WO2017002840A1

WO2017002840A1 - Endothelin receptor antagonist composition

Info

Publication number: WO2017002840A1
Application number: PCT/JP2016/069230
Authority: WO
Inventors: 伸哉富貴澤; 寿栄鈴木
Original assignee: サントリーホールディングス株式会社
Priority date: 2015-07-01
Filing date: 2016-06-29
Publication date: 2017-01-05
Also published as: JP6857602B2; JPWO2017002840A1; TW201717985A

Abstract

Provided are: an endothelin receptor antagonist composition; a use of said composition as a substance for inhibiting the binding of endothelin to endothelin receptors; and a method for inhibiting the binding of endothelin receptor-binding substances to endothelin receptors. It has been discovered that a specific cyclic dipeptide or a salt thereof exhibits endothelin receptor antagonistic action. The present invention provides a novel and effective means for contributing to the suppression of blood pressure elevation, the improvement of blood flow, the suppression of cerebral oedema formation, and the suppression of epidermal pigmentation.

Description

Endothelin receptor antagonist composition

The present invention relates to an endothelin receptor antagonist composition. More specifically, a composition for endothelin receptor antagonism comprising a specific cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient, and a specific cyclic for inhibiting the binding of an endothelin receptor binding substance to an endothelin receptor. The present invention relates to the use of a dipeptide or a salt thereof, and a method for inhibiting the binding of an endothelin receptor binding substance to an endothelin receptor.

It is widely known that lifestyle-related diseases such as hypertension and hyperlipidemia are caused by changes in dietary habits, lack of exercise, stress, smoking, genetic factors, and the like. In particular, hypertension is characterized by the progression of symptoms without significant subjective symptoms, and when it includes even the hypertension reserve army, it exhibits a very high morbidity rate. In addition, hypertension is serious such as stroke (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, etc.), heart disease (angina, myocardial infarction, cardiac hypertrophy, heart failure, etc.), and renal failure (hypertensive nephropathy, etc.). It is known to lead to various diseases. Therefore, there is a social demand for prevention and early improvement of hypertension.

It is known that endothelin receptor antagonists are useful for improving hypertension and pulmonary hypertension. There are two types of endothelin receptors, ET-A and ET-B. According to Non-Patent Document 1, the expression of ET-B receptor is increased in vascular smooth muscle during arteriosclerosis. In this case, the blood flow in the upper arm was increased when an ET-B antagonist was administered to the patient. Non-patent document 2 reports that ET-B antagonists suppress the formation of brain edema after brain injury in rats. Patent Document 1 discloses that endothelin enhances the activity of tyrosinase, which is the rate-limiting enzyme for melanin synthesis in epidermal melanocytes, and endothelin is produced in epidermal keratinocytes (keratinocytes), thereby causing UV-induced pigmentation and senileity. It has been clarified that it becomes an important factor of pigment spot formation. That is, a substance capable of suppressing the action of endothelin is considered useful for improving and preventing melanin production and pigmentation.

As endothelin receptor antagonists, drugs such as ambrisentan and bosentan are conventionally used in clinical settings. However, these drugs have been reported to have various side effects such as liver symptoms, anemia, and thrombocytopenia. Therefore, as an endothelin receptor antagonist, development of an active ingredient that is safe and can be taken for a long time is desired.

Under such circumstances, “dipeptides” in which two amino acids are combined are attracting attention as functional substances. Since dipeptides can add physical and chemical properties and new effects not found in simple amino acids, they are expected to have a wider range of applications than simple amino acids. It is used for maintenance and prevention / improvement of lifestyle-related diseases.

