VIPR2 antagonist peptide

Abstract

[Problem] To provide a novel VIPR2 antagonist peptide that is useful for usage as a medical product, a diagnostic drug, and / or a research reagent. [Solution] A cyclic peptide formed from an amino acid sequence represented by formula (1): c[XN-X4-X5-X6-c(X7-X8-X9-X10]-X11)-X12-X13-X14-X15-X16, or formula (2): c[XN-X4-X5-X6-c(X7-X8-X9-X10)]-X1-X12-X13-X14-X15-X16, or a pharmacologically acceptable salt of said cyclic peptide.

Description

Cross-reference

[0001] This application claims priority based on Japanese Patent Application No. 2020-059721 filed on March 30, 2020 in Japan, and all of the contents described in the application are hereby incorporated by reference in their entirety into this specification. Further, all of the contents described in all of the patents, patent applications and documents cited in this application are hereby incorporated by reference in their entirety into this specification.

Technical Field

[0002] The present invention relates to a peptide that inhibits the activity of VIPR2, and more particularly to a cyclic peptide having a specific amino acid sequence and a cyclic structure.

Background Art

[0003] Vasoactive intestinal peptide receptor 2 (VIPR2), also known as VPAC2, is a class B G protein-coupled receptor (GPCR). It is expressed throughout the body, including the central and peripheral nervous systems, sensory organs, digestive tract, and reproductive organs, and exhibits diverse physiological functions by interacting with its ligands, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). For example, the signals of VIP and PACAP mediated by VIPR2 and its receptor subtypes, vasoactive intestinal peptide receptor 1 (VIPR1 or VPAC1) and pituitary adenylate cyclase-activating polypeptide type-1 receptor (PAC1), are known to have a neuroprotective effect (Non-Patent Document 1 and Non-Patent Document 2). On the other hand, interestingly, in recent years, it has been reported that the overexpression and hyperactivation of VIPR2 may be involved in the onset of schizophrenia and autism spectrum disorder (Non-Patent Document 3, Non-Patent Document 4, and Non-Patent Document 5). In addition, it has been reported that the inhibition of VIP signals suppresses cancer growth and activates immunity (Non-Patent Document 6 and Non-Patent Document 7).

[0004] In 2011, Vacic et al. reported that some patients with schizophrenia and some patients with autism spectrum disorder have duplications in the gene region encoding VIPR2, and that the mRNA expression level of VIPR2 is increased in their lymphocytes, and furthermore, their reactivity to VIP is also hypersensitive (Non-Patent Document 3). In 2015, Ago et al. reported that when a VIPR2-selective agonist Ro25-1553 was administered to neonatal mice to artificially create a state of overactive VIPR2, mature individuals showed a decline in cognitive function (Non-Patent Document 4). Furthermore, in 2019, Tian et al. reported that transgenic mice with duplications in the gene region encoding VIPR2 were created, and those mice showed symptoms such as dopamine dysfunction, cognitive dysfunction, and social behavioral disorders (Non-Patent Document 5). These findings strongly suggest that excessive signal transduction via VIPR2 is involved in the onset of mental disorders such as schizophrenia and autism spectrum disorder.

[0005] Schizophrenia is said to affect 24 million people worldwide. It causes positive symptoms (such as hallucinations and delusions), negative symptoms (such as decreased motivation), and cognitive dysfunction, which not only reduces an individual's social function but also shows a high suicide rate. It is a mental disorder with a high heritability of 80%, but no specific disease-causing genes common to all patients have been identified, and the development of new therapeutic drugs and treatment methods is desired. Autism spectrum disorder is said to affect approximately 1 to 2 people per 1,000 worldwide and causes disorders in social and interpersonal communication abilities. Congenital factors are significant, and no clear preventive or treatment methods have been established.

[0006] As described above, it has been reported that some patients with schizophrenia and some patients with autism spectrum disorder overexpress VIPR2, suggesting that the overactivation of VIPR2 may be involved in the onset of the disease state. That is, when it is confirmed by genomic analysis that there are duplications in the gene region encoding VIPR2, the administration of a VIPR2 inhibitor can be expected to be effective as a means of preventing and / or treating the onset of schizophrenia and autism spectrum disorder.

[0007] In 2018, the present inventors reported having found a cyclic antagonist peptide VIpep-3: Ac-c(Cys-Pro-Pro-Tyr-Leu-Pro-Arg-Arg-Leu-Cys)-Thr-Leu-Leu-Leu-Arg-Ser-OH (SEQ ID NO: 11) that binds to the recombinant protein of the extracellular region of VIPR2 and inhibits the VIPR2-mediated signal pathway of VIP and PACAP in cell tests (Non-Patent Document 8).

PRIOR ART DOCUMENTS

NON-PATENT DOCUMENTS

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non - Patent Document 4

Non - Patent Document 5

Non - Patent Document 6

Non - Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Summary of the Invention

Problems to be Solved by the Invention

[0009] The above-mentioned VIpep-3 found by the present inventor is a cyclic antagonist peptide that strongly binds to the extracellular domain of human VIPR2 and inhibits the VIP-VIPR2 signaling pathway. However, since it is composed only of natural amino acids, there are concerns such as low resistance to protease degradation.

[0010] The present invention has been made in view of such problems, and an object thereof is to provide a novel VIPR2 antagonist peptide suitable for use as a pharmaceutical, a diagnostic agent, and / or a research reagent.

Means for Solving the Problem

[0011] In conducting optimization research on VIpep-3, the present inventor has found a novel group of VIPR2 antagonist peptides. To solve the above problems, as a result of considering (1) substitution of amino acid residues, (2) reduction of molecular weight by deletion of N-terminal amino acid residues and / or C-terminal amino acid residues, and (3) introduction of a bicyclic structure, a group of sequences of novel VIPR2 antagonist peptides having protease degradation resistance and VIPR2 antagonist activity has been found, leading to the completion of the present invention.

[0012] That is, the present invention includes the following embodiments. [1] Formula (1): c[X N -X 4 -X 5 -X 6 -c(X 7 -X 8 -X 9 -X 10 -X 11 )-X 12 -X 13 -X 14 -X 15 -X 16 (1) Or formula (2): c[X N -X 4 -X 5 -X 6 -c(X 7 -X 8 -X 9 -X 10 )]-X 11 -X 12 -X 13 -X 14 -X 15 -X 16 (2) A cyclic peptide consisting of the amino acid sequence represented thereby or a pharmaceutically acceptable salt thereof.

[0013] Here, in formula (1), X N and X 10 and X 7 and X11 and in formula (2), X N and X 7 and X 10 each independently form two cyclic structures in the molecule by covalent bonding. These covalent bonds may form direct covalent bonds between the main chain and the side chain, or between the side chains, or may be indirect covalent bonds via a linker. In the above formulas (1) and (2), X N is X 1 -X 2 -X 3 and X 1 X 2 X 3 X 7 X 10 and X 11 When involved in the cyclization within the peptide molecule, each independently represents an amino acid residue having an amino group, a carboxy group, a thiol group, an allyl group, an alkynyl group, an azide group, or a halogen atom, or a derivative thereof. When not involved in the cyclization within the peptide molecule, X 1 and X 2 each independently represent an arbitrary amino acid residue or deletion, X 3 and X 11 are each independently an arbitrary amino acid residue. Also, X 5 X 9 X 12 and X 13 each independently represent an amino acid residue having a hydrocarbon group which may have a substituent, or a derivative thereof. X 4 represents an amino acid residue having an aromatic carbocyclic group which may have a substituent, or a derivative thereof, X 6 and X 8 represent an arbitrary amino acid residue, X 14 and X 15 and X 16 each independently represent an arbitrary amino acid residue, or deletion, and the N-terminal amino group and the C-terminal carboxy group may be modified or deleted.

[0014] In the preferred or other embodiments of the present invention, and X in the above cyclic peptide 1 from X16 Preferred embodiments of each amino acid residue will be described in detail below, and each preferred embodiment is independent of each other, and each embodiment can be arbitrarily combined.

Advantages of the Invention

[0015] According to the present invention, there is provided a novel cyclic peptide useful for using a VIPR2 antagonist as a pharmaceutical, a diagnostic agent, and / or a research reagent.

Brief Description of the Drawings

[0016]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Mode for Carrying Out the Invention

[0017] Next, preferred embodiments of the present invention will be described with reference to the drawings. It should be noted that the embodiments described below do not limit the invention according to the claims, and not all of the elements and combinations thereof described in the embodiments are essential for the solution means of the present invention. Also, the disclosures of all patent documents and non-patent documents cited in this specification are incorporated herein by reference in their entirety.

[0018] (Definition) In this specification, a peptide refers to one in which two or more amino acids are linked by an amide bond (peptide bond), and for example, it can be one in which 2 to 20 amino acids are amide-bonded. Also, in accordance with the convention of peptide labeling, the left end is the N-terminus (amino terminus) and the right end is the C-terminus (carboxy terminus). The first carbon atom adjacent to the carbonyl group forming the peptide bond is referred to as the Cα carbon.

[0019] As used herein, "any amino acid, or a derivative thereof" is used in its broadest sense, and includes, in addition to natural amino acids, artificial amino acids having an unnatural structure, chemically synthesized compounds having properties known in the art that are characteristic of amino acids, and carboxylic acids having functional groups. Examples of unnatural amino acids include D-form amino acids, α / α-disubstituted amino acids (such as α-methylated amino acids like 2-aminoisobutyric acid) whose main chain structure is different from the natural type, N-alkyl-amino acids (such as N-methylated amino acids), N-substituted glycines (peptoids), amino acids with an extended main chain (β-homoamino acids and γ-homoamino acids), amino acids whose side chain structure is different from the natural type (such as cyclohexylalanine, allylglycine, 2-(2-pyridyl)-glycine, 3-(1H-benzimidazole-2-yl)-alanine, etc.), amino acids with a partially substituted side chain (such as norleucine, diaminopropanoic acid, 3-(2-pyridyl)-alanine, etc.), amino acids having an extra functional group in the side chain; amino acids having an extra C, alkyl group, or methyl group in the side chain (such as homonorleucine, γ-methylleucine, etc.), amino acids having a halogen atom (F, Cl, Br, I) in the side chain (such as 3-chloro-alanine, etc.), carboxylic acids having a halogen atom (F, Cl, Br, I) in the side chain (such as 3-chloropropanoic acid, etc.), carboxylic acids having a functional group in the side chain (such as 3-butenoic acid, etc.), amino acids having an extra N or amino group in the side chain (such as β-azidoalanine, ornithine, etc.), amino acids having an extra O or methoxy group in the side chain (such as O-methyl-serine, O-methyl-threonine, etc.), amino acids having an extra hydroxy group in the side chain (such as 3-hydroxy-phenylalanine, etc.), amino acids having an extra carboxy group (-COOH) in the side chain (such as 3-carboxy-phenylalanine, etc.), amino acids having an extra S in the side chain (such as ethionine, etc.), amino acids in which the carboxylic acid functional group in the side chain is protected by an ester (such as aspartic acid-4-methyl ester, etc.), amino acids in which the thio group (-S-) in the side chain is oxidized and converted to a sulfinyl group (-S(=O)-) or a sulfonyl group (-S(=O)2-) (such as methionine sulfoxide), etc., but are not limited thereto.

