Dithiocyclopeptide compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a disulfide cyclic peptide compound of a melanocortin receptor agonist based on polypeptide small molecules, and the disulfide cyclic peptide compound has the following structure: R2-R1-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-R3-R4, wherein R1 is selected from Arg; r2 is selected from an acetyl group or a palmitoyl group; r3 is selected from Ile, Pro or deletion; r4 is selected from amino; when R3 is lost, R2 is a palmitoyl group. The disulfide cyclopeptide compound provided by the invention has relatively good selectivity on melanocortin receptors (MCR1, MCR3, MCR4 and MCR5).

Description

[0001] This application is a divisional application of Chinese patent application No. 2024118964772, filed on December 20, 2024, entitled “A disulfide cyclic peptide compound, its preparation method and application”. The entire contents of the Chinese patent application are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medical technology, and in particular relates to a disulfide cyclic peptide compound and a preparation method and application thereof. Background Art

[0003] The melanocortin system comprises melanocortin (MCR) and its receptor (MCR), neuropeptide Y (NPY), and the endogenous melanocortin antagonists agouti and agouti-related protein (AgRP). Melanocortins are a large class of peptides that regulate diverse functions, including α-, β-, and γ-melanocyte stimulating hormones (MSH) and adrenocorticotropin (ACTH). They are all derived from tissue-specific posttranslational processing of pro-opiomelanocortin (POMC). The melanocortin receptor system includes five MCRs (MC1R–MC5R) and two receptor accessory proteins, MRAP (melanocortin receptor associated protein). While MC2R specifically binds to ACTH, MC1R, MC3R, MC4R, and MC5R can bind to all melanocortins, though their binding affinity varies among the receptors.

[0004] The function of MCR receptors is related to their specific tissue expression. MC2R, primarily located in the adrenal cortex, is a key component of the hypothalamic-pituitary-adrenal axis, stimulating glucocorticoid biosynthesis. Melanocortin receptors involved in energy metabolism regulation are MC3R and MC4R. MC4R is considered a key regulator of energy metabolism, as loss of function in both mice and humans results in an obesity-like phenotype. In addition to MC4R, MC3R is also widely distributed in the brain, primarily expressed in the hypothalamus, primarily in the arcuate nucleus and ventromedial hypothalamus. These structures are involved in regulating energy homeostasis, metabolism, and appetite. Numerous studies have demonstrated that MC3R and MC4R can function independently, playing complementary, rather than redundant, roles in controlling energy balance. MC5R, widely expressed in peripheral organs and tissues, appears to play a key role in immune and inflammatory responses and is crucial for temperature control and exocrine function.

[0005] Currently, a variety of melanocortin peptide analogs are being developed as potential treatments for conditions such as skin diseases, obesity, anorexia, and type 2 diabetes. Setmelanotide is a cyclic, high-affinity peptide with a G protein signaling profile that is biased toward Gq / 11 (phospholipase C activation) compared to native α-MSH, and exhibits 20-fold selectivity for the MC4R receptor subtype. Setmelanotide, as a targeted therapy, restores function of the impaired MC4R pathway, reestablishing energy expenditure and appetite control in patients with rare genetic obesity disorders, reducing hunger and weight loss. However, setmelanotide is associated with side effects, including injection site reactions, skin hyperpigmentation (skin patches darker than the surrounding skin), headaches, and gastrointestinal side effects (such as nausea, diarrhea, and abdominal pain). Adverse reproductive effects have also been reported during treatment.

[0006] Therefore, there is still a need to develop a melanocortin receptor ligand with better selectivity, stronger stability and fewer side effects for melanocortin receptors (MC1R-MC5R). Summary of the Invention

[0007] The purpose of the present invention is to provide a disulfide cyclic peptide compound and a preparation method and application thereof.

[0008] In order to achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows: In a first aspect of an embodiment of the present invention, a disulfide cyclic peptide compound is provided, wherein the disulfide cyclic peptide compound has the following structure: R2-R1-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-R3-R4; wherein R2 and R4 are each independently selected from an amino group, an acetyl group or a palmitoyl group; R1 and R3 are each independently selected from Ile, Arg, D-Phe, Pro or are missing, R1 and R3 are not missing at the same time, and when R1 or R3 is missing, at least one of R2 and R4 is a palmitoyl group.

[0009] In one aspect of the present invention, the disulfide cyclic peptide compound has the following structural formula:

[0010] Wherein, R1, R2, R3 and R4 are as defined above.

[0011] In one aspect of the invention, R3 is selected from Ile, D-Phe, Pro or deletion, and R1 is Arg.

[0012] In one aspect of the present invention, R2 is selected from an acetyl group or a palmitoyl group, and R4 is an amino group.

[0013] In one aspect of the invention, when R3 is absent, R4 is a palmitoyl group.

[0014] In one aspect of the present invention, the disulfide cyclic peptide compound is selected from at least one of the following compounds:

[0015]

[0016] In one aspect of the present invention, the present invention provides a disulfide cyclic peptide compound, wherein the disulfide cyclic peptide compound is compound WP302-1.

[0017] Specifically, compound WP302-1 has the following structure:

[0018] Specifically, compound WP302-1 is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-D-Phe-NH2.

[0019] Specifically, the compound WP302-1 has the amino acid sequence shown in SEQ ID NO.1.

[0020] Specifically, the molecular formula of compound WP302-1 is C 58 H 77 O 10N 19 S2.