Recently, a cyclic dipeptide having a cyclic structure generated by dehydration condensation of an amino group and a carboxyl group present at the end of the dipeptide has been developed. The cyclic dipeptide has been reported to have various physiological activities, and demand is expected to expand in the medical and pharmacological fields. For example, Patent Document 2 reports that a cyclic dipeptide has an antidepressant action, a learning motivation improving action, and the like. Non-Patent Document 3 discloses that cyclohistidylproline [Cyclo (His-Pro)] is a central nervous system action such as a body temperature lowering action and an appetite suppressing action, a prolactin secretion inhibiting action, a growth hormone secretion promoting action and the like. It has been described that it exhibits many physiological activities such as hormone-like action, and cycloleusylglycine [Cyclo (Leu-Gly)] has been reported to show memory function improving action.

Non-patent document 4 discloses that cyclotryptophanylproline [Cyclo (Trp-Pro)] has anticancer activity, cyclohistidylproline [Cyclo (His-Pro)] and cycloglycylproline [Cyclo (Gly-Pro)]. ] Antibacterial action, cyclohistidylproline [Cyclo (His-Pro)] neuroprotective action, cycloglycylproline [Cyclo (Gly-Pro)] memory function improving action, cyclotryptophanylproline [Cyclo (Trp -Pro)] and cyclophenylalanylproline [Cyclo (Phe-Pro)] have been described as having action as biological herbicides.

Regarding endothelin receptor antagonism, it has been reported that linear dipeptides having Trp-Trp as a basic skeleton can be used (Patent Document 3). 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 5). It is conceivable that becomes lower. From the above points, among the highly effective endothelin receptor antagonists, those that have fewer side effects, can be applied to oily base materials, and are excellent in absorbability into the body are desirable. .

JP 2012-20950 A Special table 2012-517998 gazette Japanese Patent Laid-Open No. 5-331186

An object of the present invention is to provide an endothelin receptor antagonizing composition that has high safety, is excellent in usability in formulation, and can be expected to have high absorbability into the body. Another object of the present invention is to provide use of the composition for inhibiting the binding of endothelin to the endothelin receptor, and the inhibition of the binding of endothelin to the endothelin receptor.

As a result of intensive studies on the above problems, the present inventors have focused on the use of a cyclic dipeptide having an amino acid as a structural unit, and have found for the first time that the cyclic dipeptide has an endothelin receptor antagonistic action. Based on this finding, the present inventors have completed the present invention.

That is, the present invention relates to the following, but is not limited thereto.
(1) A composition for endothelin receptor antagonism comprising a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient.
(2) Cyclic dipeptide or a salt thereof is cycloarginylvaline [Cyclo (Arg-Val)], cycloglutaminylvaline [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloiso Leucylserine (Cyclo (Ile-Ser)), cycloceryl valine (Cyclo (Ser-Val)), cyclohistidyl valine (Cyclo (His-Val)), cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloasparaginyl tyrosine [Cyclo (Asn-Tyr)], cycloisoleucil proline [Cyclo (Ile-Pro)], cycloarginyl aspartic acid [Cyclo (Arg-Asp)], and cycloasparaginyltryptophan [Cyclo (Asn-Trp)] The composition for antagonistic endothelin receptor according to (1), comprising one or more selected from the group consisting of:
(3) The endothelin receptor antagonist composition according to (1) or (2), wherein the endothelin receptor is endothelin receptor B (ET-B).
(4) For increasing blood pressure, for improving blood flow, for suppressing cerebral edema formation, for improving or preventing melanin production or pigmentation in the epidermis, or for preventing or treating hypertension (1) to (3) An endothelin receptor antagonist composition according to any one of the above.
(5) The endothelin receptor antagonist 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 endothelin receptor antagonist composition according to any one of (1) to (5), which is labeled with a function exhibited by binding inhibition of the endothelin receptor binding substance to the endothelin receptor.
(7) Function indications are “expect blood pressure drop”, “suppress blood pressure rise”, “slow blood pressure rise”, “suppress sudden blood pressure rise when waking up”, “ "I expect improvement in blood flow", "Improve blood flow", "Slow blood flow", "Suppress cerebral edema formation", "I am concerned about skin pigmentation", "Prevent hypertension The composition for antagonistic endothelin receptor according to (6), which is selected from the group consisting of “to do” and “helps to improve hypertension”.
(8) The endothelin receptor antagonist 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 inhibiting the binding of an endothelin receptor binding substance to an endothelin receptor,
The cyclic dipeptide or a salt thereof may be cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloisoleucyl. Serine (Cyclo (Ile-Ser)), Cycloceryl valine (Cyclo (Ser-Val)), Cyclohistidyl valine (Cyclo (His-Val)), Cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloaspara Ginyltyrosine (Cyclo (Asn-Tyr)), cycloisoleucine proline (Cyclo (Ile-Pro)), cycloarginylaspartic acid (Cyclo (Arg-Asp)), and cycloasparaginyltryptophan [Cyclo (Asn -Trp)], wherein said use comprises one or more selected from the group consisting of:
(10) A method for inhibiting the binding of an endothelin receptor binding substance to an endothelin receptor, 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 may be cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloisoleucyl. Serine (Cyclo (Ile-Ser)), Cycloceryl valine (Cyclo (Ser-Val)), Cyclohistidyl valine (Cyclo (His-Val)), Cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloaspara Ginyltyrosine (Cyclo (Asn-Tyr)), cycloisoleucine proline (Cyclo (Ile-Pro)), cycloarginylaspartic acid (Cyclo (Arg-Asp)), and cycloasparaginyltryptophan [Cyclo (Asn -Trp)], which comprises one or more selected from the group consisting of.