[0020] In this specification, the hydrocarbon group which may have a substituent includes, for example, C alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. 1-10 alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, etc. 2-10 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl, etc. C 2-10 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl, etc. 3-10 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. 3-10Refers to a cycloalkenyl group. An aromatic carbocyclic group which may have a substituent refers to, for example, a phenyl group, a naphthyl group, etc. An aromatic heterocyclic group which may have a substituent refers to, for example, 5- or 6-membered monocyclic aromatic heterocyclic groups such as pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and further benzo-furanyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiynyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc., 8- to 14-membered condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups, but is not limited thereto.

[0021] In the present specification, "VIPR2" means a protein of mammals such as mouse, rat, dog, monkey, human, etc.

[0022] As used herein, when it is stated that a peptide "has VIPR2 antagonist activity", it means that in in vitro tests, the peptide of the present invention: (1) inhibits the binding of a biotinylated form of the previously reported VIPR2 antagonist peptide VIpep-3 to VIPR2 recombinant protein; (2) inhibits the binding of a biotinylated form of the previously reported VIPR2 antagonist peptide VIpep-3 to VIPR2-expressing cells; (3) binds to VIPR2 recombinant protein in a concentration-dependent manner; (4) binds to VIPR2-expressing cells in a concentration-dependent manner; (5) suppresses the increase in intracellular calcium concentration in VIPR2-expressing cells when added prior to or co-added with VIP; (6) suppresses the increase in intracellular cAMP concentration in VIPR2-expressing cells when added prior to or co-added with VIP; (7) suppresses the recruitment of β-arrestin in VIPR2-expressing cells when added prior to or co-added with VIP. When any one of these effects is exhibited, it is stated that the peptide "has VIPR2 antagonist activity". The presence or absence of VIPR2 antagonist activity can be confirmed by those skilled in the art according to known methods with reference to Non-Patent Document 7 and the like, but is not limited thereto.

[0023] (Cyclic peptide) The structure of the cyclic peptide according to an embodiment of the present invention will be described with reference to FIG. 1. FIG. 1 schematically shows the characteristics (pharmacophore) related to the VIPR2 binding activity of VIpep-3, which is the basis of cyclic peptide design, the structure related to the function of cyclic structure regulation (S-S bond), and the relationship between the cyclic peptide of this embodiment obtained by modifying VIpep-3. The 1st to 13th amino acid residues of VIpep-3 correspond to the 1st to 13th amino acid residues of the cyclic peptide of this embodiment, but in the cyclic peptide of this embodiment, the 1st amino acid, or the 1st and 2nd amino acid residues may be deleted. The cyclization between the 1st and 10th cysteine residues in VIpep-3 is, in the cyclic peptide of this embodiment, (1) two cyclic structures formed by bond A between the 1st and 10th amino acid residues and bond B between the 7th and 11th amino acid residues, (2) two cyclic structures formed by bond C between the 2nd and 10th amino acid residues and bond D between the 7th and 11th amino acid residues, or two cyclic structures formed by bond G between the 2nd and 10th amino acid residues and bond H between the 7th and 11th amino acid residues, (3) two cyclic structures formed by bond E between the 3rd and 10th amino acid residues and bond F between the 7th and 11th amino acid residues, or two cyclic structures formed by bond I between the 3rd and 10th amino acid residues and bond J between the 7th and 11th amino acid residues, (4) two cyclic structures formed by bond K between the 1st, 7th, and 10th amino acid residues, (5) two cyclic structures formed by bond L or bond N between the 2nd, 7th, and 10th amino acid residues, (6) two cyclic structures formed by bond M or bond O between the 3rd, 7th, and 10th amino acid residues, and is more stabilized. Examples of amino acids used for substitution of amino acid residues at each amino acid position of VIpep-3 and the positions of amino acid residues considered for bicyclization are shown in FIG. 2.

[0024] [1] The cyclic peptide shown in FIG. 1 is more specifically the following formula (1): c[X N -X 4 -X 5 -X 6 -c(X7 -X 8 -X 9 -X 10 -X 11 )-X 12 -X 13 -X 14 -X 15 -X 16 (1), or the following formula (2): c[X N -X 4 -X 5 -X 6 -c(X 7 -X 8 -X 9 -X 10 )]-X 11 -X 12 -X 13 -X 14 -X 15 -X 16 can be represented by (2).

[0025] Here, in formula (1), X N and X 10 and X 7 and X 11 and in formula (2), X N and X 7 and X 10 each independently form two cyclic structures in the molecule by forming a covalent bond. These covalent bonds may form a direct covalent bond between the main chain and the side chain, or between side chains, or may be an indirect bond via a linker.

[0026] In the above formulas (1) and (2), X N is X 1 -X 2 -X 3 and X 1 , X 2 , X 3 , X 7 , X 10 and X 11When involved in the cyclization within a peptide molecule, it independently represents an amino acid residue having an amino group, a carboxy group, a thiol group, an allyl group, an alkynyl group, an azide group, or a halogen atom, or a derivative thereof. When not involved in the cyclization within the peptide molecule, X 1 and X 2 each independently represent an arbitrary amino acid residue or deletion, X 3 and X 11 are each independently an arbitrary amino acid residue. Also, X 5 , X 9 , X 12 and X 13 each independently represent an amino acid residue having a hydrocarbon group which may have a substituent, or a derivative thereof. X 4 represents an amino acid residue having an aromatic carbocyclic group which may have a substituent, or a derivative thereof, X 6 and X 8 represent an arbitrary amino acid residue, X 14 and X 15 and X 16 each independently represent an arbitrary amino acid residue or deletion, and the N-terminal amino group and the C-terminal carboxy group may be modified or deleted.

[0027] [2] Preferred embodiments included in formula (1) are the following formula (3): c[X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -c(X 7 -X 8 -X 9 -X 10 -X 11 )-X 12 -X 13 (3) It is a cyclic peptide consisting of the amino acid sequence represented by or a pharmaceutically acceptable salt thereof. In formula (3), X 1 and X 10 and X 7 and X 11 each independently form two cyclic structures in the molecule by covalent bonding, and the covalent bond is X1 between the main chain or side chain of 10 and the side chain of X, and between the side chain of X 7 and the side chain of X 11 and the side chain of X, formed between X 1 ~X 13 is as described in [1].

[0028] In one embodiment, X 1 represents cysteine, D-cysteine, 3-mercaptopropanoic acid, 2,3-diaminopropanoic acid, D-2,3-diaminopropanoic acid, β-alanine, aspartic acid, or glutamic acid, and X 10 represents cysteine, D-cysteine, 2,3-diaminopropanoic acid, D-2,3-diaminopropanoic acid, aspartic acid, or glutamic acid, and X 2 and X 3 each independently represent an arbitrary amino acid residue, preferably proline, and X 4 and X 8 each independently represent an amino acid residue having an aromatic carbocyclic group, preferably tyrosine, phenylalanine, or derivatives thereof, and X 5 X 9 X 12 and X 13 each independently represent leucine, isoleucine, or derivatives thereof, and X 7 and X 11 each independently represent lysine, ornithine, arginine, 2,3-diaminopropanoic acid, 2,4-diaminobutanoic acid, aspartic acid, glutamic acid, cysteine, homocysteine, or derivatives thereof.

[0029] [3] Here, the bond between the Cα carbon atoms of X 1 and X 10 is the following formula (4): Cα 1 -(CH2) A -L 1 -(CH2) B -Cα 10 (4) Preferably has a structure represented by the formula. In the formula, A and B each independently represent an integer of 0 to 2. The sum of A and B is an integer of 1 to 4. The linker L 1 represents S, S-S, CH2-CH2, S-CH2, CH2-S, O-CH2, CH2-O, CH=CH, NH-C(=O), N(CH3)-C(=O), NH-C(=S), N(CH3)-C(=S), O-C(=O), C(=O)-NH, C(=O)-N(CH3), C(=S)-NH, C(=S)-N(CH3), C(=O)-O, CH2-CH2-CH2, S-CH2-CH2, CH2-CH2-S, CH2-S-CH2, O-CH2-CH2, CH2-CH2-O, CH2-O-CH2, S-CH2-S, S-C(=CH2)-S, S-(CH2)2-S, or triazole.

[0030] Among these, L 1 preferably represents S-S, NH-C(=O), CH2-S-CH2, CH=CH, CH2-CH2, and more preferably, L 1 represents S-S or NH-C(=O). When L 1 represents S-S, for example, X 1 and X 10 are both amino acid residues or derivatives thereof having a thiol group, and have a structure in which a disulfide bond is formed under oxidative conditions. When L 1 represents NH-C(=O), for example, X 1 is an amino acid residue having an amino group in the side chain, X 10 is an amino acid residue having a carboxy group in the side chain, and has a structure cyclized by dehydration condensation of these amino group and carboxy group. Examples of the amino acid residue having a thiol group in the side chain include cysteine, D-cysteine, 3-mercaptopropanoic acid, homocysteine, and D-homocysteine. Examples of the amino acid residue having an amino group in the side chain include 2,3-diaminopropanoic acid, D-2,3-diaminopropanoic acid, or β-alanine. Examples of the amino acid residue having a carboxy group in the side chain include aspartic acid and glutamic acid.

[0031] [4] Another preferred embodiment included in the above formula (1) is formula (5): c[X 2 -X 3 -X 4 -X 5 -X 6 -c(X 7 -X 8 -X 9 -X 10 -X 11 )-X 12 -X 13 (5) It is a cyclic peptide consisting of the amino acid sequence represented by or a pharmaceutically acceptable salt thereof. In formula (5), X 2 and X 10 and X 7 and X 11 form two cyclic structures in the molecule by covalently bonding independently of each other, and the covalent bond is between the main chain or side chain of X 2 and the side chain of X 10 and between the side chain of X 7 and the side chain of X 11 formed, and X 2 ~X 13 is as described in [1].