[0021] In one aspect of the present invention, the present invention provides a disulfide cyclic peptide compound, wherein the disulfide cyclic peptide compound is compound WP302-2.

[0022] Specifically, compound WP302-2 has the following structure:

[0023] Specifically, compound WP302-2 is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Pro-NH2.

[0024] Specifically, the compound WP302-2 has the amino acid sequence shown in SEQ ID NO.2.

[0025] Specifically, the molecular formula of compound WP302-2 is C 54 H 75 O 10 N 19 S2.

[0026] In one aspect of the present invention, the present invention provides a disulfide cyclic peptide compound, wherein the disulfide cyclic peptide compound is compound WP302-3.

[0027] Specifically, compound WP302-3 has the following structure:

[0028] Specifically, compound WP302-3 is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Ile-NH2.

[0029] Specifically, the compound WP302-3 has the amino acid sequence shown in SEQ ID NO.3.

[0030] Specifically, the molecular formula of compound WP302-3 is C 55 H 79 O 10 N 19 S2.

[0031] In one aspect of the present invention, the present invention provides a disulfide cyclic peptide compound, wherein the disulfide cyclic peptide compound is compound WP302-4.

[0032]

[0033] Specifically, compound WP302-4 is Palm-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2.

[0034] Specifically, the compound WP302-4 has the amino acid sequence shown in SEQ ID NO.4.

[0035] Specifically, the molecular formula of compound WP302-4 is C 63 H 96 N 18 O9S2.

[0036] In one aspect of the present invention, the present invention provides a disulfide cyclic peptide compound, wherein the disulfide cyclic peptide compound is compound WP302-5.

[0037] Specifically, compound WP302-5 has the following structure:

[0038] Specifically, compound WP302-5 is Palm-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-D-Phe-NH2.

[0039] Specifically, the compound WP302-5 has the amino acid sequence shown in SEQ ID NO.5.

[0040] Specifically, the molecular formula of compound WP302-5 is C 72 H 105 N 19 O 10 S2.

[0041] In one aspect of the present invention, the present invention provides a disulfide cyclic peptide compound, wherein the disulfide cyclic peptide compound is compound WP302-6.

[0042] Specifically, compound WP302-6 has the following structure:

[0043] Specifically, compound WP302-6 is Palm-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Pro-NH2.

[0044] Specifically, the compound WP302-6 has the amino acid sequence shown in SEQ ID NO.6.

[0045] Specifically, the molecular formula of compound WP302-6 is C 68 H 103N 19 O 10 S2.

[0046] In one aspect of the present invention, the present invention provides a disulfide cyclic peptide compound, wherein the disulfide cyclic peptide compound is compound WP302-7.

[0047] Specifically, compound WP302-7 has the following structure:

[0048] Specifically, compound WP302-7 is Palm-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Ile-NH2.

[0049] Specifically, the compound WP302-7 has the amino acid sequence shown in SEQ ID NO.7.

[0050] Specifically, the molecular formula of compound WP302-7 is C 69 H 107 N 19 O 10 S2.

[0051] In a second aspect of the embodiments of the present invention, a method for preparing the aforementioned disulfide cyclic peptide compound is provided, the method comprising the following steps: Step 1: Select a resin and remove the Fmoc protecting group to obtain a resin from which the Fmoc protecting group has been removed; Step 2: Weigh Fmoc-R3-OH or Fmoc-Cys(Trt)-OH and PyBop, and perform a coupling reaction on the resin with the Fmoc protecting group removed to obtain a coupled resin; Step 3: According to the peptide sequence, the coupling resin is coupled from the C-terminus to the N-terminus to obtain a linear peptide resin; Step 4: reacting the cleavage solution with the linear peptide resin to remove the protecting group and obtain a polypeptide; Step 5: dissolving the polypeptide in water, adjusting the pH and adding H2O2 to react to obtain the disulfide cyclic peptide compound.

[0052] In a third aspect of the embodiments of the present invention, there is provided a use of the aforementioned disulfide cyclic peptide compound or the disulfide cyclic peptide compound prepared by the aforementioned method in preparing a drug.

[0053] In one aspect of the invention, the medicament includes a medicament for treating or preventing acute or chronic inflammatory diseases, autoimmune diseases, transplant rejection, metabolic diseases associated with weight gain, metabolic diseases associated with weight loss, diabetes, diabetic complications, cancer, cancerous hyperplasia, reproductive system diseases, peripheral or central nervous system diseases, cardiovascular diseases or respiratory system diseases.

[0054] Specifically, the acute or chronic inflammatory diseases include but are not limited to systemic inflammation, inflammatory bowel disease, cerebral inflammation, sepsis, and septic shock.

[0055] Specifically, the autoimmune diseases include but are not limited to systemic lupus erythematosus, rheumatoid arthritis, gouty arthritis, psoriatic arthritis, axial spondyloarthritis, myasthenia gravis, multiple sclerosis, psoriasis, pemphigus, vitiligo, narcolepsy, neuromyelitis optica, hyperthyroidism, hypothyroidism, autoimmune gastritis, autoimmune hepatitis, primary biliary cholangitis, Crohn's disease, ulcerative colitis, celiac disease, lupus nephritis, Goodpasture's syndrome, autoimmune oophoritis, autoimmune orchitis, polymyositis, vasculitis or diffuse connective tissue diseases such as Sjögren's disease.

[0056] Specifically, the organs causing transplant rejection include but are not limited to kidney, heart, liver, pancreas and pancreatic islets, parathyroid glands, heart and lungs, bone marrow, and cornea.