According to the present invention, a composition having an excellent endothelin receptor antagonistic effect can be provided. If the composition of the present invention is used, the effect of preventing or treating hypertension, particularly pulmonary hypertension, can be expected, and the composition of the present invention can be effective for the purpose of improving blood flow and suppressing cerebral edema formation. In addition, the composition of the present invention can be expected to effectively suppress melanin production and pigmentation in the epidermis by suppressing the action of endothelin.

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.

1. Endothelin receptor antagonism As used herein, “endothelin receptor antagonism” means an action that antagonizes (competes) the binding of endothelin to the endothelin receptor and inhibits the binding of endothelin. A composition having an antagonistic action is referred to as an “endothelin receptor antagonist composition”. Endothelin is a peptide derived from various tissues such as lung, kidney, brain, pituitary, placenta or vascular endothelium, and there are three types of peptide isomers, ET-1, ET-2, and ET-3. The endothelin receptor has two subtypes, ET-A and ET-B, of which ET-A has a high affinity for ET-1 and ET-2, and for ET-3 Shows low affinity. On the other hand, the endothelin receptor ET-B shows an equivalent affinity for the above three peptide isomers.

Endothelin receptor antagonism can be evaluated according to a known method. For example, using cells expressing endothelin receptor, measure the change in intracellular calcium ion concentration when endothelin is added, and compare and evaluate the measured values when the sample is present and not present Can do. More specifically, when the measured value in which the sample is present is lower than the measured value in the absence of the sample (that is, the change in intracellular calcium ion concentration is smaller), the endothelin receptor antagonistic action is greater. Can be evaluated.

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 the present specification, cyclic dipeptides or salts thereof may be collectively referred to simply as cyclic dipeptides. 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.

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.