[0032] [5] Here, the bond between the Cα carbon atoms of X 2 and X 10 is the following formula (6): Cα 2 -(CH2) A -L 2 -(CH2) B -Cα 10 (6) Preferably, it has a structure represented by. In the formula, A and B each independently represent an integer from 0 to 6, and the sum of A and B is an integer from 4 to 7. L 2represents S, S-S, CH2-CH2, S-CH2, CH2-S, O-CH2, CH2-O, CH=CH, NH-C(=O), N(CH3)-C(=O), NH-C(=S), N(CH3)-C(=S), O-C(=O), C(=O)-NH, C(=O)-N(CH3), C(=S)-NH, C(=S)-N(CH3), C(=O)-O, CH2-CH2-CH2, S-CH2-CH2, CH2-CH2-S, CH2-S-CH2, O-CH2-CH2, CH2-CH2-O, CH2-O-CH2, S-CH2-S, S-C(=CH2)-S, S-(CH2)2-S, S-(CH2)3-S, S-(CH2)4-S, S-(CH2)5-S, S-CH2-CH=CH-CH2-S, S-CH2-C(=O)-NH, NH-C(=O)-CH2-S, S-CH2-C6H4-CH2-S (the bonding site of the methylene group to the phenylene ring may be ortho, meta or para), S-CH2-C 10 H6-CH2-S, S-CH2-C(=O)-CH2-S, or S-CH2-C(=CH2)-CH2-S, triazole, or dithiotetrafluorobenzene.

[0033] Among these, L 2 preferably represents S-(CH2)2-S, S-(CH2)3-S, S-(CH2)4-S, S-(CH2)5-S. For example, X 2 and X 10 are both amino acid residues or their derivatives having a thiol group, and a thioether bond can be formed between the thiol groups of these residues and a halogenated alkyl linker such as 1,2-diiodoethane, 1,3-diiodopropane, 1,4-diiodobutane.

[0034] [6] Another preferred embodiment included in the above formula (1) is formula (7): c[X 3 -X 4 -X 5 -X 6 -c(X 7 -X 8 -X 9 -X 10 -X 11 )-X12 -X 13 (7) It is a cyclic peptide consisting of the amino acid sequence represented by or a pharmacologically acceptable salt thereof. In formula (7), X 3 and X 10 and X 7 and X 11 each independently form two cyclic structures in the molecule by covalent bonding, and the covalent bond is between the main chain or side chain of X 3 and the side chain of X 10 , and between the side chain of X 7 and the side chain of X 11 , and X 3 ~X 13 is as described in [1].

[0035] In one embodiment, X 3 represents cysteine, D-cysteine, homocysteine, D-homocysteine, 3-mercaptopropanoic acid, 6-mercaptohexanoic acid, or 8-mercaptohexanoic acid, X 10 represents cysteine, D-cysteine, homocysteine, or D-homocysteine, X 4 and X 8 each independently represent an amino acid residue having an aromatic carbocyclic group, preferably tyrosine, phenylalanine, or derivatives thereof, X 5 , X 9 , X 12 and X 13 each independently represent leucine, isoleucine, or derivatives thereof, X 7 and X 11 each independently represent lysine, ornithine, arginine, 2,3-diaminopropanoic acid, 2,4-diaminobutanoic acid, aspartic acid, glutamic acid, or derivatives thereof.

[0036] [7] Here, the bond between the Cα carbon atoms of X 3 and X 10 is the following formula (8): Cα 3 -(CH2) A -L 3 -(CH2) B -Cα10 (8) Preferably has a structure represented by the formula. In the formula, A and B each independently represent an integer from 0 to 10, and the sum of A and B is an integer from 7 to 10, and L 3 represents S, S-S, CH2-CH2, S-CH2, CH2-S, O-CH2, CH2-O, CH=CH, NH-C(=O), N(CH3)-C(=O), NH-C(=S), N(CH3)-C(=S), O-C(=O), C(=O)-NH, C(=O)-N(CH3), C(=S)-NH, C(=S)-N(CH3), C(=O)-O, CH2-CH2-CH2, S-CH2-CH2, CH2-CH2-S, CH2-S-CH2, O-CH2-CH2, CH2-CH2-O, CH2-O-CH2, S-CH2-S, S-C(=CH2)-S, S-(CH2)2-S, S-(CH2)3-S, S-(CH2)4-S, S-(CH2)5-S, S-(CH2)6-S, S-(CH2)7-S, S-(CH2)8-S, S-CH2-CH=CH-CH2-S, S-CH2-C(=O)-NH, NH-C(=O)-CH2-S, S-CH2-C6H4-CH2-S (the bonding site of the methylene group to the phenylene ring may be any of ortho, meta and para), S-CH2-C6H4-C6H4-CH2-S, S-CH2-C5NH3-C5NH3-CH2-S, S-CH2-C 10 H6-CH2-S, S-CH2-C(=O)-CH2-S, or S-CH2-C(=CH2)-CH2-S, triazole, or dithiotetrafluorobenzene.)

[0037] Among these, L 3 preferably represents S-(CH2)3-S, S-(CH2)4-S, S-(CH2)5-S, S-(CH2)6-S, or S-CH2-C6H4-CH2-S (the bonding site of the methylene group to the phenylene ring may be any of ortho, meta and para). For example, X 3 and X 10are both amino acid residues or derivatives thereof having a thiol group, and a thioether bond can be formed between the thiol groups of these residues and a halogenated alkyl linker such as 1,3-diiodopropane, 1,4-diiodobutane, 1,5-diiodopentane, 1,6-diiodohexane, 1,2-bis(bromomethyl)benzene, 1,3-bis(bromomethyl)benzene, or 1,4-bis(bromomethyl)benzene.

[0038] [8] As other preferred embodiments included in the above formulas (1), (3), (5), and (7), X 7 and X 11 preferably have a bond between the Cα carbon atoms represented by the following formula (9): Cα 7 -(CH2) A -L 7 -(CH2) B -Cα 11 (9) Preferably, it has a structure represented by the formula. In the formula, A and B each independently represent an integer from 0 to 7, the sum of A and B is an integer from 2 to 7, and L 7 represents S, S-S, CH2-CH2, S-CH2, CH2-S, O-CH2, CH2-O, CH=CH, NH-C(=O), N(CH3)-C(=O), NH-C(=S), N(CH3)-C(=S), O-C(=O), C(=O)-NH, C(=O)-N(CH3), C(=S)-NH, C(=S)-N(CH3), C(=O)-O, CH2-CH2-CH2, S-CH2-CH2, CH2-CH2-S, CH2-S-CH2, O-CH2-CH2, CH2-CH2-O, CH2-O-CH2, S-CH2-S, S-C(=CH2)-S, S-(CH2)2-S, S-(CH2)3-S, S-(CH2)4-S, S-CH2-CH=CH-CH2-S, S-CH2-C(=O)-NH, NH-C(=O)-CH2-S, S-CH2-C6H4-CH2-S (the bonding site of the methylene group to the phenylene ring may be any of ortho, meta, and para), S-CH2-C(=O)-CH2-S, or S-CH2-C(=CH2)-CH2-S, triazole, or dithiotetrafluorobenzene.

[0039] Among these, L 7 preferably represents NH-C(=O), S-S, or S-(CH2)3-S. When L 7 represents NH-C(=O), for example, X 7 is an amino acid residue having an amino group in the side chain, X 11 is an amino acid residue having a carboxy group in the side chain, and it is a structure cyclized by dehydration condensation of these amino group and carboxy group. When L 7 represents S-S, for example, X 7 and X 11 are both amino acid residues having a thiol group or derivatives thereof, and it is a structure in which a disulfide bond is formed under oxidative conditions. When L 7 represents S-(CH2)3-S, for example, X 7 and X 11 are both amino acid residues having a thiol group or derivatives thereof, and a thioether bond can be formed between the thiol groups of these residues and an alkyl halide linker such as 1,3-diiodopropane. Examples of the amino acid residue having an amino group in the side chain include lysine and ornithine. Examples of the amino acid residue having a carboxy group in the side chain include aspartic acid and glutamic acid. Examples of the amino acid residue having a thiol group in the side chain include cysteine, D-cysteine, homocysteine, D-homocysteine, and the like.

[0040] [9] A preferred embodiment included in the above formula (2) is formula (10): c[X 3 -X 4 -X 5 -X 6 -c(X 7 -X 8 -X 9 -X 10 )]-X 11 -X 12 -X 13 (10) It is a cyclic peptide consisting of the amino acid sequence represented by or a pharmacologically acceptable salt thereof. In formula (10), X 3 and X7 and X 10 forms two cyclic structures within the molecule by covalent bonding, and X 3 ~X 13 is as described in [1].

[0041] In one embodiment, X 3 represents cysteine, D-cysteine, homocysteine, D-homocysteine, or 3-mercaptopropanoic acid, and X 7 and X 10 each independently represent cysteine, D-cysteine, homocysteine, or D-homocysteine, and X 4 and X 8 each independently represent an amino acid residue having an aromatic carbocyclic group, preferably tyrosine, phenylalanine, or derivatives thereof, and X 5 , X 9 , X 12 and X 13 each independently represent leucine, isoleucine, or derivatives thereof, and X 11 represents serine, threonine, diaminopropanoic acid, diaminobutanoic acid, or derivatives thereof.

[0042]

[10] Here, in the cyclic peptide represented by the above formula (2) or formula (10), the bond between the Cα carbon atoms of X 1 and X 7 and X 10 , X 2 and X 7 and X 10 , or X 3 and X 7 and X 10 is the following formula (11):

Chemical formula

[0043] Among these, it is preferable that Y represents [(S-CH3)3-C6H3]. For example, X 3 is 3-mercaptopropanoic acid (Mpa), X 7 and X 10 are both amino acid residues having a thiol group such as cysteine (Cys). In this case, the peptide can be cyclized by a thioether bond between the thiol groups of these residues and an alkyl halide linker such as 1,3,5-tris(bromomethyl)benzene.

[0044]

[11] Also, in the cyclic peptide represented by the above formula (2) or formula (10), X 1 and X 7 and X 10 , X 2 and X 7 and X 10 , or X 3 and X 7 and X 10 The bond between the Cα carbon atoms of is the following formula (12):

Chemical formula

[0045]

[12] In the cyclic peptides represented by the above formulas (1) to (3), (5), (7), and (10), X 5 , X 9 , X 12 and X 13 are each independently the following formula (13): [Chemical formula] are preferably amino acid residues represented by the formula: In the formula, the wavy line represents the attachment point to the carbonyl group or nitrogen atom forming the amide bond of the main chain; R 1 , R 2 , R 6 and R 7 each independently represent a hydrogen atom or a methyl group; R 3 , R 4 , R 5 each independently represent a hydrogen atom, a methyl group, or a halogen atom (F, Cl, Br, I); n represents an integer from 0 to 10. Particularly preferred among these are leucine, N-methylated leucine, α-methylated leucine, isoleucine, β-homoleucine, norvaline, norleucine, 2-aminoheptanoic acid, 2-aminooctanoic acid, 2-aminononanoic acid, etc.