[0057] Specifically, the metabolic diseases associated with weight gain include but are not limited to obesity, eating disorders, and Prader-Willi syndrome.

[0058] Specifically, the metabolic disease accompanied by weight loss includes but is not limited to anorexia or bulimia.

[0059] Specifically, the diabetic complications include but are not limited to diabetic nephropathy, diabetic retinopathy, diabetic cataracts, diabetic foot, cardiovascular complications of diabetes, diabetic cerebrovascular disease, and diabetic neuropathy.

[0060] Specifically, the cancer includes but is not limited to mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer , melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoid leukemia, chronic lymphoid leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.

[0061] Specifically, the cancerous hyperplasia includes but is not limited to squamous epithelial dysplasia and glandular epithelial dysplasia.

[0062] Specifically, the reproductive system diseases include but are not limited to abnormal urination, pyuria, abnormal urethral discharge, pain, lumps, sexual dysfunction, male infertility, female infertility, polycystic ovary syndrome, menstrual disorders, dysmenorrhea, abnormal pregnancy, and uterine lesions.

[0063] In particular, the peripheral or central nervous system diseases include, but are not limited to, depression, bipolar depression or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, vascular dementia, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused by stroke, hypoxia or craniocerebral trauma.

[0064] Specifically, the cardiovascular diseases include but are not limited to coronary heart disease, stroke, ischemic stroke, cerebral hemorrhage, subarachnoid hemorrhage, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, abnormal heart rhythm, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral arterial disease, thromboembolic disease, and venous thrombosis.

[0065] Specifically, the respiratory diseases include but are not limited to upper respiratory tract infection, acute bronchitis, acute pharyngitis, pneumonia, chronic bronchitis, chronic obstructive pulmonary disease, tuberculosis, lung tumors, bronchiectasis, lung abscess, pulmonary interstitial fibrosis, pulmonary embolism, acute respiratory distress syndrome, and cor pulmonale.

[0066] In one aspect of the present invention, the use is achieved by binding the disulfide cyclic peptide compound to a melanocortin receptor.

[0067] In one aspect of the present invention, the melanocortin receptor comprises at least one of MC1R, MC3R, MC4R and MC5R.

[0068] In a fourth aspect of an embodiment of the present invention, a pharmaceutical composition is provided, which includes the aforementioned disulfide cyclic peptide compound or an analog thereof, wherein the analog includes a derivative of the disulfide cyclic peptide compound, a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof.

[0069] In one aspect of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0070] In one aspect of the present invention, a pharmaceutically acceptable carrier or excipient refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or subject. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc.

[0071] The beneficial effects of the present invention are: The present invention prepares a disulfide cyclic peptide compound for the first time. The disulfide cyclic peptide compound has the following structure: R2-R1-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-R3-R4. The disulfide cyclic peptide compound provided by the present invention can act as a ligand of one or more melanocortin receptors, can bind well to the melanocortin receptors, and produce good effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 is the MS spectrum of compound WP302-1 of Example 1; Figure 2 HPLC spectrum of compound WP302-1 of Example 1; Figure 3 is the MS spectrum of compound WP302-2 of Example 2; Figure 4 HPLC spectrum of compound WP302-2 of Example 2; Figure 5 is the MS spectrum of compound WP302-3 of Example 3; Figure 6 HPLC spectrum of compound WP302-3 of Example 3; Figure 7 is the MS spectrum of compound WP302-4 of Example 4; Figure 8 HPLC spectrum of compound WP302-4 of Example 4; Figure 9 is the MS spectrum of compound WP302-5 of Example 5; Figure 10 HPLC spectrum of compound WP302-5 of Example 5; Figure 11 is the MS spectrum of compound WP302-6 of Example 6; Figure 12 HPLC spectrum of compound WP302-6 of Example 6; Figure 13 is the MS spectrum of compound WP302-7 of Example 7; Figure 14 is the HPLC spectrum of compound WP302-7 of Example 7; Figure 15 HPLC spectrum of compound WP300 of Comparative Example 1; Figure 16 This is the MS spectrum of compound WP300 in Comparative Example 1. DETAILED DESCRIPTION

[0073] The following non-limiting examples are provided to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way. The following is merely an illustrative description of the scope of the present invention, and those skilled in the art may make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of protection claimed in this application.

[0074] Terms and abbreviations:

[0075] The present invention will be further described below by way of specific examples. The various chemical reagents used in the examples of the present invention were obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all by weight. Unless otherwise specified, it is understood that the experiments were conducted at room temperature.

[0076] Example 1: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-D-Phe-NH2 (SEQ ID NO. 1) The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry in a 100 mL reactor.

[0077] 1 g of Ramage Amide AM resin with a loading of 0.30 mmol / g was swollen and then the Fmoc protecting group was removed. 0.35 g of Fmoc-D-Phe-OH, 468 mg of PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate), and 0.34 mL of DIEA were dissolved in 25 mL of DMF at 0°C. After complete dissolution, the column was added and reacted at room temperature for 1 hour. The reaction progress was assessed by a negative ninhydrin test. After the coupling reaction, the reaction solution was drained, washed with 30 mL of DMF, and then reacted with 40 mL of 20% hexahydropyridine in DMF for 5 minutes. The reaction was then washed once with DMF. After washing, 30 mL of 20% hexahydropyridine in DMF was added again. The reaction was allowed to react for 10 minutes, then drained, washed three times with DMF, twice with DCM, and once with DMF.