In the present invention, a cyclic dipeptide or a salt thereof is used as an active ingredient. In one embodiment of the present invention, the cyclic dipeptide or a salt thereof includes cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)]. ], Cycloisoleucylserine [Cyclo (Ile-Ser)], cycloserylvaline [Cyclo (Ser-Val)], cyclohistidylvaline [Cyclo (His-Val)], cycloglutamylleucine [Cyclo (Glu- Leu)], cycloasparaginyl tyrosine [Cyclo (Asn-Tyr)], cycloisoleucylproline [Cyclo (Ile-Pro)], cycloarginyl aspartic acid [Cyclo (Arg-Asp)], and cycloasparagine. One or more selected from the group consisting of nyltryptophan [Cyclo (Asn-Trp)]. Although the number of cyclic dipeptide or its salt is not specifically limited, In this invention, it is preferable to use 3 or more selected from the cyclic dipeptide mentioned above or its salt as an active ingredient. Among the cyclic dipeptides or salts thereof, cycloseryl valine [Cyclo (Ser-Val)], cyclohistidyl valine [Cyclo (His-Val)], cycloisoleusil serine [Cyclo (Ile-Ser)] ], Cycloarginyl aspartic acid [Cyclo (Arg-Asp)], cycloglutamyl leucine [Cyclo (Glu-Leu)], and cycloisoleucil proline [Cyclo (Ile-Pro)] One or two or more are preferable, and cycloseryl valine [Cyclo (Ser-Val)] and / or cyclohistidyl valine [Cyclo (His-Val)] is more preferable.

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.

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 dipeptides can be obtained by subjecting the animal and plant derived peptide obtained by subjecting the raw material containing animal and plant derived protein to enzyme treatment and heat treatment at a high temperature as described below. it can. 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. 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. 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. 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. 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. 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. 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. 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). 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.

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 an 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.

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].

In addition, you may perform processes, such as filtration, centrifugation, concentration, ultrafiltration, freeze-drying, and pulverization, with respect to the heat-processed peptide derived from animals and plants as desired. 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). Endothelin receptor antagonist composition 5-1. Cyclic dipeptide-containing endothelin receptor antagonist composition One embodiment of the present invention is an endothelin receptor antagonist composition containing a cyclic dipeptide or a salt thereof as an active ingredient.

As a further aspect of the present invention, the composition for antagonistic endothelin receptor is cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Cyclo Ser-Thr)), cycloisoleucine serine (Cyclo (Ile-Ser)), cycloseryl valine (Cyclo (Ser-Val)), cyclohistidyl valine (Cyclo (His-Val)), cycloglutamyl leucine [ Cyclo (Glu-Leu)], cycloasparaginyl tyrosine (Cyclo (Asn-Tyr)), cycloisoleucil proline (Cyclo (Ile-Pro)), cycloarginyl aspartic acid (Cyclo (Arg-Asp)), And one or more cyclic dipeptides selected from the group consisting of cycloasparaginyltryptophan [Cyclo (Asn-Trp)] or a salt thereof as an active ingredient. The number of cyclic dipeptides or salts thereof contained in the endothelin receptor antagonist composition of the present invention is not particularly limited, but in the present invention, it is preferable that three or more selected from the above-mentioned cyclic dipeptides or salts thereof are included. . Among the cyclic dipeptides or salts thereof, cycloserylvaline [Cyclo (Ser-Val)], cyclohistidylvaline [Cyclo (His-Val)], cycloisoleucine serine [Cyclo (Ile-Ser)], One selected from the group consisting of cycloarginyl aspartic acid [Cyclo (Arg-Asp)], cycloglutamyl leucine [Cyclo (Glu-Leu)], and cycloisoleucil proline [Cyclo (Ile-Pro)] Two or more are preferable, and cycloseryl valine [Cyclo (Ser-Val)] and / or cyclohistidyl valine [Cyclo (His-Val)] are more preferable.

The content of the cyclic dipeptide or the salt thereof in the composition for antagonizing the endothelin receptor of the present invention may be an amount that can achieve the desired effect of the present invention, taking into consideration its administration form, administration method, etc. It is not limited. For example, when an animal or plant-derived peptide is used as a raw material, cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloseryl in the endothelin receptor antagonist composition of the present invention. Threonine (Cyclo (Ser-Thr)), cycloisoleucine serine (Cyclo (Ile-Ser)), cycloseryl valine (Cyclo (Ser-Val)), cyclohistidyl valine (Cyclo (His-Val)), Cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloasparaginyl tyrosine (Cyclo (Asn-Tyr)), cycloisoleucine proline (Cyclo (Ile-Pro)), cycloarginyl aspartic acid (Cyclo (Arg- Asp)], cycloasparaginyltryptophan [Cyclo (Asn-Trp)], or the total salt content of each, is 1.0 × 10 ppm / Brix or more, preferably 1.0 × 10 ² ppm / More than Brix 1.0 × 10 ⁴ ppm / Brix or less, preferably 5.0 × 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 herein 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.