[0046] Or, X5 , X 9 , X 12 and X 13 are represented by the following formula (14): [Chemical formula] It may be an amino acid residue represented by. In the formula, the wavy line represents the attachment point to the carbonyl group or nitrogen atom that forms the amide bond of the main chain, Z represents C or N, and R 8 and R 9 represent a hydrogen atom or a methyl group, and n represents an integer of any one of 1 to 6. Among these, particularly preferred are cyclopropylalanine and cyclobutylalanine and the like.

[0047]

[13] In the cyclic peptides shown in the above formulas (1) to (3), (5), (7) and (10), X 4 is preferably an amino acid residue represented by the following formula (15): [Chemical formula] In the formula, the wavy line represents the attachment point to the carbonyl group or nitrogen atom that forms the amide bond of the main chain, and R 10 , R 11 , R 12 , R 13 and R 14 each independently represent a hydrogen atom, a hydroxy group, a hydroxymethyl group, a methoxy group, a methoxymethyl group, an amino group, an aminomethyl group, a monomethylated amino group, a dimethylated amino group, a trimethylated amino group, a monomethylated aminomethyl group, a dimethylated aminomethyl group, a trimethylated aminomethyl group, an acetyl group, an amide group, a methyl group, a tert-butyl group, a halogenated methyl group, or a halogen atom (F, Cl, Br, I), and R 15 and R 16 represent a hydrogen atom or a methyl group.

[0048] Among these, X 4is preferably represented by tyrosine, 3-hydroxyphenylalanine, 4-fluorophenylalanine, 4-aminophenylalanine, 4-aminomethylphenylalanine, 4-aminamidophenylalanine, N-methylated tyrosine, α-methylated tyrosine, O-methyl-tyrosine, 3-methoxy-phenylalanine, 4-acetyl-phenylalanine.

[0049]

[14] Also, in the cyclic peptides represented by the above formulas (1) to (3), (5), (7) and (10), X 8 is preferably an amino acid residue having an optionally substituted aromatic carbocyclic group, or a derivative thereof.

[0050]

[15] X which is an aromatic carbocyclic group 8 As a specific embodiment of, the following formula (16):

Chemical formula

[0051] Among these, X 8It is more preferable that it represents tyrosine, 3-hydroxyphenylalanine, 4-fluorophenylalanine, 4-aminophenylalanine, 4-aminomethylphenylalanine, 4-aminophenylalanine amide, N-methylated tyrosine, α-methylated tyrosine, O-methyl-tyrosine, 3-methoxy-phenylalanine, 4-acetyl-phenylalanine.

[0052]

[16] Further, in the cyclic peptides represented by the above formulas (1) to (3), (5), (7) and (10), X 6 is preferably glycine, N-methylated glycine, alanine, N-methylated alanine, D-alanine, N-methylated D-alanine, 2-aminoisobutyric acid, N-methylated 2-aminoisobutyric acid, 2-azetidine-2-carboxylic acid, D-2-azetidine-2-carboxylic acid, proline, D-proline, thioproline, D-thioproline, 3,4-dehydroproline, D-3,4-dehydroproline, pipecolic acid, D-pipecolic acid, or derivatives thereof.

[0053] Among these, X 6 is more preferably proline, N-methylated glycine, N-methylated alanine, 2-azetidine-2-carboxylic acid, pipecolic acid.

[0054]

[17] The cyclic peptide in one embodiment of the present invention is represented by the following formula (17): c[X 1 -Pro 2 -X 3 -Tyr 4 -Leu 5 -Pro 6 -c(X 7 -X 8 -Leu 9 -Cys 10 -X 11 )-X 12 -X 13 (17) and consists of the amino acid sequence represented thereby. In formula (17), X 1 represents cysteine, Mpa (3-mercaptopropionic acid) or D-cysteine, and X 3represents N-methylated glycine, N-methylated alanine, 2-azetidine-2-carboxylic acid, proline, hydroxyproline, 3,4-dehydroproline, pipecolic acid, serine or lysine, X 8 represents tyrosine, proline or arginine, X 7 and X 11 represents any combination of lysine and aspartic acid, ornithine and glutamic acid, aspartic acid and lysine, glutamic acid and ornithine, lysine and glutamic acid, or glutamic acid and lysine, X 12 and X 13 each independently represents leucine, isoleucine or norleucine, X 1 and Cys 10 form a disulfide bond between their respective side chains, X 7 and X 11 form an amide bond between their respective side chains, whereby the peptide of formula (17) has two cyclic structures in the molecule, and the N-terminal amino group and the C-terminal carboxy group may be modified or deleted.

[0055]

[18] In a more preferred embodiment of the cyclic peptide, in the above formula (17), X 1 represents cysteine, X 3 represents proline or serine, X 7 represents lysine, X 8 represents tyrosine, X 11 represents aspartic acid, and X 12 and X 13 each independently represents leucine, isoleucine or norleucine. The N-terminal amino group is acetylated and the C-terminal carboxy group is amidated.

[0056] Examples of the individual cyclic peptides included in the above formula (17) or formula (18) include, for example, the following. Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6-c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Ile 13 -NH2 (SEQ ID NO: 10) Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Orn 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Orn 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Asp7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Asp 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Orn 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Orn 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Asp 7 -Tyr 8 -Leu9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Asp 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys10 -Asp 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Orn 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Orn 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Asp 7 -Tyr 8 -Leu 9 -Cys 10 -Lys11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Asp 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Asp 11 )-Nle12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Orn 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Orn 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Asp 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Asp 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Leu 13 -NH2

[0057] Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Asp 11 )-Leu12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg4 -Leu 5 -Pro 6 -c(Asp 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Leu 13 -NH2

[0058] Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg4 -Leu 5 -Pro 6 -c(Asp 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro6 -c(Asp 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Orn 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys7 -Pro 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Pro8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Asp 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu9 -Cys 10 -Asp 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Orn 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Asp 7 -Pro 8 -Leu 9 -Cys10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Arg 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Orn 11 )-Nle 12 -Leu 13 -NH2

[0059] Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu9 -Cys 10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Glu11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Leu12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Arg 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Leu13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Pro 8 -Leu 9 -Cys 10 -Glu 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Tyr 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Arg 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Leu 12 -Leu 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Ile 13 -NH2 Ac-c[Cys 1 -Pro 2 -Ser 3 -Tyr 4 -Leu 5 -Pro 6 -c(Glu 7 -Pro 8 -Leu 9 -Cys 10 -Lys 11 )-Nle 12 -Leu 13 -NH2

[0060] The peptides according to the present invention include peptides having homology with the amino acid sequences represented by the above [1] to

[17] , in which 1 to several amino acids are deleted, added, and / or substituted, and which have binding activity to VIPR2. In the present specification, when referring to "peptides in which 1 to several amino acids are deleted, added, and / or substituted", the number of these amino acids is not particularly limited as long as the peptide has VIPR2 binding activity, but is preferably 1 to 5, more preferably 1 or 2. The positions where deletion, addition, and / or substitution occur may be at the ends of the peptide or in the middle, and may be at one position or at two or more positions.

[0061] As an amino acid sequence in which one to several amino acids are deleted, added, and / or substituted in the above amino acid sequence, when calculated using the above amino acid sequence and BLAST (Basic Local Alignment Search Tool at the National Center for Biological Information) or the like (for example, using default or initial parameters), those having a homology of at least 50% or more, preferably 70% or more, more preferably 80% or more, and particularly preferably 90% or more are exemplified.

[0062] It is also known that there are peptides and protein domains with highly similar three-dimensional structures even though their primary structures have low homology. Therefore, the present embodiment also includes peptides having a three-dimensional structure homology of at least 50% or more, preferably 70% or more, more preferably 80% or more, and particularly preferably 90% or more with the above amino acid sequence and having VIPR2 binding activity. The homology of the three-dimensional structures of such peptides can be predicted as follows from the amino acid sequence of a peptide with an unknown three-dimensional structure using a homology modeling method or the like. For example, when any amino acid sequence (target sequence) having a sequence similar to the cyclic peptide (reference peptide) of the present embodiment is given, an alignment (a juxtaposed sequence) between the target sequence and the reference sequence is given. By using the alignment calculated by FASTA, PSI-BLAST, LIBRA, etc., the correspondence relationship of each amino acid between the target sequence and the reference sequence is determined. Based on this relationship, the three-dimensional coordinates of each amino acid on the target sequence are created from the three-dimensional coordinates of the reference peptide. In the construction of the three-dimensional coordinates, structural gaps, collisions, or distortions may occur between amino acid residues. Therefore, these structural distortions are eliminated by energy minimization calculations. Depending on the modeling software, in order to smoothly eliminate these structural distortions, some perform them not simultaneously for all atoms of the peptide but step by step. That is, first, it is performed for the α-carbon atoms forming the peptide backbone, then for the main chain atoms including the α-carbon atoms, and finally for the entire peptide including the side chain atoms. If an alignment for the target sequence is obtained in this way, its three-dimensional structure can be predicted and constructed. The index of three-dimensional structure homology can be compared using, for example, RMSD (Root Mean Square Deviation), which is the difference in XYZ coordinates when optimally superimposed.

