件を適用した。
（基本条件）
流速：0.2mL/分
分析時間：
　Cyclo(Tyr-Gly): 15分/サンプル
　直鎖Tyr-Gly: 13分/サンプル
カラム：Cadenza CD-C18 150(mm)×2(mm), 粒子径3μm
（移動相）
Ａ相：0.1％ ギ酸水溶液
Ｂ相：メタノール
（グラジェント条件） <Analysis conditions for LC-MS / MS>
[HPLC conditions]
The following solvents were used for the mobile phase, and the following gradient conditions were applied.
(Basic conditions)
Flow rate: 0.2 mL / min Analysis time:
Cyclo (Tyr-Gly): 15 min / sample Linear Tyr-Gly: 13 min / sample Column: Cadenza CD-C18 150 (mm) × 2 (mm), particle size 3μm
(Mobile phase)
Phase A: 0.1% formic acid aqueous solution Phase B: methanol (gradient conditions)
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　[MS/MS条件]
測定モード：
　Cyclo(Tyr-Gly): MRM negative
　直鎖Tyr-Gly: MRM positive
Q1/Q3：  219 > 113（Cyclo(Tyr-Gly)）
　　　　 239 > 136 (直鎖Tyr-Gly)
　上記の結果から、環状ジペプチドCyclo(Tyr-Gly)は直鎖ジペプチドTyr-Glyと比較して、同等の投与量においてはるかに高い血漿中濃度に達することが明らかとなった。仮定として環状ジペプチドと直鎖ジペプチドとで試験管レベルでの試験（in vitro試験）におけるレニン－アンジオテンシン系抑制作用の強さが同等であったとしても、環状ジペプチドではその良好な血中動態に基づいて、直鎖ジペプチドと比較して動物やヒトにおいて強力なレニン－アンジオテンシン系抑制作用が期待できる可能性がある。 [MS / MS conditions]
Measurement mode:
Cyclo (Tyr-Gly): MRM negative
Linear Tyr-Gly: MRM positive
Q1 / Q3: 219> 113 (Cyclo (Tyr-Gly))
239> 136 (linear Tyr-Gly)
From the above results, it was revealed that the cyclic dipeptide Cyclo (Tyr-Gly) reaches a much higher plasma concentration at the same dose compared to the linear dipeptide Tyr-Gly. Assuming that cyclic dipeptides and linear dipeptides have similar inhibitory effects on the renin-angiotensin system in in vitro tests (in vitro tests), cyclic dipeptides are based on their good blood dynamics. Thus, there is a possibility that a stronger renin-angiotensin system inhibitory action can be expected in animals and humans compared to linear dipeptides.
　本発明は、特定の環状ジペプチド又はその塩を有効成分として含有するレニン－アンジオテンシン系抑制用組成物を提供するものである。本発明は、血圧上昇抑制などに資する安全で効果的な新たな手段を提供するものであるため、産業上の利用性が高い。 The present invention provides a composition for renin-angiotensin system inhibition containing a specific cyclic dipeptide or a salt thereof as an active ingredient. Since the present invention provides a new safe and effective means that contributes to suppression of blood pressure increase, etc., the industrial applicability is high.

Claims (10)

  1. 　アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として含有するレニン－アンジオテンシン系抑制用組成物であって、
    　前記環状ジペプチド又はその塩が、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記レニン－アンジオテンシン系抑制用組成物。     A renin-angiotensin system-suppressing composition comprising a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
    The cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cycloisoleucine serine (Cyclo (Ile-Ser)), cyclo Arginyltyrosine [Cyclo (Arg-Tyr)], Cycloarginylphenylalanine [Cyclo (Arg-Phe)], Cyclolysylphenylalanine [Cyclo (Lys-Phe)], Cycloasparaginyllysine [Cyclo (Asn-Lys)] , Cyclolysyl Bali (Cyclo (Lys-Val)), cycloseryltyrosine (Cyclo (Ser-Tyr)), cycloaspartylglutamic acid (Cyclo (Asp-Glu)), cyclohistidylisoleucine (Cyclo (His-Ile)), cycloaralyl Nylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloalanyl leucine (Cyclo (Ala-Leu)), cycloisoleuyl proline (Cyclo (Ile-Pro)), Cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln-Phe)) Cyclothreonyl valine [Cyclo (Thr-Val)], cycloaspartyl valine [Cyclo (Asp-Val)], cyclomethionyl arginine [Cyclo (Met-Arg)], cycloaspartyl leucine [Cyclo (Asp-Leu)] )], Cycloisoleucylthreonine (Cyclo (Ile-Thr)), cyclo Lanylmethionine (Cyclo (Ala-Met)), Cyclolysylproline (Cyclo (Lys-Pro)), Cycloseryltryptophan (Cyclo (Ser-Trp)), Cycloleusyltryptophan (Cyclo (Leu-Trp)), and The renin-angiotensin system-suppressing composition comprising one or more selected from the group consisting of cyclovalyl valine [Cyclo (Val-Val)].