5-2. Mechanism of action Endothelin has a transient vasodilatory action followed by a sustained vasoconstrictive action. Endothelin produced in the body expresses its vasoconstriction function by binding to the endothelin receptor. Therefore, inhibiting the binding of endothelin to its receptor leads to suppression of vasoconstriction, thereby suppressing an increase in blood pressure or improving blood flow. Endothelin also enhances the activity of tyrosinase and causes UV-induced pigmentation and senile pigmentation. Therefore, by inhibiting the binding of endothelin to its receptor, it prevents melanin formation and pigmentation. It is effective for improvement. This binding inhibition of endothelin to a receptor can be performed using the composition for endothelin receptor antagonism of the present invention.

5-3. Other Components The composition for antagonizing the endothelin receptor 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. Use The endothelin receptor antagonist composition 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 antagonize the binding of endothelin to its receptor. As described above, since the endothelin receptor includes two subtypes of ET-A and ET-B, the composition of the present invention is an endothelin receptor ET-A antagonist composition and / or endothelin receptor. It can be a body ET-B antagonistic composition. Moreover, the active ingredient in the present invention can block not only binding of endothelin but also binding of an analogous compound having the same effect to the endothelin receptor. Therefore, in the present specification, substances that can bind to endothelin receptors (ET-A and / or ET-B) including endothelin and similar compounds are referred to as “endothelin receptor binding substances”.

The aforementioned cyclic dipeptide or salt thereof contained in the endothelin receptor antagonist composition of the present invention can suppress an increase in blood pressure or improve blood flow through inhibition of binding of endothelin to the receptor. Therefore, one aspect of the present invention is an endothelin receptor antagonistic composition for suppressing blood pressure elevation, which contains a cyclic dipeptide or a salt thereof as an active ingredient. Based on the said use, the composition for endothelin receptor antagonism of this invention can also become a composition for blood pressure rise suppression. Another aspect of the present invention is an endothelin receptor antagonist composition for improving blood flow, which contains a cyclic dipeptide or a salt thereof as an active ingredient. Based on the use, the endothelin receptor antagonist composition of the present invention can be a blood flow improving composition.

The aforementioned cyclic dipeptide or salt thereof contained in the endothelin receptor antagonist composition of the present invention may also be useful for improving or preventing melanin production and pigmentation in the epidermis. Therefore, the composition of the present invention is an endothelin receptor antagonistic composition containing a cyclic dipeptide or a salt thereof as an active ingredient, and can be a composition for preventing or treating melanin production, pigmentation, and the like. Based on these uses, the endothelin receptor antagonist composition of the present invention can be a composition for preventing or treating melanin production, pigmentation and the like.

The aforementioned cyclic dipeptide or a salt thereof contained in the endothelin receptor antagonist composition of the present invention may also be useful for the suppression of brain edema formation and the prevention or treatment of hypertension. Therefore, the composition of the present invention is an endothelin receptor antagonist composition containing a cyclic dipeptide or a salt thereof as an active ingredient, and can be a composition for inhibiting cerebral edema formation or for preventing or treating hypertension. . Based on these uses, the composition for endothelin receptor antagonist of the present invention can be a composition for inhibiting cerebral edema formation or a composition for preventing or treating hypertension.

The composition of the present invention having a blood pressure increase inhibiting action and / or a blood flow improving action is also useful as a composition for reducing blood pressure. In addition, for the treatment and / or prevention of hypertension, pulmonary hypertension, and diseases caused by hypertension (stroke, heart disease, renal failure, etc.) related to elevated blood pressure, the endothelin receptor antagonist of the present invention is also used. The composition is useful. 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 composition for antagonizing the endothelin receptor of the present invention includes, for example, a solvent, a dispersant, an emulsifier, a buffer, a stabilizer, an excipient, a binder, and a disintegrant as a raw material containing the cyclic dipeptide or a salt thereof. Or a lubricant, etc., and 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 according to a known method. can do. 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.