[0063] The peptide of the present invention also includes various derivatives and / or modified forms thereof as long as they solve the problems of the present invention.Examples of such derivatives include those in which the saturated fatty chain of the peptide is replaced by an unsaturated fatty chain, those in which some of the atoms of the peptide are replaced by other atoms containing radioactive or non-radioactive isotope atoms, those in which the amide bond of the peptide is replaced by a thioamide bond (-NH-C(=S)-), those in which the amide bond of the peptide is replaced by an alkene (-C=C-), those in which the amide bond of the peptide is replaced by an alkyl (-C-C-), those in which the amide bond of the peptide is replaced by hydroxyethylene (-C(-OH)-C-), those in which the amide bond of the peptide is replaced by an ester (-O-C(=O)-), those in which the amide bond of the peptide is replaced by an alkene (-C=C-), those in which the amide bond of the peptide is replaced by (-C-NH-), or those in which the amide bond of the peptide is replaced by (-C(=O)-C-), etc. Examples of such modified forms include those in which the α-carbon of the peptide is disubstituted, those in which the amide bond of the peptide is N-alkylated, those in which some of the functional groups of the peptide are modified by halogenation, cyanation, nitration, oxidation, hydroxylation, amination, deamination, dehydrogenation, amidation, acetylation, methoxylation, prenylation, alkylation, etc. (for example, those in which some of the amino groups of the peptide are acetylated, formylated, myristoylated, palmitoylated, pyroglutaminated, alkylated or deaminated, those in which some of the carboxy groups of the peptide are N-pyrrolidinylated or N-piperidinylated, or those in which they are amides (amide, methylamide, ethylamide, p-nitroanilide, β-naphthylamide, etc.) or esters (methyl ester, ethyl ester, thioester, etc.)), those in which the S of the peptide becomes sulfoxide S(=O) or sulfone S(=O)2, those in which the peptide is multimerized via a chemical linker, those in which the peptide is biotinylated, those in which the peptide is fluorescently labeled, those in which the peptide is luminescently labeled, and further those in which the peptide is fused with an alkyl chain, polyethylene glycol, antibody, lectins, sugar chain, enzyme, membrane-permeable peptide, low molecular weight compound, or a molecule that induces ubiquitination of a protein, etc., but are not limited thereto.

[0064] The peptide of the present invention also includes salts of the peptide. As salts of the peptide, salts with physiologically acceptable bases and acids are used. For example, addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc.), inorganic bases (ammonium hydroxide, or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), addition salts of amino acids, and the like can be mentioned.

[0065] The peptide of the present invention may be a prodrug. A prodrug is a compound that is converted into the peptide of the present invention by reactions with enzymes, gastric acid, etc. under physiological conditions in the living body, that is, a compound that undergoes enzymatic oxidation, reduction, hydrolysis, etc. and changes into the peptide of the present invention, or a compound that undergoes hydrolysis, etc. by gastric acid, etc. and changes into the peptide of the present invention.

[0066] Examples of prodrugs of the peptide of the present invention include compounds in which the amino group of the peptide of the present invention is acylated, alkylated, or phosphorylated (for example, compounds in which the amino group of the peptide of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated), compounds in which the hydroxy group of the peptide of the present invention is acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxy group of the peptide of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated), compounds in which the hydroxy group and carboxy group of the peptide of the present invention are esterified or amidated (for example, compounds in which the hydroxy group and carboxy group of the peptide of the present invention are C 1-6Examples include, but are not limited to, alkyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification, or methyl amidated compounds. These compounds can be produced from the peptide of the present invention by methods known per se.

[0067] The prodrug of the peptide of the present invention may be one that changes to the peptide of the present invention under physiological conditions as described in "Drug Development", Volume 7, Molecular Design, pages 163-198, published by Hirokawa Shoten in 1990.

[0068] In the present specification, the prodrug may form a salt, and examples of such salts include those exemplified as salts of the peptide of the present invention.

[0069] The peptide of the present invention may be a crystal, and the present invention encompasses the peptide whether the crystal form is single or a mixture of crystal forms. Crystals can be produced by applying crystallization methods known per se to effect crystallization.

[0070] The peptide of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt means a crystalline substance composed of two or more unique solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability, etc.). Cocrystals or cocrystal salts can be produced according to cocrystallization methods known per se.

[0071] (Action and effect of cyclic peptide) As shown in the examples described below, Seq-1 to 10, which are representative examples of the amino acid sequence groups represented in this embodiment, exhibit binding activity to VIPR2-expressing cells. Seq-1, 6, 9, and 10 have antagonist activity against VIPR2-expressing cells and protease degradation resistance. Since the amino acid sequence groups represented in this embodiment have amino acid sequences and conformational features similar to those of Seq-1 to 10, it is highly likely that they also have resistance to protease degradation, VIPR2 binding activity, and VIPR2 antagonist activity.

[0072] The VIPR2 binding activity of the peptides shown in the examples described below indicates the following. (1) Deletion of the C-terminal 3 residues (amino acid residues 14 to 16: Leu-Arg-Ser) of VIpep-3 does not result in loss of binding activity to VIPR2. (2) Cross-linking positions 7 and 11 improves VIPR2 binding activity. (3) VIpep-3 is cyclized by an S-S bond formed between the cysteine residues at positions 1 and 10, but cyclization for VIPR2 binding activity is not limited to between positions 1 and 10. By introducing an amino acid residue with a long side chain at position 2 or 3 and directly cross-linking it to position 10, or indirectly cross-linking it using linkers of different lengths and structures, the interatomic distance between positions 2 and 10 and the interatomic distance between positions 3 and 10 can be made close to the interatomic distance between positions 1 and 10, and cross-linking between positions 2 and 10 and between positions 3 and 10 can be substituted. (4) Peptides that are bicyclized between three amino acid residues also exhibit VIPR2 binding activity, and it is considered that any combination of cross-linking patterns between positions 1-7-10, 2-7-10, and 3-7-10 is acceptable. Regarding (3) and (4) above, a more specific explanation is as follows. As shown in the examples described below, the cyclic structure formed between the 1st to 3rd amino acid residues and the 10th amino acid residue of VIpep-3: Cα 3 -NH-C(=O)-Cα 2 -NH-C(=O)-Cα 1 -CH2-S-S-CH2-Cα 10 is, for example, a cyclic structure formed between the 3rd amino acid residue having a non-natural structure side chain and the 10th amino acid residue: Cα3 -CH2-CH2-CH2-CH2-CH2-CH2-CH2-S-S-CH2-CH2-Cα 10 It can be substituted with etc. That is, the 1st to 3rd amino acid residues of VIpep-3 are not significantly involved in the VIPR2 binding activity, suggesting that the cyclic size regulation of the peptide is important for the VIPR2 binding activity. The peptide of the present invention can be cyclized not only between the 1st and 10th positions, but also between the 2nd and 10th positions, and between the 3rd and 10th positions. As long as the cyclic size of the peptide falls within a certain range, it is considered to accept a wide range of chemical structures such as amide bonds, disulfide bonds, thioether bonds, C=C bonds, C-C bonds, bonds via triazole, and bonds via dithiotetrafluorobenzene. This property is considered to be retained even when passing through the 7th position (between the 1st-7th-10th positions, between the 2nd-7th-10th positions, and between the 3rd-7th-10th positions).

[0073] Since the amino acid sequence groups represented by the above [1] to

[16] have amino acid sequences and conformational characteristics similar to those of VIpep-3 having antagonist activity against VIPR2 of humans, mice, and rats, they are highly likely to bind to VIPR2 of mammals other than humans such as mice and rats and inhibit their functions.

[0074] (Method for producing cyclic peptide) The peptide of the present embodiment can be produced by known peptide production methods such as chemical synthesis methods such as the liquid phase method, the solid phase method, or a hybrid method combining the liquid phase method and the solid phase method.

[0075] For the solid-phase method, a commercially available automatic synthesizer can be used. For example, the hydroxyl group of a resin having a hydroxyl group and the carboxyl group of a first amino acid (usually the C-terminal amino acid of the target peptide) whose α-position amino group is protected by a protecting group such as an Fmoc group are esterified. As the esterification catalyst, known dehydration condensing agents such as 1-mesitylenesulfonyl-3-nitro-1,2,4-triazole (MSNT), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIPCDI) can be used. Next, the protecting group of the α-position amino group of the first amino acid is removed, and a second amino acid in which all functional groups other than the carboxyl group of the main chain are protected is added, and the carboxyl group is activated to bond the first and second amino acids. Further, the α-position amino group of the second amino acid is deprotected, a third amino acid in which all functional groups other than the carboxyl group of the main chain are protected is added, and the carboxyl group is activated to bond the second and third amino acids. This is repeated to synthesize a peptide of the desired length. The linear peptide is cleaved from the resin, and after purification, the functional group for cyclizing the peptide is deprotected, and the peptide is cyclized according to a conventional method.

[0076] Examples of solid-phase synthesis resins include Merrifield resin, MBHA resin, Cl-Trt resin, SASRIN resin, Wang resin, Rink amide resin, HMFS resin, Amino-PEGA resin (Merck), HMPA-PEGA resin (Merck), etc. These resins may be washed with a solvent (dimethylformamide (DMF), 2-propanol, methylene chloride, etc.) before use. Examples of protecting groups for the α-position amino group include benzyloxycarbonyl (Cbz) group, tert-butoxycarbonyl (Boc) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyl group, allyl group, allyloxycarbonyl (Alloc) group, etc. The Cbz group can be deprotected by hydrofluoric acid, hydrogenation, etc., the Boc group can be deprotected by trifluoroacetic acid (TFA), and the Fmoc group can be deprotected by treatment with piperidine. For the protection of the α-position carboxy group, methyl ester, ethyl ester, benzyl ester, tert-butyl ester, cyclohexyl ester, etc. can be used. As other functional groups of amino acids, hydroxy groups such as serine and threonine can be protected with a benzyl group or a tert-butyl group, and hydroxy groups such as tyrosine can be protected with a 2-bromobenzyloxycarbonyl group or a tert-butyl group. Amino groups in side chains such as lysine, carboxy groups such as glutamic acid and aspartic acid can be protected in the same manner as the α-position amino group and the α-position carboxy group.

[0077] The activation of the carboxy group can be carried out using a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or WSC), (1H-benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-[bis(dimethylamino)methyl]-1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU), and the like. Cleavage of the peptide chain from the resin can be carried out by treatment with an acid such as TFA, hydrogen fluoride (HF), or the like.

[0078] The peptide of the present embodiment is cyclized as one aspect. In the present specification, cyclization means that in one peptide, two or more amino acids separated by one or more amino acids are directly or indirectly covalently bonded via a linker to form one or more cyclic structures in the molecule. Cyclization can be carried out according to the methods described in Non-Patent Document 9, Non-Patent Document 10, and Non-Patent Document 11. For example, an amide bond between an amino group and a carboxy group, a disulfide bond between a thiol group and a thiol group, a thioether bond between a thiol group and a halogen group, a thioether bond by a thiol-ene reaction between a thiol group and an allyl group, a C=C bond by an olefin metathesis reaction between an allyl group and an allyl group (the C=C bond may be converted to a C-C bond by a reduction reaction), a bond via a triazole by a click reaction between an alkynyl group and an azide group, a thioether bond between a linker having a halogen group and two thiol groups, and the like, but is not limited thereto. The direct or linker-mediated indirect covalent bond for cyclization may be any of main chain-main chain, main chain-side chain, side chain-main chain, and side chain-side chain.