[0078] According to the peptide sequence, coupling was performed sequentially from the C-terminus to the N-terminus until Fmoc-Arg(Pbf)-OH was reached, and Fmoc was removed and the amino groups were blocked with acetic anhydride and pyridine to form acetylation. The side chain protecting groups of Arg, Cys, His, and Trp were Pbf, Trt, Trt, and Boc, respectively; the α-amino groups of all amino acids were protected with Fmoc. The cleavage solution (TFA: triisopropylsilane: water = 95:2.5:2.5) was reacted with the linear peptide resin to obtain approximately 386.2 mg of the peptide with all side chain protecting groups removed; Dissolve the peptide in 400 mL of pure water, adjust the pH to 8.0, add 1 mL of H2O2, and react at room temperature. After 30 minutes of reaction, the peptide was completely converted into a cyclic peptide as monitored by analytical HPLC. The crude linear peptide solution was filtered through a 0.45 μm filter membrane and purified using high-performance liquid chromatography (HPLC). The purified solution was separated and purified using a DAC-HB50 dynamic axial compression column with mobile phases A (0.05% by mass trifluoroacetic acid in water) and B (0.05% by mass trifluoroacetic acid in acetonitrile). Gradient elution was used for separation and purification. UV detection was used to detect the sample, and the peptide solution containing the target peak was collected in sections. HPLC purification yielded 80 mL of a finished peptide solution with a purity greater than 95%. The resulting solution was equilibrated with 1 / 1000 acetic acid and acetonitrile and concentrated by rotary evaporation to yield 30 mL of the solution. This solution was then pre-lyophilized and lyophilized to yield 45.7 mg of the refined peptide, compound WP302-1.

[0079] The structure of compound WP302-1 is shown below:

[0080] The MS spectrum and HPLC mass spectrum of compound WP302-1 are shown as follows: Figure 1 and Figure 2 shown.

[0081] Example 2: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Pro-NH2 (SEQ ID NO. 2) The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry in a 100 mL reactor.

[0082] 1 g of Ramage Amide AM resin with a loading of 0.30 mmol / g was swollen and then the Fmoc protecting group was removed. 0.53 g of Fmoc-Cys(Trt)-OH, 468 mg of PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate), and 0.34 mL of DIEA were dissolved in 25 mL of DMF at 0°C. After complete dissolution, the column was added and reacted at room temperature for 1 hour. The reaction progress was assessed by a negative ninhydrin test. After the coupling reaction, the reaction solution was drained, washed with 30 mL of DMF, and then reacted with 40 mL of 20% hexahydropyridine in DMF for 5 minutes. The reaction was then washed once with DMF. After washing, 30 mL of 20% hexahydropyridine in DMF was added again. The reaction was allowed to react for 10 minutes, then drained, washed three times with DMF, twice with DCM, and once with DMF.

[0083] According to the peptide sequence, coupling was performed sequentially from the C-terminus to the N-terminus until Fmoc-Arg(Pbf)-OH was reached, and Fmoc was removed and the amino groups were blocked with acetic anhydride and pyridine to form acetylation. The side chain protecting groups of Arg, Cys, His, and Trp were Pbf, Trt, Trt, and Boc, respectively; the α-amino groups of all amino acids were protected with Fmoc. The cleavage solution (TFA: triisopropylsilane: water = 95:2.5:2.5) was reacted with the linear peptide resin to obtain approximately 368.9 mg of the peptide with all side chain protecting groups removed; The peptide was dissolved in 400 mL of pure water, the pH was adjusted to 8.0, 1 mL of H2O2 was added, and the reaction was carried out at room temperature. After 30 min of reaction, the peptide was completely converted into a cyclic peptide as monitored by analytical HPLC. The crude linear peptide solution was filtered through a 0.45 μm filter membrane and purified using high-performance liquid chromatography (HPLC). The purified solution was separated and purified using a DAC-HB50 dynamic axial compression column with mobile phases A (0.05% by mass trifluoroacetic acid in water) and B (0.05% by mass trifluoroacetic acid in acetonitrile). Gradient elution was used for separation and purification. UV detection was used to detect the sample, and the peptide solution containing the target peak was collected in sections. HPLC purification yielded 80 mL of a finished peptide solution with a purity greater than 95%. The resulting solution was equilibrated with 1 / 1000 acetic acid and acetonitrile and concentrated by rotary evaporation to yield 30 mL of the solution. This solution was then pre-lyophilized and lyophilized to yield 42.5 mg of the refined peptide, compound WP302-2.

[0084] The structure of compound WP302-2 is shown below:

[0085] The MS spectrum and HPLC mass spectrum of compound WP302-2 are shown as follows: Figure 3 and Figure 4 shown.

[0086] Example 3: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Ile-NH2 (SEQ ID NO. 3) The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry in a 100 mL reactor.

[0087] 1 g of Ramage Amide AM resin with a loading of 0.30 mmol / g was swollen and then the Fmoc protecting group was removed. 0.32 g of Fmoc-Ile-OH, 468 mg of PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate), and 0.34 mL of DIEA were dissolved in 250 mL of DMF at 0°C. After complete dissolution, the column was added and reacted at room temperature for 1 hour. The reaction progress was assessed by a negative ninhydrin test. After the coupling reaction, the reaction solution was drained, washed with 30 mL of DMF, and then reacted with 40 mL of 20% hexahydropyridine in DMF for 5 minutes. The reaction was then washed once with DMF. After washing, 30 mL of 20% hexahydropyridine in DMF was added again. The reaction was allowed to react for 10 minutes, then drained, washed three times with DMF, twice with DCM, and once with DMF.