The endothelin receptor antagonist 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.

The endothelin receptor antagonist composition of the present invention can be applied to any therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, pharmaceuticals, quasi-drugs, cosmetics, etc. and the Pharmaceutical Affairs Law do not belong to these, but the effect of expecting a decrease in blood pressure, the effect of suppressing an increase in blood pressure, the effect of slowing the increase in blood pressure, Use as a composition that explicitly or implicitly promotes effects such as improving blood flow, slowing blood flow, suppressing melanin production and pigmentation in the epidermis, and suppressing brain edema formation Is mentioned.

In another aspect, the present invention relates to a composition containing the composition for endothelin receptor antagonism, which is labeled with a function exhibited by suppressing blood pressure elevation and / or improving blood flow. Such display or function display is not particularly limited. For example, “expect blood pressure reduction”, “suppress blood pressure increase”, “moderate blood pressure increase”, “improve blood flow”, Examples include “relaxing blood flow”, “suppressing cerebral edema formation”, and “suppressing pigmentation”. In the present specification, such indications and indications such as function indications may be attached to the composition itself, or may be attached to the container or packaging of the composition.

The endothelin receptor antagonist composition of the present invention can be ingested by an appropriate method according to the form. The intake method is not particularly limited as long as the cyclic dipeptide or a salt thereof according to the present invention 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.

The application amount of the composition for antagonizing the endothelin receptor of the present invention is set in a timely manner according to the form, administration method, purpose of use, and age, weight and symptom of the patient or animal to be administered, 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 is the intake of the endothelin receptor antagonistic composition of the present invention showing an effective effect in humans, and the type of cyclic dipeptide contained in the composition Is not particularly limited.

The subject of application of the composition for antagonistic endothelin receptor 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, guinea pigs, It may be a laboratory animal such as a monkey.

6). Use of cyclic dipeptide or a salt thereof for inhibiting binding of endothelin receptor binding substance to endothelin receptor One embodiment of the present invention is an endothelin receptor binding of a specific cyclic dipeptide having amino acid as a constituent unit or a salt thereof. Use to inhibit binding of a substance to an endothelin receptor. Preferably, cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloisoleucil serine [Cyclo (Ile -Ser)], cycloseryl valine (Cyclo (Ser-Val)), cyclohistidyl valine (Cyclo (His-Val)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloasparaginyl tyrosine (Cyclo (Asn-Tyr)], cycloisoleucylproline [Cyclo (Ile-Pro)], cycloarginylaspartic acid [Cyclo (Arg-Asp)], and cycloasparaginyltryptophan [Cyclo (Asn-Trp)] Use of one or two or more cyclic dipeptides selected from the group consisting of the salts, or salts thereof for inhibiting the binding of an endothelin receptor-binding substance to an endothelin receptor. More preferably, it is a use for inhibiting the binding of an endothelin receptor binding substance to an endothelin receptor, although it contains three or more selected from the cyclic dipeptides or salts thereof. In the use of the present invention, the endothelin receptor binding substance is preferably endothelin.