[0079] For the cyclization of the peptide of the present invention, for example, (1) cysteine, D-cysteine, homocysteine, D-homocysteine having a thiol group can be used as amino acid 1 and amino acid 2 independently, and the disulfide bond formed between their thiol groups can be used; (2) an amino acid having a nucleophilic halogen atom (chloro, bromo, or iodo) (e.g., 3-chloroalanine), or a carboxylic acid having a halogen atom (chloro, bromo, or iodo) (e.g., 3-chloropropanoic acid) can be used as amino acid 1, and the thioether bond formed between it and amino acid 2 having a thiol group can be used; (3) amino acid 1 and amino acid 2 having a thiol group, and a linker having a nucleophilic halogen atom (chloro, bromo, or iodo) (e.g., 1,3-diiodopropane, 1,4-diiodobutane, 1,5-diiodopentane, 1,6-diiodohexane, 1,2-bis(bromomethyl)benzene, 1,3-bis(bromomethyl)benzene, 1,4-bis(bromomethyl)benzene, etc.) can be used to form the thioether bond formed between them; (4) β-azidoalanine having an azide group can be used as amino acid 1, 2-amino-5-hexynoic acid having an alkynyl group can be used as amino acid 2, and the covalent bond via triazole formed by the click reaction between them can be used; (5) an amino acid having an allyl group (e.g., allylglycine, D-allylglycine, homoallylglycine, D-homoallylglycine, etc.), or a carboxylic acid having an allyl group (e.g., 3-butenoic acid) can be used as amino acid 1, and the thioether bond formed by the thiol-ene reaction between it and amino acid 2 having a thiol group can be used; (6) an amino acid having an allyl group, or a carboxylic acid having an allyl group can be used as amino acid 1 and amino acid 2 independently, and the C=C bond formed by the olefin metathesis reaction between their allyl groups can be used; (7) the C-C formed by reducing the C=C bond formed by the olefin metathesis reaction can be used; (8) amino acid 1 having an amino group (e.g., 2,3-diaminopropanoic acid, 2,The amide bond between amino acid 1 (such as 4-diaminobutanoic acid, ornithine, lysine, their D-form amino acids, etc.) and amino acid 2 having a carboxy group (such as aspartic acid, glutamic acid, their D-form amino acids, etc.) can be used. The amide bond between the (9) N-terminal amino group (such as β-alanine or γ-aminobutyric acid) and an amino acid having a carboxy group can be used. Either of these amino acid 1 and amino acid 2 may come to the N-terminal side. Further, the thioether bond formed among amino acid 1, amino acid 2, and amino acid 3 having a thiol group and a linker having a nucleophilic halogen atom (chloro, bromo, or iodo) (for example, 1,3,5-tris(bromomethyl)benzene) can be used. Any of amino acid 1, amino acid 2, and amino acid 3 may come to the N-terminal side.,

[0080] (Pharmaceuticals, diagnostic agents, research reagents including cyclic peptides) The pharmaceutical composition according to the present invention contains the above-described amino acid sequence as an active ingredient. By binding of the peptide to VIPR2, it is possible to inhibit the binding of the natural ligand to VIPR2 and suppress the signal transduction via VIPR2. The dosage form of the above pharmaceutical composition is not particularly limited, and may be oral administration or parenteral administration. Examples of parenteral administration include transmucosal administration (transnasal, transoral, transocular, transtracheal, transvaginal, or rectal administration), injection administration (intravenous injection, subcutaneous injection, intramuscular injection, etc.), transdermal administration, etc. In view of the property that the peptide in the pharmaceutical composition is easily metabolized and excreted, various modifications can be made. For example, by adding an alkyl chain, polyethylene glycol, or sugar chain to the peptide, the residence time in blood can be prolonged and the antigenicity can be reduced. Also, biodegradable polymer compounds such as polylactic acid-glycolic acid (PLGA), porous hydroxyapatite, liposomes, surface-modified liposomes, emulsions prepared with unsaturated fatty acids, nanoparticles, nanospheres, etc. can be used as sustained-release bases, and the peptide may be encapsulated therein. In the case of transdermal administration, a weak current can also be passed through the skin surface to permeate the stratum corneum (iontophoresis method).

[0081] The above pharmaceutical composition may use the active ingredient as it is, or may be formulated by adding pharmaceutically acceptable carriers, excipients, additives, etc. Examples of dosage forms include, for example, liquid preparations (such as injections), dispersants, suspensions, tablets, pills, powders, suppositories, powders, fine granules, granules, capsules, syrups, troches, inhalants, ointments, eye drops, nasal drops, ear drops, poultices, etc. These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (such as sustained-release microcapsules). Formulation can be carried out by appropriately using, for example, excipients, binders, disintegrants, lubricants, solvents, solubilizing agents, coloring agents, flavoring agents, stabilizing agents, emulsifying agents, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, etc. according to conventional methods. Examples of components used in formulation include pharmaceutically acceptable organic solvents such as purified water, saline, phosphate buffer, dextrose, glycerol, ethanol, animal and vegetable oils, lactose, mannitol, glucose, sorbitol, crystalline cellulose, hydroxypropyl cellulose, starch, corn starch, silicic anhydride, magnesium aluminum silicate, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methyl cellulose, ethyl cellulose, xanthan gum, gum arabic, tragacanth, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, petrolatum, paraffin, octyldodecyl myristate, isopropyl myristate, higher alcohols, stearyl alcohol, stearic acid, human serum albumin, etc., but are not limited thereto.When a peptide is poorly absorbed transmucosally, as absorption enhancers for improving the absorption of poorly absorbable drugs, surfactants such as polyoxyethylene lauryl ethers, sodium lauryl sulfate, and saponin; bile acid salts such as glycolic acid, deoxycholic acid, and taurocholic acid; chelating agents such as EDTA and salicylic acids; fatty acids such as caproic acid, capric acid, lauric acid, oleic acid, linoleic acid, and mixed micelles; enamine derivatives, N-acyl collagen peptides, N-acyl amino acids, cyclodextrins, chitosans, nitric oxide donors, etc. may be used.

[0082] The pills or tablets can also be coated with sugar coating, gastric-soluble, or enteric-soluble substances. The injections can contain distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, vegetable oil, alcohols, etc. Further, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, solubilization aids, preservatives, etc. can be added. If necessary, additives such as ordinary preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents, etc. can be appropriately used in appropriate amounts.

[0083] The pharmaceutical composition of the present invention is involved in the activation of VIPR2 and is useful for the prevention and / or treatment of central nervous system diseases, such as mental disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, etc.), pediatric mental disorders (attention deficit disorder, attention deficit / hyperactivity disorder, conduct disorder, autism, etc.), neurodegenerative disorders, neural stem cell disorders, neural progenitor disorders, ischemic disorders, traumatic nerve disorders, mood disorders, psychomotor disorders, sleep disorders (hypersomnia, circadian rhythm sleep disorder, insomnia, abnormal behavior during sleep, sleep disruption, etc.), mental disorders such as anxiety (acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, agoraphobia, obsessive-compulsive disorder, etc.), factitious mental disorders (acute hallucinatory mania, etc.), impulse control disorders (compulsive gambling, intermittent explosive disorder, etc.), mood disorders (bipolar type I disorder, bipolar type II disorder, mania, mixed mood state, etc.), major depression, chronic depression, seasonal depression, psychotic depression, seasonal depression, cognitive disorders (amnesia, senile dementia, HIV-related dementia, Alzheimer's disease, Huntington's disease, Lewy body dementia, vascular dementia, drug-related dementia, tardive dyskinesia, intergenerational muscle spasm, dystonia, delirium, Pick's disease, Creutzfeldt-Jakob disease, HIV disease, Gilles de la Tourette syndrome, epilepsy, muscle spasm, mild cognitive impairment, etc.), mental retardation (spasticity, Down syndrome, fragile X syndrome, etc.); premenstrual syndrome (PMS), premenstrual dysphoric disorder (PDD), postpartum depression, neuron damage disorders (eye injury, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment, cerebral edema, etc.), Parkinson's disease, Parkinson's disease-like disorder, migraine, epilepsy, Alzheimer's disease, brain injury, stroke, cerebrovascular diseases (cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, cerebral hypoxia-ischemia, etc.), drug dependence (narcotic dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, drug withdrawal syndrome, etc.), eating disorders (anorexia nervosa, bulimia nervosa, binge eating disorder, polyphagia, obesity, compulsive eating disorder, pica, etc.), etc., but not limited thereto. As additional diseases, although not particularly limited, for example, it can be used for the growth inhibition of cancers expressing VIPR2 and the activation of immunity by inhibiting the function of VIPR2.

[0084] The pharmaceutical composition of the present invention may be used in combination with various other pharmaceuticals and treatment methods, such as various chemotherapy, surgical treatment, and radiation therapy useful for the above-mentioned diseases.

[0085] When the pharmaceutical composition of the present invention is administered to mammals (e.g., humans, mice, rats, guinea pigs, rabbits, dogs, horses, monkeys, pigs, etc.), particularly humans, the dosage varies depending on symptoms, the patient's age, sex, weight, sensitivity differences, administration method, administration interval, type of active ingredient, and type of formulation, and is not particularly limited. For example, 30 μg to 1000 mg, 100 μg to 500 mg, or 100 μg to 100 mg can be administered once or divided into several times.

[0086] The following examples are merely illustrative and are intended only to explain the present invention in detail together with the above-described embodiments, and do not limit the present invention. Those skilled in the art can modify the present invention in various ways without departing from the meaning of the present invention, and such modifications are also included in the scope of the present invention.