[0088] According to the peptide sequence, coupling was performed sequentially from the C-terminus to the N-terminus until Fmoc-Arg(Pbf)-OH was reached, and Fmoc was removed and the amino groups were blocked with acetic anhydride and pyridine to form acetylation. The side chain protecting groups of Arg, Cys, His, and Trp were Pbf, Trt, Trt, and Boc, respectively; the α-amino groups of all amino acids were protected with Fmoc. The cleavage solution (TFA: triisopropylsilane: water = 95:2.5:2.5) was reacted with the linear peptide resin to obtain approximately 396.3 mg of the peptide with all side chain protecting groups removed; The peptide was dissolved in 400 mL of pure water, the pH was adjusted to 8.0, 1 mL of H2O2 was added, and the reaction was carried out at room temperature. After 30 min of reaction, the peptide was completely converted into a cyclic peptide as monitored by analytical HPLC. The crude linear peptide solution was filtered through a 0.45 μm filter membrane and purified using high-performance liquid chromatography (HPLC). The purified solution was separated and purified using a DAC-HB50 dynamic axial compression column with mobile phases A (0.05% by mass trifluoroacetic acid in water) and B (0.05% by mass trifluoroacetic acid in acetonitrile). Gradient elution was used for separation and purification. UV detection was used to detect the sample, and the peptide solution containing the target peak was collected in sections. HPLC purification yielded 75 mL of a finished peptide solution with a purity greater than 95%. The resulting solution was equilibrated with 1 / 1000 acetic acid and acetonitrile and concentrated by rotary evaporation to yield 30 mL of the solution. This solution was then pre-lyophilized and lyophilized to yield 35.6 mg of the refined peptide, compound WP302-3.

[0089] The structure of compound WP302-3 is shown below:

[0090] The MS spectrum and HPLC mass spectrum of compound WP302-3 are shown as follows: Figure 5 and Figure 6 shown.

[0091] Example 4: Palm-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO. 4) The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry in a 100 mL reactor.

[0092] 1 g of Ramage Amide AM resin with a loading of 0.30 mmol / g was swollen and then the Fmoc protecting group was removed. 0.53 g of Fmoc-Cys(Trt)-OH, 468 mg of PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate), and 0.34 mL of DIEA were dissolved in 25 mL of DMF at 0°C. After complete dissolution, the column was added and reacted at room temperature for 1 hour. The reaction progress was assessed by a negative ninhydrin test. After the coupling reaction, the reaction solution was drained, washed with 30 mL of DMF, and then reacted with 40 mL of 20% hexahydropyridine in DMF for 5 minutes. The reaction was then washed once with DMF. After washing, 30 mL of 20% hexahydropyridine in DMF was added again. The reaction was allowed to react for 10 minutes, then drained, washed three times with DMF, twice with DCM, and once with DMF.

[0093] According to the peptide sequence, coupling was performed sequentially from the C-terminus to the N-terminus until Fmoc-Arg(Pbf)-OH was reached, and Fmoc was removed and palmitic acid was used to react with the α-amino group of Arg to form an amide bond. The side chain protecting groups of Arg, Cys, His, and Trp were Pbf, Trt, Trt, and Boc, respectively; the α-amino groups of all amino acids were protected with Fmoc. The cleavage solution (TFA: triisopropylsilane: water = 95:2.5:2.5) was reacted with a linear peptide resin to obtain approximately 4.5.2 mg of a peptide with all side chain protecting groups removed. The peptide was dissolved in 450 mL of pure water, the pH was adjusted to 8.0, 1 mL of H2O2 was added, and the reaction was carried out at room temperature. After 30 minutes of reaction, the peptide was completely converted into a cyclic peptide as monitored by analytical HPLC. The crude linear peptide solution was filtered through a 0.45 μm filter membrane and purified using high-performance liquid chromatography (HPLC). The purified solution was separated and purified using a DAC-HB50 dynamic axial compression column with mobile phases A consisting of 0.05% trifluoroacetic acid in water and B consisting of 0.05% trifluoroacetic acid in acetonitrile. A gradient elution method was used for separation and purification. UV detection was used to detect the sample, and the peptide solution containing the target peak was collected in sections. HPLC purification yielded 120 mL of a finished peptide solution with a purity greater than 95%. The resulting solution was equilibrated with 1 / 1000 acetic acid and acetonitrile and concentrated by rotary evaporation to yield 50 mL of the solution. This solution was then pre-lyophilized and lyophilized to yield 32.7 mg of the refined peptide, compound WP302-4.

[0094] The structure of compound WP302-4 is shown below:

[0095] The MS spectrum and HPLC mass spectrum of compound WP302-4 are shown as follows: Figure 7 and Figure 8 shown.

[0096] Example 5: Palm-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-D-Phe-NH2 (SEQ ID NO. 5) The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry in a 100 mL reactor.