The use of the present invention includes, but is not limited to, the use of the cyclic dipeptide or a salt thereof for suppressing blood pressure increase and / or improving blood flow, for example. 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). Method for Inhibiting Binding of Endothelin Receptor Binding Substance to Endothelin Receptor One embodiment of the present invention is an endothelin receptor of an endothelin receptor binding substance using, as an active ingredient, a cyclic dipeptide having amino acid as a structural unit or a salt thereof. It is a method of inhibiting the binding to. The method is preferably cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloisoleucine serine. (Cyclo (Ile-Ser)), cycloceryl valine (Cyclo (Ser-Val)), cyclohistidyl valine (Cyclo (His-Val)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloasparagine Nyltyrosine [Cyclo (Asn-Tyr)], cycloisoleucine proline [Cyclo (Ile-Pro)], cycloarginylaspartic acid [Cyclo (Arg-Asp)], and cycloasparaginyltryptophan [Cyclo (Asn- Trp) is a method for inhibiting the binding of an endothelin receptor-binding substance to an endothelin receptor, comprising using as an active ingredient one or more cyclic dipeptides or salts thereof selected from the group consisting of . More preferably, it is a method for inhibiting the binding of an endothelin receptor-binding substance to an endothelin receptor, comprising using as an active ingredient a substance containing three or more selected from the cyclic dipeptides or salts thereof. In the method of the present invention, the endothelin receptor binding substance is preferably endothelin.

Another aspect of the method includes administering a therapeutically effective amount of a specific cyclic dipeptide or a salt thereof as an active ingredient to a subject in need of inhibition of binding of an endothelin receptor binding substance to an endothelin receptor. Is a method of inhibiting the binding of endothelin to the endothelin receptor. Preferably, cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloisoleucil serine [Cyclo (Ile -Ser)], cycloseryl valine (Cyclo (Ser-Val)), cyclohistidyl valine (Cyclo (His-Val)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloasparaginyl tyrosine (Cyclo (Asn-Tyr)], cycloisoleucylproline [Cyclo (Ile-Pro)], cycloarginylaspartic acid [Cyclo (Arg-Asp)], and cycloasparaginyltryptophan [Cyclo (Asn-Trp)] A method for inhibiting the binding of an endothelin receptor-binding substance to an endothelin receptor, comprising administering a therapeutically effective amount of one or more cyclic dipeptides or salts thereof selected from the group consisting of the active ingredient. . More preferably, it is a method of inhibiting the binding of endothelin to the endothelin receptor, comprising administering a therapeutically effective amount using as an active ingredient a substance containing three or more selected from the above cyclic dipeptides or salts thereof. In the method, the endothelin receptor binding substance is preferably endothelin.

In the above method, the subject requiring inhibition of binding of the endothelin receptor binding substance to the endothelin receptor is the same as the subject to which the composition for antagonizing the endothelin receptor of the present invention is applied. In the present specification, the therapeutically effective amount means that when the composition for antagonizing the endothelin receptor of the present invention is administered to the above-mentioned subject, the endothelin receptor binding substance of the endothelin receptor-binding substance is compared with the subject not administered. It is the amount at which the binding to the body is suppressed, the amount at which the blood pressure increase inhibitory effect and / or the blood flow improving effect is exhibited, or the amount at which the melanin production inhibitory effect and / or pigmentation inhibitory effect is exhibited. 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.

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.

According to the method of the present invention, inhibiting the binding of endothelin to the endothelin receptor without causing side effects, suppressing blood pressure increase and / or improving blood flow, or suppressing melanin production and / or pigmentation. It becomes possible to do.

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.

Example 1. Endothelin receptor (ET-B) antagonism To investigate the antagonistic action of cyclic dipeptide preparations on endothelin receptors (ie, inhibition of endothelin receptor binding to endothelin receptors), binding assay for endothelin receptors Carried out. Specifically, using human recombinant endothelin receptor (ET-B) -expressing CHO cells, 1nM endothelin-1 and various concentrations of chemically synthesized cyclic dipeptide preparations were added to this, and calcium ion influx was achieved. The change in intracellular calcium ion concentration due to was measured. The intracellular calcium ion concentration was quantified by fluorometric analysis.

For the antagonistic action of the test cyclic dipeptide, the response rate (change in intracellular calcium ion concentration) when no cyclic dipeptide is added is defined as 100%, and the response rate (%) when a cyclic dipeptide is added is evaluated. did. The results are shown in Table 1.