Examples

[0087] The abbreviations used in this specification represent the following meanings. VIPR2: Vasoactive intestinal peptide receptor 2 VIP: Vasoactive intestinal peptide BSA: Bovine serum albumin RP-HPLC: Reverse-phase high performance liquid chromatography HRP: Horseradish peroxidase SA: Streptavidin HBSS: Hank’s balanced salt solution ELISA: Enzyme-linked immunosorbent assay Ac: Acetyl Cys: L-Cysteine hmC:L-homocystein Mpa:3-mercaptopropanoic acid Pro:L-Proline Tyr:L-Tyrosine Leu:L-Leucine Ile:L-Isoleucine Arg:L-Arginine Asp:L-Aspartic acid Glu:L-Glutamic acid Dap:(S)-2,3-Diaminopropanonic acid Dab:(S)-2,4-Diaminobutanoic acid Tyr(Ome):O-methyl-L-Tyrosine 4aF:4-amino-L-Phenylalanine 4AcF:4-acetyl-L-Phenylalanine 4amdF:4-amide-L-Phenylalanine 3hF:3-hydroxy-L-Phenylalanine 3(Ome)F:3-methoxy-L-Phenylalanine 4amF:4-aminomethyl-L-Phenylalanine 4fF:4-fluoro-L-Phenylalanine Gly:Glycine Ala:L-Alanine Aze:L-Azetidine carboxylic acid thioP:L-Thioproline Dhp:3,4-dehydro-L-Proline Pip:L-Pipecolic acid Val:L-Valine Nle:L-Norleucine Ahep:(S)-2-Aminoheptanonic acid Aoc: (S)-2-Aminooctanonic acid Anon: (S)-2-Aminononanonic acid CprA: L-Cyclopropylalanine CbuA: L-Cyclobutylalanine βhmLeu: β-homo―L-Leucine M6a: 6-Mercaptohexanoic acid M8a: 8-Mercaptooctanoic acid DIBut: 1,4-Diiodobutane DIPen: 1,5-Diiodopentane DIHex: 1,6-Diiodohexane DBoXy: 1,2-Bis(bromomethyl)benzene DBmXy: 1,3-Bis(bromomethyl)benzene DBpXy: 1,4-Bis(bromomethyl)benzene TBMB: 1,3,5-Tris(bromomethyl)benzene Nme-X: N-methylated amino acid X aMe-X: α-methylated amino acid X D X: D-amino acid X c[XY], c(XY): Cyclization between amino acid X to amino acid Y

[0088] (Peptide synthesis) The chemical synthesis of all the peptides used in this example was entrusted to Scrum Co., Ltd. (Tokyo, Japan), and carried out on an automatic synthesizer Syro II (manufactured by Biotage) using a standard solid-phase synthesis method with a 9-fluorenylmethoxycarbonyl group (Fmoc group) as the protecting group for the α-amino group. The side-chain protected amino acid-resin located at the C-terminus was placed in the synthesis column, and the apparatus was set up. Subsequently, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) / diisopropylethylamine (DIEA) was added to the next amino acid protected with the Fmoc group for activation, and then placed in the column for reaction. After completion of the reaction, it was washed, and the Fmoc group was deprotected using 20% piperidine. By repeating this process, the peptide chain was extended. After deprotecting the Fmoc group of the final amino acid, the peptide-resin was taken out from the apparatus.

[0089] The cyclization of the peptides was based on the methods described in Non-Patent Documents 8, 9, 10, and 11. As an example, the cyclization of Seq-1, 6, and 9 is shown below. For Seq-1 and Seq-6, the linear side-chain protected peptide-resin was swollen in dimethylformamide (DMF) and reacted in a 2% hydrazine solution for 5 to 10 minutes to deprotect the protecting group (Dde) of the lysine side chain and the protecting group (ODmab) of the aspartic acid side chain. Then, Oxima Pure, a coupling reagent, and diisopropylcarbodiimide (DIC) were added and reacted at 50 °C for 3 hours. After washing the resin, trifluoroacetic acid (TFA) was added to deprotect the protecting group of the thiol group and simultaneously cleave the monocyclic peptide from the resin. The monocyclic peptide was purified by reverse-phase high-performance liquid chromatography (RT-HPLC) using a SunFire C18 column (10 × 150 mm) (manufactured by Waters), and then lyophilized.

[0090] For Seq-1, the monocyclic peptide was dissolved in a mixed solution of Tris-HCl buffer (pH 8.5) and acetonitrile, DMSO was added, and the mixture was stirred at room temperature for 36 hours to cyclize the peptide by disulfide bond formation. For Seq-6, the monocyclic peptide was dissolved in dimethyl sulfoxide (DMSO), and 3 equivalents of 1,3-bis(bromomethyl)benzene dissolved in DMF, and 0.1 M NaHCO3 and acetonitrile containing 10 mM tris(2-carboxyethyl)phosphine (TCEP) were added, and the reaction was carried out overnight at room temperature to cyclize the peptide by thioether bond formation between the thiol group and the alkyl halide linker. The bicyclic peptides Seq-1 and 6 were purified by RT-HPLC using a SunFire C18 column (10×150 mm) (manufactured by Waters) and then lyophilized. The molecular weight of the finally obtained peptide was measured using microflex (Bruker) to identify the target product.

[0091] For Seq-9, after washing the resin, TFA was added to deprotect the protecting group of the thiol group and simultaneously cleave the linear peptide from the resin. After purification by RT-HPLC using a SunFire C18 column (10×150 mm) (manufactured by Waters), it was lyophilized. The linear peptide was dissolved in dimethyl sulfoxide (DMSO), and 3 equivalents of 1,3,5-tris(bromomethyl)benzene (TBMB) dissolved in DMF, 0.1 M NaHCO3 containing 10 mM tris(2-carboxyethyl)phosphine (TCEP), and acetonitrile were added, and the reaction was carried out at 80 °C for 3 hours to cyclize the peptide by a thioether bond between the thiol group and the alkyl halide linker. The bicyclic peptide was purified by RT-HPLC using a SunFire C18 column (10×150 mm) (manufactured by Waters) and then lyophilized. The molecular weight of the finally obtained peptide was measured using microflex (manufactured by Bruker) to identify the target product. The theoretical molecular weight, measured molecular weight, purity, cyclization type, and sequence of the peptides synthesized in this example are shown in Table 1. In addition, the amino acid sequences of Seq-1 to 9 among these are shown below, and their structural formulas are shown in Figure 7. In Table 1 and the following amino acid sequences, amino acids without D notation represent the L form.

[0092]

Table 1-1

[0093]

Table 1-2

[0094] Seq-1: c(Mpa-Pro-Pro-Tyr-Leu-Pro-c[Lys-Tyr-Leu-Cys)-Asp]-Leu-Ile-NH2 (SEQ ID NO: 1) Seq-2: c(Mpa-NmeTyr-Leu-Pro-c[Lys-Tyr-Leu-Cys)-Asp]-Leu-Ile-NH2 (SEQ ID NO: 2) Seq-3: c(Mpa-NmeTyr-Leu-Pro-c[Lys-Tyr-Leu-Cys)-Asp]-Leu-Ile-NH2 (SEQ ID NO: 3) Seq-4: c(Mpa-NmeTyr-Leu-Pro-c[Lys-Tyr-Leu-Cys)-Asp]-Leu-Ile-NH2 (SEQ ID NO: 4) Seq-5: c(Mpa-NmeTyr-Leu-Pro-c[Lys-Tyr-Leu-Cys)-Asp]-Leu-Ile-NH2 (SEQ ID NO: 5) Seq-6: c(Mpa-NmeTyr-Leu-Pro-c[Lys-Tyr-Leu-Cys)-Asp]-Leu-Ile-NH2 (SEQ ID NO: 6) Seq-7: c(Mpa-NmeTyr-Leu-Pro-c[Lys-Tyr-Leu-Cys)-Asp]-Leu-Ile-NH2 (SEQ ID NO: 7) Seq-8: c(Mpa-NmeTyr-Leu-NmeGly-c(Cys)-Tyr-Leu-Cys)-Ser-Leu-Ile-NH2 (SEQ ID NO: 8) Seq-9: c(Mpa-NmeTyr-Leu-NmeGly-c(Cys)-Tyr-Leu-Cys)-Dap-Leu-Ile-NH2 (SEQ ID NO: 9) Seq-10: Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Ile 13 -NH2 (SEQ ID NO: 10)

[0095] Seq-1 and Seq-10 are peptides obtained by removing the C-terminal 3 residues (Leu-Arg-Ser) of VIpep-3 and cyclizing them with an S-S bond between positions 1 and 10 and an amide bond between positions 7 and 11. (Seq-2 to 7) are peptides obtained by removing the N-terminal 2 residues (Cys-Pro) and the C-terminal 3 residues (Leu-Arg-Ser) of VIpep-3 and cyclizing them with a thioether bond via a chemical linker between positions 3 and 10 and an amide bond between positions 7 and 11. (Seq-8 to 9) are peptides obtained by removing the N-terminal 2 residues (Cys-Pro) and the C-terminal 3 residues (Leu-Arg-Ser) of VIpep-3 and cyclizing them with a thioether bond via a TBMB linker between positions 3, 7, and 10.

[0096] (Construction of competitive binding assay by cell ELISA method) To confirm the binding activity of the amino acid-substituted peptide to VIPR2, a competitive binding assay by cell ELISA shown in Figure 3 was constructed. Hereinafter, this cell ELISA method will be briefly described. A human VIPR2-expressing cell line (Catalog No. HTS079RTA, manufactured by Eurofins) was seeded in a 96-well plate using the medium provided by the manufacturer and cultured overnight at 37°C in a CO2 incubator. After washing the plate with HBSS containing 0.1% BSA, a mixture of Biotin-VIpep-3 (1000 nM) diluted with HBSS containing 0.1% BSA and an amino acid-substituted peptide or VIpep-3 at an arbitrary concentration was prepared and added at 50 μL / well. After reacting for 60 minutes on ice, the plate was washed with HBSS containing 0.1% BSA. Biotin-VIpep-3 bound to the VIPR2-expressing cells adhering to the plate was detected with SA-HRP (Catalog No. ab7403, manufactured by Abcam). For the quantification of HRP, the chemiluminescence value was measured using SuperSignal ELISA Pico Chemiluminescent Substrate (Catalog No. 37070, manufactured by Thermo Fisher). Since the binding of Biotin-VIpep-3 to cell surface VIPR2 competes with the binding of the amino acid-substituted peptide or VIpep-3 coexisting in the solution, it is inhibited in a concentration-dependent manner by the amino acid-substituted peptide or VIpep-3. That is, the binding activity of the amino acid-substituted peptide or VIpep-3 to VIPR2 is detected as a competitive inhibitory activity against the binding of Biotin-VIpep-3. Taking the luminescence value of the well without the addition of Biotin-VIpep-3 as 100% inhibitory activity and the luminescence value of the well without the addition of the amino acid-substituted peptide or VIpep-3 as 0% inhibitory activity, the 50% inhibitory activity values of the amino acid-substituted peptide and VIpep-3 were calculated. Subsequently, taking the 50% inhibitory activity value of VIpep-3 as 1, the relative value of the inhibitory activity value of the amino acid-substituted peptide was calculated.