  2. 　アンジオテンシン変換酵素阻害作用を有する、請求項１に記載のレニン－アンジオテンシン系抑制用組成物であって、
    　環状ジペプチド又はその塩が、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、及びシクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記レニン－アンジオテンシン系抑制用組成物。     The composition for inhibiting a renin-angiotensin system according to claim 1, which has an angiotensin converting enzyme inhibitory action,
    Cyclic dipeptide or a salt thereof may be cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [Cyclo (Glu-Tyr)], cycloaspartyl lysine [Cyclo (Asp-Lys)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloglutamyl histidine [Cyclo (Glu-His)], cyclotryptophanyl Asparagine (Cyclo (Trp-Asn)), Cyclolysyl lysine (Cyclo (Lys-Lys)), Cyclovalylserine (Cyclo (Val-Ser)), Cycloisoleucine serine (Cyclo (Ile-Ser)), and Cyclo The renin-angiotensin system-suppressing composition comprising one or more selected from the group consisting of arginyltyrosine [Cyclo (Arg-Tyr)].
  3. 　アンジオテンシンＩＩ受容体拮抗作用を有する、請求項１に記載のレニン－アンジオテンシン系抑制用組成物であって、
    　環状ジペプチド又はその塩が、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、シクロバリルバリン〔Cyclo(Val-Val)〕、及びシクログルタミルチロシン〔Cyclo(Glu-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記レニン－アンジオテンシン系抑制用組成物。     The composition for inhibiting a renin-angiotensin system according to claim 1, which has an angiotensin II receptor antagonistic action,
    Cyclic dipeptide or a salt thereof may be cycloarginylphenylalanine [Cyclo (Arg-Phe)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloasparaginyllysine [Cyclo (Asn-Lys)], cyclolysylvaline [ Cyclo (Lys-Val)], cycloseryltyrosine [Cyclo (Ser-Tyr)], cycloaspartylglutamic acid [Cyclo (Asp-Glu)], cyclohistidylisoleucine [Cyclo (His-Ile)], cycloalanyl Glutamic acid [Cyclo (Ala-Glu)], cyclovalylglycine [Cyclo (Val-Gly)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyl leucine [Cyclo (Ala-Leu)], cycloisoleucine Sylproline (Cyclo (Ile-Pro)), cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cyclo Glutaminylphenylalanine Cyclo (Gln-Phe)], cyclothreonyl valine (Cyclo (Thr-Val)), cycloaspartyl valine (Cyclo (Asp-Val)), cyclomethionyl arginine (Cyclo (Met-Arg)), cycloaspartyl Leucine (Cyclo (Asp-Leu)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloalanyl methionine (Cyclo (Ala-Met)), cycloaspartyl phenylalanine (Cyclo (Asp-Phe)), Cyclolysylproline (Cyclo (Lys-Pro)), cycloseryltryptophan (Cyclo (Ser-Trp)), cycloleucyltryptophan (Cyclo (Leu-Trp)), cyclovalylvaline (Cyclo (Val-Val)), and The renin-angiotensin system-suppressing composition comprising one or more selected from the group consisting of cycloglutamyltyrosine [Cyclo (Glu-Tyr)].
  4. 　血圧上昇抑制用、血圧降下用、腎機能保護用、又は脳卒中若しくは心疾患の予防若しくは改善用である、請求項１～３のいずれか１項に記載のレニン－アンジオテンシン系抑制用組成物。 The composition for renin-angiotensin system suppression according to any one of claims 1 to 3, which is used for suppressing blood pressure increase, for decreasing blood pressure, for protecting renal function, or for preventing or improving stroke or heart disease.