[0097] Select 1g of Ramage Amide AM resin with a loading of 0.30mmol / g, and remove the Fmoc protecting group after swelling; Weigh 0.34 g of Fmoc-D-Phe-OH, 468 mg of PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), and 0.34 mL of DIEA and dissolve them in 25 mL of DMF at 0°C. Once completely dissolved, add the mixture to the reaction column and react at room temperature for 1 hour. Ninhydrin assay confirms the reaction progress by a negative result. After the coupling reaction, drain the reaction solution and wash with 30 mL of DMF. Add 40 mL of 20% hexahydropyridine in DMF and react for 5 minutes. Wash once with DMF. After washing, add 30 mL of 20% hexahydropyridine in DMF again. React for 10 minutes, drain the solution, and wash three times with DMF, twice with DCM, and once with DMF.

[0098] According to the peptide sequence, coupling was performed sequentially from the C-terminus to the N-terminus until Fmoc-Arg(Pbf)-OH was reached, and Fmoc was removed and palmitic acid was used to react with the α-amino group of Arg to form an amide bond. The side chain protecting groups of Arg, Cys, His, and Trp were Pbf, Trt, Trt, and Boc, respectively; the α-amino groups of all amino acids were protected with Fmoc. The cleavage solution (TFA: triisopropylsilane: water = 95:2.5:2.5) was reacted with the linear peptide resin to obtain approximately 488.89 mg of the peptide with all side chain protecting groups removed; The peptide was dissolved in 500 mL of pure water, the pH was adjusted to 8.0, 1 mL of H2O2 was added, and the reaction was carried out at room temperature. After 30 min of reaction, the peptide was completely converted into a cyclic peptide as monitored by analytical HPLC. The crude linear peptide solution was filtered through a 0.45 μm filter membrane and purified using high-performance liquid chromatography (HPLC). The purified solution was separated and purified using a DAC-HB50 dynamic axial compression column with mobile phases A consisting of 0.05% trifluoroacetic acid in water and B consisting of 0.05% trifluoroacetic acid in acetonitrile. Gradient elution was used for separation and purification. UV detection was used to detect the sample, and the peptide solution containing the target peak was collected in sections. HPLC purification yielded 150 mL of a finished peptide solution with a purity greater than 95%. The resulting solution was equilibrated with 1 / 1000 acetic acid and acetonitrile and concentrated by rotary evaporation to yield 65 mL of the solution. This solution was then pre-lyophilized and lyophilized to yield 35.1 mg of the refined peptide, compound WP302-5.

[0099] The structure of compound WP302-5 is shown below:

[0100] The MS spectrum and HPLC mass spectrum of compound WP302-5 are shown as follows: Figure 9 and Figure 10 shown.

[0101] Example 6: Palm-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Pro-NH2 (SEQ ID NO. 6) The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry in a 100 mL reactor.

[0102] 1 g of Ramage Amide AM resin with a loading of 0.30 mmol / g was swollen and then the Fmoc protecting group was removed. 0.30 g of Fmoc-Pro-OH, 468 mg of PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate), and 0.34 mL of DIEA were dissolved in 25 mL of DMF at 0°C. After complete dissolution, the column was added and reacted at room temperature for 1 hour. The reaction progress was assessed by a negative ninhydrin test. After the coupling reaction, the reaction solution was drained, washed with 30 mL of DMF, and then reacted with 40 mL of 20% hexahydropyridine in DMF for 5 minutes. The reaction was then washed once with DMF. After washing, 30 mL of 20% hexahydropyridine in DMF was added again. The reaction was allowed to react for 10 minutes, then drained, washed three times with DMF, twice with DCM, and once with DMF.

[0103] According to the peptide sequence, coupling was performed sequentially from the C-terminus to the N-terminus until Fmoc-Arg(Pbf)-OH was reached, and Fmoc was removed and palmitic acid was used to react with the α-amino group of Arg to form an amide bond. The side chain protecting groups of Arg, Cys, His, and Trp were Pbf, Trt, Trt, and Boc, respectively; the α-amino groups of all amino acids were protected with Fmoc. The cleavage solution (TFA: triisopropylsilane: water = 95:2.5:2.5) was reacted with the linear peptide resin to obtain approximately 436.12 mg of the peptide with all side chain protecting groups removed; The peptide was dissolved in 450 mL of pure water, the pH was adjusted to 8.0, 1 mL of H2O2 was added, and the reaction was carried out at room temperature. After 30 min of reaction, the peptide was completely converted into a cyclic peptide as monitored by analytical HPLC. The crude linear peptide solution was filtered through a 0.45 μm filter membrane and purified using high-performance liquid chromatography (HPLC). The purified solution was separated and purified using a DAC-HB50 dynamic axial compression column with mobile phases A (0.05% by mass trifluoroacetic acid in water) and B (0.05% by mass trifluoroacetic acid in acetonitrile). Gradient elution was used for separation and purification. UV detection was used to detect the sample, and the peptide solution containing the target peak was collected in sections. HPLC purification yielded 120 mL of a finished peptide solution with a purity greater than 95%. The resulting solution was equilibrated with 1 / 1000 acetic acid and acetonitrile and concentrated by rotary evaporation to yield 50 mL of the solution. This solution was then pre-lyophilized and lyophilized to yield 29.6 mg of the refined peptide, compound WP302-6.

[0104] The structure of compound WP302-6 is shown below:

[0105] The MS spectrum and HPLC mass spectrum of compound WP302-6 are shown as follows: Figure 11 and Figure 12 shown.

[0106] Example 7: Palm-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Ile-NH2 (SEQ ID NO. 7) The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry in a 100 mL reactor.