From the above results, it was clarified that all of the cyclic dipeptides shown in Table 1 have an antagonistic action on the endothelin receptor (that is, an inhibitory action of the endothelin receptor binding substance to the endothelin receptor).

The present invention provides an endothelin receptor antagonist composition containing a specific cyclic dipeptide or a salt thereof as an active ingredient. The present invention provides a safe and effective new means that contributes to suppression of blood pressure increase, improvement of blood flow, suppression of brain edema formation, suppression of pigmentation of the epidermis, and the like, and thus has high industrial applicability.

Claims

An endothelin receptor antagonistic composition comprising a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient.
Cyclic dipeptide or a salt thereof may be cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloisoleucyl serine. (Cyclo (Ile-Ser)), cycloceryl valine (Cyclo (Ser-Val)), cyclohistidyl valine (Cyclo (His-Val)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloasparagine Nyltyrosine [Cyclo (Asn-Tyr)], cycloisoleucine proline [Cyclo (Ile-Pro)], cycloarginylaspartic acid [Cyclo (Arg-Asp)], and cycloasparaginyltryptophan [Cyclo (Asn- The composition for antagonistic endothelin receptors according to claim 1, comprising one or more selected from the group consisting of Trp)].
The composition for endothelin receptor antagonism according to claim 1 or 2, wherein the endothelin receptor is endothelin receptor B (ET-B).
The use according to any one of claims 1 to 3, which is used for suppressing blood pressure elevation, improving blood flow, suppressing cerebral edema formation, improving or preventing melanin production or pigmentation in the epidermis, or preventing or treating hypertension. The composition for endothelin receptor antagonism described in 1.
The composition for antagonistic endothelin receptor 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.
The composition for antagonistic endothelin receptor according to any one of claims 1 to 5, which is labeled with a function exhibited by binding inhibition of the endothelin receptor binding substance to the endothelin receptor.
Function indications are “expect blood pressure”, “suppress blood pressure rise”, “moderate blood pressure rise”, “suppress sudden blood pressure rise when getting up”, “improve blood flow” , “Improve blood flow”, “Slow blood flow”, “Suppress brain edema formation”, “I am concerned about skin pigmentation”, “Prevent hypertension”, And an endothelin receptor antagonist composition according to claim 6, which is selected from the group consisting of “helps to improve hypertension”.
The composition for antagonistic endothelin receptor according to any one of claims 1 to 7, wherein the composition is an agent.
Use of a cyclic dipeptide comprising amino acids as a structural unit or a salt thereof for inhibiting the binding of an endothelin receptor binding substance to an endothelin receptor,
The cyclic dipeptide or a salt thereof may be cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloisoleucyl. Serine (Cyclo (Ile-Ser)), Cycloceryl valine (Cyclo (Ser-Val)), Cyclohistidyl valine (Cyclo (His-Val)), Cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloaspara Ginyltyrosine (Cyclo (Asn-Tyr)), cycloisoleucine proline (Cyclo (Ile-Pro)), cycloarginylaspartic acid (Cyclo (Arg-Asp)), and cycloasparaginyltryptophan [Cyclo (Asn -Trp)], wherein said use comprises one or more selected from the group consisting of:
A method for inhibiting the binding of an endothelin receptor-binding substance to an endothelin receptor, 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 may be cycloarginyl valine [Cyclo (Arg-Val)], cycloglutaminyl valine [Cyclo (Gln-Val)], cycloserylthreonine [Cyclo (Ser-Thr)], cycloisoleucyl. Serine (Cyclo (Ile-Ser)), Cycloceryl valine (Cyclo (Ser-Val)), Cyclohistidyl valine (Cyclo (His-Val)), Cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloaspara Ginyltyrosine (Cyclo (Asn-Tyr)), cycloisoleucine proline (Cyclo (Ile-Pro)), cycloarginylaspartic acid (Cyclo (Arg-Asp)), and cycloasparaginyltryptophan [Cyclo (Asn -Trp)], which comprises one or more selected from the group consisting of.