  5. 　環状ジペプチド又はその塩が動植物由来ペプチドから得られるものである、請求項１～４のいずれか１項に記載のレニン－アンジオテンシン系抑制用組成物。 The composition for renin-angiotensin system inhibition according to any one of claims 1 to 4, wherein the cyclic dipeptide or a salt thereof is obtained from an animal or plant-derived peptide.
  6. 　レニン－アンジオテンシン系の抑制により発揮される機能の表示を付した、請求項１～５のいずれか１項に記載のレニン－アンジオテンシン系抑制用組成物。 6. The composition for inhibiting renin-angiotensin system according to any one of claims 1 to 5, which is labeled with a function exhibited by inhibiting the renin-angiotensin system.
  7. 　機能の表示が、「血圧低下を期待する」、「血圧の上昇を抑制する」、「血圧の上昇を緩やかにする」、「高血圧症を予防する」、「高血圧症の改善に役立つ」、「腎機能を保護する」、及び「腎機能を改善する」からなる群から選択されるものである、請求項６に記載のレニン－アンジオテンシン系抑制用組成物。 Function indications are "Expect blood pressure", "Suppress blood pressure rise", "Slow blood pressure rise", "Prevent hypertension", "Help improve hypertension", " The renin-angiotensin system-suppressing composition according to claim 6, which is selected from the group consisting of "protecting renal function" and "improving renal function".
  8. 　前記組成物が剤である、請求項１～７のいずれか１項に記載のレニン－アンジオテンシン系抑制用組成物。 The renin-angiotensin-based composition according to any one of claims 1 to 7, wherein the composition is an agent.
  9. 　レニン－アンジオテンシン系を抑制するための、アミノ酸を構成単位とする環状ジペプチド又はその塩の使用であって、
    　前記環状ジペプチド又はその塩が、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記使用。     Use of a cyclic dipeptide having an amino acid as a structural unit or a salt thereof for suppressing the renin-angiotensin system,
    The cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cycloisoleucine serine (Cyclo (Ile-Ser)), cyclo Arginyltyrosine [Cyclo (Arg-Tyr)], Cycloarginylphenylalanine [Cyclo (Arg-Phe)], Cyclolysylphenylalanine [Cyclo (Lys-Phe)], Cycloasparaginyllysine [Cyclo (Asn-Lys)] , Cyclolysyl Bali (Cyclo (Lys-Val)), cycloseryltyrosine (Cyclo (Ser-Tyr)), cycloaspartylglutamic acid (Cyclo (Asp-Glu)), cyclohistidylisoleucine (Cyclo (His-Ile)), cycloaralyl Nylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloalanyl leucine (Cyclo (Ala-Leu)), cycloisoleuyl proline (Cyclo (Ile-Pro)), Cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln-Phe)) Cyclothreonyl valine [Cyclo (Thr-Val)], cycloaspartyl valine [Cyclo (Asp-Val)], cyclomethionyl arginine [Cyclo (Met-Arg)], cycloaspartyl leucine [Cyclo (Asp-Leu)] )], Cycloisoleucylthreonine (Cyclo (Ile-Thr)), cyclo Lanylmethionine (Cyclo (Ala-Met)), Cyclolysylproline (Cyclo (Lys-Pro)), Cycloseryltryptophan (Cyclo (Ser-Trp)), Cycloleusyltryptophan (Cyclo (Leu-Trp)), and The use as described above, which comprises one or more selected from the group consisting of cyclovalylvaline [Cyclo (Val-Val)].