[0107] 1 g of Ramage Amide AM resin with a loading of 0.30 mmol / g was swollen and then the Fmoc protecting group was removed. 0.31 g of Fmoc-Ile-OH, 468 mg of PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate), and 0.34 mL of DIEA were dissolved in 25 mL of DMF at 0°C. After complete dissolution, the column was added and reacted at room temperature for 1 hour. The reaction progress was assessed by a negative ninhydrin test. After the coupling reaction, the reaction solution was drained, washed with 30 mL of DMF, and then reacted with 40 mL of 20% hexahydropyridine in DMF for 5 minutes. The reaction was then washed once with DMF. After washing, 30 mL of 20% hexahydropyridine in DMF was added again. The reaction was allowed to react for 10 minutes, then drained, washed three times with DMF, twice with DCM, and once with DMF.

[0108] According to the peptide sequence, coupling was performed sequentially from the C-terminus to the N-terminus until Fmoc-Arg(Pbf)-OH was reached, and Fmoc was removed and palmitic acid was used to react with the α-amino group of Arg to form an amide bond. The side chain protecting groups of Arg, Cys, D-His, and Trp were Pbf, Trt, Trt, and Boc, respectively; the α-amino groups of all amino acids were protected with Fmoc. The cleavage solution (TFA: triisopropylsilane: water = 95:2.5:2.5) was reacted with the linear peptide resin to obtain approximately 469.52 mg of the peptide with all side chain protecting groups removed; Dissolve the peptide in 480 mL of pure water, adjust the pH to 8.0, add 1 mL of H2O2, and react at room temperature. After 30 minutes of reaction, the peptide was completely converted into a cyclic peptide as monitored by analytical HPLC. The crude linear peptide solution was filtered through a 0.45 μm filter membrane and purified using high-performance liquid chromatography (HPLC). The purified solution was separated and purified using a DAC-HB50 dynamic axial compression column with mobile phases A consisting of 0.05% trifluoroacetic acid in water and B consisting of 0.05% trifluoroacetic acid in acetonitrile. A gradient elution method was used for separation and purification. UV detection was used to detect the sample, and the peptide solution containing the target peak was collected in sections. HPLC purification yielded 135 mL of a finished peptide solution with a purity exceeding 95%. The resulting solution was equilibrated with 1 / 1000 acetic acid and acetonitrile and concentrated by rotary evaporation to yield 55 mL of the solution. This solution was then pre-lyophilized and lyophilized to yield 36.8 mg of the refined peptide, compound WP302-7.

[0109] The structure of compound WP302-7 is shown below:

[0110] The MS spectrum and HPLC mass spectrum of compound WP302-7 are shown as follows: Figure 13 and Figure 14 shown.

[0111] Comparative Example 1: Ac-Arg-c(Cys-DAla-His-DPhe-Arg-Trp-Cys)-NH2 (SEQ ID NO.8) The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry in a 5-L reactor. Rink Amide 4-methylbenzhydrylamine (MBHA) resin (Novabiochem®, San Diego, CA) with 0.451 mmol / g substitution was used. The Fmoc amino acids used in the synthesis were Fmoc-Arg(pbf)-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Ala-OH, Fmoc-His(Trt)-OH, Fmoc-D-Phe-OH, and Fmoc-Trp(Boc)-OH. The synthesis was performed on a 50 mmol scale. The Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (DMF) for 30 minutes. In each coupling step, Fmoc amino acid (3 eq, 150 mmol), N,N-diisopropylcarbodiimide (DIC) (3 eq, 150 mmol) and 1-hydroxybenzotriazole (HOBT) (3 eq, 150 mmol) were coupled in DMF. The resin was subjected to the following cycle in the reactor: (1) washing with DMF, (2) removal of the Fmoc protecting group by treatment with 20% piperidine in DMF for 30 min, (3) washing with DMF, and (4) coupling with Fmoc amino acid in the presence of DIC and HOBT for 1 hour. The resin was successfully coupled according to the sequence of the title peptide. After the peptide chain was assembled and the last Fmoc protecting group was removed, acetylation was carried out using a solution of acetic anhydride, N-methylmorpholine (NMM) and DMF (v / v / v: 6 / 10 / 84). The resin was washed thoroughly with dichloromethane (DCM) and methanol and then dried by suction.

[0112] To cleave the title peptide, the resin was treated with a solution of TFA, phenol, EDT, H2O, and thioanisole (v / v / v / v / v: 87.5 / 2.5 / 2.5 / 2.5 / 5) at room temperature for 3 hours. The resin was filtered, and the filtrate was poured into diethyl ether, and the precipitate was collected by centrifugation. The centrifuged precipitate was washed three times with diethyl ether to obtain a final precipitate, which was then dried under vacuum to yield the crude peptide.

[0113] The crude peptide was dissolved in 0.1% TFA aqueous solution, and then 10 g / L iodine-methanol solution was added dropwise to the solution for oxidative bridging. The addition of iodine was stopped when the solution changed from colorless to pale yellow. After standing for 3 minutes, VC was added dropwise to the solution. The addition was stopped when the solution changed from pale yellow to colorless, thus completing the oxidation. The crude oxidized product was purified on a reverse-phase preparative HPLC system using a Luna C18 100A (650 x 650 x 2350 mm) (Varian) column. Elution was performed using a linear gradient from 80% A:20% B to 50% A:50% B over approximately 1 hour, where A was 0.1% TFA aqueous solution and B was a mixture of 0.1% TFA in 80% acetonitrile and 20% water. The obtained TFA salt product (more than 90%) was exchanged for Ac salt using a Luna C18 100A (650*650*2350mm) (Varian) column on a reverse phase preparative HPLC system. The column was eluted using a linear gradient from 100% A:0% B to 40% A:60% B for about 1 hour, where A was a 0.5% HAc aqueous solution and B was a mixture of 0.5% HAc in 80% acetonitrile and 20% water. The results were detected by analytical HPLC ( Figure 5 ) The qualified product was lyophilized to obtain 21635 mg of 95% white solid with a yield of 34.7%, namely compound WP300.