[0097] (Evaluation of the Binding Activity of Amino Acid-Substituted Peptide to VIPR2) The results of the competition binding test on VIPR2-expressing cells, with N = 4, are shown in Figure 4. Representative examples of the peptides of the present invention (Seq-1 to 9) all competed with Biotin-VIpep-3. From these results, it was shown that the peptides of the present invention into which amino acid substitution and bicyclization were introduced had VIPR2 binding activity. In particular, the binding activities of Seq-1 to 4 and Seq-6 were equal to or higher than that of VIpep-3.

[0098] (Evaluation of the antagonist activity of the peptides of the present invention against VIPR2) As one of the downstream signals of VIPR2, a change in the intracellular calcium concentration is known. For a human VIPR2-expressing cell line (Catalog No. HTS079RTA, manufactured by eurofins), Scree Quest TM Fluo-8, an indicator reagent for measuring changes in intracellular calcium concentration by fluorescence, was introduced using the Fluo-8 No Wash Calucium Assay Kit (Catalog No. 36315, manufactured by AAT Bioquest). The natural ligand VIP (final concentration 150 nM) and VIpep-3 (final concentration 750 nM) or representative examples of the peptides of the present invention (Seq-1, 5 to 9) (final concentration 750 nM) were co-added, and changes in fluorescence intensity were observed over time with a fluorescence microscope. Using the difference between the fluorescence intensity before VIP addition and the strongest fluorescence intensity after VIP addition as 100%, it was compared with the difference in fluorescence intensity when VIpep-3 or the peptide of the present invention was co-added.

[0099] As shown in Figure 5, VIpep-3 and representative examples of the peptides of the present invention (Seq-1, 5 to 9) inhibited the receptor activating activity of VIP against VIPR2. In particular, the inhibitory activities of Seq-1 and Seq-6 were equal to or higher than that of VIpep-3.

[0100] (Evaluation of the resistance of the peptides of the present invention to protease degradation) To confirm that the peptide of the present invention has resistance to proteolytic degradation as compared to VIpep-3, VIpep-3 or representative peptides of the present invention (Seq-1, 6, 9, 10) were mixed in rat plasma, and after culturing for a certain period of time, the remaining peptides were evaluated by the presence or absence of peaks in RP-HPLC. To 1 μL of each 10 mM peptide, 20 μL of rat plasma was added and cultured at 37°C for an arbitrary time (0 or 24 hours). Then, 200 μL of 80% acetonitrile was added to VIpep-3 and 200 μL of acetonitrile was added to the other peptides, and after thorough mixing, the mixture was allowed to stand on ice for 10 minutes and centrifuged at 15,000 rpm for 10 minutes at 4°C to remove plasma proteins. The supernatant was collected, and the remaining amount of the peptide was detected by RP-HPLC using a SunFire C18 column (5 μm 4.6×150 mm) (mobile phase A: 0.1% TFA / water, mobile phase B: 0.1% TFA / acetonitrile, gradient from 80% mobile phase A to 10% mobile phase A at 1 mL / min for 20 minutes). As shown in Figure 6, the peak derived from VIpep-3 decreased significantly after 24 hours of culture, suggesting that some part of the sequence was subjected to proteolytic degradation. On the other hand, the peaks derived from the representative peptides of the present invention (Seq-1, 6, 9, 10) maintained almost the same level even after 24 hours as compared to 0 hours of culture. From these results, it was shown that the peptide of the present invention into which amino acid substitution and bicyclization were introduced has resistance to proteolytic degradation.

[0101] (Evaluation of the Selective Antagonist Activity of the Peptide of the Present Invention against VIPR2) A representative example of the peptide of the present invention (Seq-10) at any concentration was added to VIPR1-expressing cells transfected with an intracellular calcium concentration indicator, VIPR2-expressing cells transfected with an intracellular calcium concentration indicator, or PAC1-expressing cells transfected with an intracellular calcium concentration indicator, and cultured for 30 minutes. Subsequently, for VIPR1 cells and VIPR2 cells, VIP (25 nM and 150 nM) was added, and for PAC1 cells, PACAP (35 nM) was added. Immediately thereafter, changes in intracellular calcium concentration for 2 minutes were measured with FLIPR Tetra. The change in intracellular calcium concentration when only the ligand of VIP or PACAP was added was defined as an inhibition rate of 0%, and the change in intracellular calcium concentration when the antagonist peptide and the ligand were not added together was defined as an inhibition rate of 100%. The inhibition rate of the antagonist peptide was calculated.

[0102] As shown in Fig. 7, the antagonist activity of the representative example of the peptide of the present invention (Seq-10) was significantly stronger against the VIP-VIPR2 interaction than against the VIP-VIPR1 interaction or the PACAP-PAC1 interaction.

[0103] (Evaluation of the VIPR2 antagonist activity of the peptide of the present invention in vivo) Ro25-1553 (Peptide Institute, Inc.), which is an analog of VIP and a selective agonist for VIPR2 (0.4 nmol / g body weight), was dissolved in PBS and then mixed with a representative example of the peptide of the present invention (Seq-10) (1 nmol / g body weight or 10 nmol / g body weight) dissolved in DMSO or DMSO (vehicle group) at a ratio of 9:1 (final concentration of DMSO 10%). These solutions were administered subcutaneously to ICR mice (12-day-old, male). One hour later, the brains were removed, the prefrontal cortex was separated, and phosphorylation of intracellular cyclic AMP response element-binding protein (CREB) (one of the VIPR2 downstream signals) was evaluated by Western blotting. The antibodies used for Western blotting were anti-phospho-CREB antibody (#9198) and anti-CREB antibody (#9197) purchased from Cell Signaling Technology.

[0104] As shown in Fig. 8, in the presence of Seq-10, phosphorylation of CREB was clearly suppressed, indicating that a representative example of the peptide of the present invention has antagonist activity against VIPR2 in vivo.

[0105] (Evaluation of improvement in recognition function of mice for novel objects by administration of the peptide of the present invention) As reported in Non-Patent Document 12, after Ro25-1553 was subcutaneously administered once a day to day-1-old mice for 14 days, the recognition function of the grown mice (8-week-old) for novel objects continued to decline significantly (Figure 9(A)). It was evaluated whether the peptide of the present invention could improve the recognition function for novel objects that is reduced by the activation of VIPR2. Ro25-1553 (Peptide Institute, Inc.), which is an analog of VIP and a selective agonist for VIPR2 (0.07 nmol / g body weight), was dissolved in PBS and then mixed with a representative example of the peptide of the present invention (Seq-10) (1 nmol / g body weight) or DMSO (vehicle group) dissolved in DMSO at a ratio of 99:1 (final concentration of DMSO: 1%). These solutions were subcutaneously administered once a day to ICR male mice on day 1 after birth for 14 days, and then the mice were continuously bred and subjected to a recognition test for novel objects at 8 weeks of age. The novel object recognition test was conducted during the light period (8:00 - 20:00) according to Non-Patent Document 12. First, the test mice were acclimated for 10 minutes a day for 3 consecutive days in an acrylic-modified polyvinyl chloride test cage (30 cm × 30 cm × 35 cm) lined only with a sterilized wooden soft tip (Sankyo Labo Service Co., Ltd.) in a soundproof laboratory set at an illuminance of 30 lux. On the 4th day, two different objects (objects a and b were randomly selected from two of a golf ball, a Lego block, a plastic cylinder, and an outlet) were placed at a position 8 cm away from the wall, and the mice were allowed to freely explore for 10 minutes (training trial). Twenty-four hours later, the mice were allowed to freely explore for 5 minutes in the test cage where object b was replaced with object c, which was a novel object (test trial). The behaviors of the animals during the training trial and the test trial were video-recorded, and the exploration time for each of the two objects was measured. The ratio (%) of the difference in the exploration time between object c and object a to the total exploration time during the test trial was calculated as the discrimination index.

[0106] As shown in Fig. 9(B), the recognition function of mice administered with Ro25-1553 was clearly reduced. On the other hand, in the mice administered with the representative example of the peptide of the present invention (Seq-10) in combination, the reduction in the recognition function for novel objects was significantly improved (p-value by Student's t-test was 0.001 or less). And the recognition function was almost equivalent to that of normal mice. This result indicates that administration of the peptide of the present invention can significantly prevent and improve the reduction in the recognition function of mice for novel objects due to the activation of VIPR2.

Industrial Applicability

[0107] The peptide according to the present invention has protease resistance, and when the peptide binds to VIPR2, it inhibits the signal transduction of VIPR2 via the natural ligand. Therefore, the peptide according to the present invention is considered to be useful for the prevention and treatment of diseases involving the activation of VIPR2, such as schizophrenia and autism spectrum disorder.

[0108] The peptide according to the present invention can not only be used as a drug itself, but also as a delivery molecule to tissues expressing VIPR2 and as a molecule for detecting the expression of VIPR2.

[0109] Furthermore, it is expected that the peptide according to the present invention will exert a more effective effect on the prevention and treatment of schizophrenia and autism spectrum disorder by being used in combination with pharmaceuticals and therapies having other mechanisms of action.

Claims

1. Formula (17): c[X １ -Pro ２ -X ３ -Tyr ４ -Leu ５ -Pro ６ -c(X ７ -X ８ -Leu ９ -Cys １０ -X １１ )-X １２ -X １３ (17) (wherein, X １ represents cysteine, X ３ represents 2-azetidine-2-carboxylic acid, proline, hydroxyproline, 3,4-dehydroproline, pipecolic acid, serine or lysine, X ８ represents tyrosine, proline or arginine, and X ７ and X １１ represents any combination of lysine and aspartic acid, aspartic acid and lysine, lysine and glutamic acid, or glutamic acid and lysine, X １２ and X １３ each independently represents leucine, isoleucine or norleucine, X １ and Cys １０ form a disulfide bond between their respective side chains, and X ７ and X １１ form an amide bond between their respective side chains, whereby the peptide of formula (17) has two cyclic structures in the molecule, and the N-terminal amino group and the C-terminal carboxy group may be modified.) consisting of an amino acid sequence represented by, a cyclic peptide having VIPR2 antagonist activity or a pharmaceutically acceptable salt.

2. X １ represents cysteine, X ３ represents proline or serine, and X ７ represents lysine, and X ８ represents tyrosine, and X １１ represents aspartic acid, and X １２ and X １３ each independently represents leucine, isoleucine or norleucine, wherein the N-terminal amino group is acetylated and the C-terminal carboxy group is amidated, the cyclic peptide according to claim 1, or a pharmacologically acceptable salt thereof.

3. A cyclic peptide having the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 10, or a pharmaceutically acceptable salt thereof.

4. A medicament, diagnostic agent, and / or research reagent comprising the cyclic peptide or pharmaceutically acceptable salt according to any one of Claims 1 to 3.

Images