  10. 　アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として使用する、レニン－アンジオテンシン系を抑制する方法であって、
    　前記環状ジペプチド又はその塩が、シクロアスパルチルフェニルアラニン〔Cyclo(Asp-Phe)〕、シクログルタミルフェニルアラニン〔Cyclo(Glu-Phe)〕、シクロアラニルリシン〔Cyclo(Ala-Lys)〕、シクログルタミルチロシン〔Cyclo(Glu-Tyr)〕、シクロアスパルチルリシン〔Cyclo(Asp-Lys)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクログルタミルヒスチジン〔Cyclo(Glu-His)〕、シクロトリプトファニルアスパラギン〔Cyclo(Trp-Asn)〕、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロバリルセリン〔Cyclo(Val-Ser)〕、シクロイソロイシルセリン〔Cyclo(Ile-Ser)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクロアスパラギニルリシン〔Cyclo(Asn-Lys)〕、シクロリシルバリン〔Cyclo(Lys-Val)〕、シクロセリルチロシン〔Cyclo(Ser-Tyr)〕、シクロアスパルチルグルタミン酸〔Cyclo(Asp-Glu)〕、シクロヒスチジルイソロイシン〔Cyclo(His-Ile)〕、シクロアラニルグルタミン酸〔Cyclo(Ala-Glu)〕、シクロバリルグリシン〔Cyclo(Val-Gly)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロイソロイシルプロリン〔Cyclo(Ile-Pro)〕、シクログルタミルバリン〔Cyclo(Glu-Val)〕、シクロアラニルチロシン〔Cyclo(Ala-Tyr)〕、シクログリシルチロシン〔Cyclo(Gly-Tyr)〕、シクログルタミニルフェニルアラニン〔Cyclo(Gln-Phe)〕、シクロトレオニルバリン〔Cyclo(Thr-Val)〕、シクロアスパルチルバリン〔Cyclo(Asp-Val)〕、シクロメチオニルアルギニン〔Cyclo(Met-Arg)〕、シクロアスパルチルロイシン〔Cyclo(Asp-Leu)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロアラニルメチオニン〔Cyclo(Ala-Met)〕、シクロリシルプロリン〔Cyclo(Lys-Pro)〕、シクロセリルトリプトファン〔Cyclo(Ser-Trp)〕、シクロロイシルトリプトファン〔Cyclo(Leu-Trp)〕、及びシクロバリルバリン〔Cyclo(Val-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記方法。     A method for inhibiting the renin-angiotensin system, comprising using as an active ingredient a cyclic dipeptide having amino acid as a structural unit or a salt thereof,
    The cyclic dipeptide or a salt thereof is cycloaspartylphenylalanine [Cyclo (Asp-Phe)], cycloglutamylphenylalanine [Cyclo (Glu-Phe)], cycloalanyllysine [Cyclo (Ala-Lys)], cycloglutamyltyrosine [ Cyclo (Glu-Tyr)], cycloaspartyl lysine (Cyclo (Asp-Lys)), cycloisoleucil lysine (Cyclo (Ile-Lys)), cycloglutamyl histidine [Cyclo (Glu-His)], cyclotrypto Fanyl asparagine (Cyclo (Trp-Asn)), cyclolysyl lysine (Cyclo (Lys-Lys)), cyclovalylserine (Cyclo (Val-Ser)), cycloisoleucine serine (Cyclo (Ile-Ser)), cyclo Arginyltyrosine [Cyclo (Arg-Tyr)], Cycloarginylphenylalanine [Cyclo (Arg-Phe)], Cyclolysylphenylalanine [Cyclo (Lys-Phe)], Cycloasparaginyllysine [Cyclo (Asn-Lys)] , Cyclolysyl Bali (Cyclo (Lys-Val)), cycloseryltyrosine (Cyclo (Ser-Tyr)), cycloaspartylglutamic acid (Cyclo (Asp-Glu)), cyclohistidylisoleucine (Cyclo (His-Ile)), cycloaralyl Nylglutamic acid (Cyclo (Ala-Glu)), cyclovalylglycine (Cyclo (Val-Gly)), cycloalanyl leucine (Cyclo (Ala-Leu)), cycloisoleuyl proline (Cyclo (Ile-Pro)), Cycloglutamylvaline (Cyclo (Glu-Val)), cycloalanyltyrosine (Cyclo (Ala-Tyr)), cycloglycyltyrosine (Cyclo (Gly-Tyr)), cycloglutaminylphenylalanine (Cyclo (Gln-Phe)) Cyclothreonyl valine [Cyclo (Thr-Val)], cycloaspartyl valine [Cyclo (Asp-Val)], cyclomethionyl arginine [Cyclo (Met-Arg)], cycloaspartyl leucine [Cyclo (Asp-Leu)] )], Cycloisoleucylthreonine (Cyclo (Ile-Thr)), cyclo Lanylmethionine (Cyclo (Ala-Met)), Cyclolysylproline (Cyclo (Lys-Pro)), Cycloseryltryptophan (Cyclo (Ser-Trp)), Cycloleusyltryptophan (Cyclo (Leu-Trp)), and The method as described above, which comprises one or more selected from the group consisting of cyclovalylvaline [Cyclo (Val-Val)].
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