[0114] The structure of compound WP300 is shown below:

[0115] The MS spectrum and HPLC mass spectrum of compound WP300 are shown in Figure 2. Figure 16 and Figure 15 shown.

[0116] Test 1: Serum stability assay 1. Add 594 µL of serum to a 96-well plate and pre-incubate at 37°C for 5 minutes.

[0117] 2. Add 6 µL of test substance / positive control to the 96-well plate and mix thoroughly by pipetting. Continue to incubate at 37°C with constant shaking for 48 hours.

[0118] 3. For the test substance, remove 50 µL at 0, 0.5, 1.5, 3, 6, 24, and 48 hours and add to 150 µL of a 0.1% FA (formic acid) solution in methanol containing the internal standard. For the positive control, remove 50 µL at 0, 15, 30, 60, and 120 minutes and add to 150 µL of a 0.1% FA (formic acid) solution in methanol containing the internal standard.

[0119] 4. Vortex and mix for 10 minutes, then centrifuge at 6000 x g for 10 minutes. Inject the supernatant into the LC-MS / MS system for analysis.

[0120] The measurement results are shown in Table 1: Table 1

[0121] Test 2: EC50 determination Intracellular cyclic AMP (cAMP) levels were measured by electrochemiluminescence (ECL) assay (Meso Scale Discovery®, Gaithersburg, MD; hereinafter referred to as MSD).

[0122] 1. Remove MC1, MC3, MC4, and MC5 stable transfected cell lines from liquid nitrogen storage. Thaw rapidly in a 37°C electric water bath. Use a pipette to transfer the cell suspension into a 15 mL centrifuge tube and add 10 mL of complete culture medium. (MC1 cells: F12K + 10% FBS + 400 μg / mL G418; MC3 cells: F12K + 10% FBS + 100 μg / mL Hygromycin B + 200 μg / mL Zeocin; MC4 cells: F12K + 10% FBS + 100 μg / mL Hygromycin B + 8 μg / mL Promycin; MC5 cells: F12K + 10% FBS + 100 μg / mL Hygromycin B + 400 μg / mL G418).

[0123] 2. Centrifuge at 1000 rpm for 4 minutes and discard the supernatant. Resuspend the cell pellet in 5 mL of complete culture medium, transfer to a T75 culture flask, add 15 mL of culture medium, and culture in a 37°C, 5% CO2 incubator. After the cells have been passaged once, they can be used in this cell experiment.

[0124] 3. When the cell density reaches 80%-90%, discard the culture medium and wash the cells with 5 mL of phosphate buffer. 4. Remove the phosphate buffer, add 3 mL of trypsin, and place in a 37°C carbon dioxide incubator for 2-5 minutes. 5. Add 10 mL of complete culture medium to collect cells, centrifuge at 1000 rpm for 4 min, and discard the supernatant.

[0125] 6. Adjust the cell suspension to the appropriate density with Stimulation Buffer: 1000 cells / well for MC1, MC3, and MC5 cells; 2000 cells / well for MC4 cells.

[0126] Transfer 10 μL of the cell solution to the assay plate. Centrifuge at 600 rpm for 3 minutes and incubate at room temperature for 60 minutes. After incubation, add 5 μL of Eu-cAMP tracer solution and 5 μL of ULight™ anti-cAMP solution from the cAMP assay kit to the assay plate. Centrifuge again at 600 rpm for 3 minutes and incubate at room temperature for 60 minutes.

[0127] cAMP signals were read on a multi-function microplate reader, and data were processed, analyzed, and reported as EC50 values ​​using GraphPad Prism 6. The experimental results are shown in Tables 2 to 5.

[0128] Table 2: MC1 agonist experiments

[0129] Table 3: MC3 agonist experiments

[0130] Table 4: MC4 agonistic experiments

[0131] Table 5: MC5 agonist experiments

[0132] The cellular effects of the compound WP302 provided herein binding to melanocortin receptors were measured using intracellular cyclic adenosine monophosphate (cAMP) levels. The EC50 represents the concentration of the agonist compound required to achieve 50% of the maximal response. The results demonstrate that the compound provided herein exhibits a favorable effect on melanocortin receptors.

[0133] The present invention provides a series of compounds with the general formula R2-R1-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-R3-R4; and from the above experimental data, it can be seen that as the molecular weight of the N-terminal substitution increases, the activity of the MC5 target decreases and the selectivity increases, that is, the target is related to the N-terminal substituent.

[0134] The above detailed description is a specific description of one feasible embodiment of the present invention and is not intended to limit the scope of the present invention. It should be noted that any equivalent implementation or modification that does not depart from the present invention should be included within the scope of the technical solution of the present invention. Therefore, the scope of protection of the patent of this invention should be based on the attached requirements.

Claims

1. A disulfide cyclic peptide compound, characterized in that: The disulfide cyclic peptide compound has the following structure: R2-R1-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-R3-R4 in, R1 is selected from Arg; R2 is selected from an acetyl group or a palmitoyl group; R3 is selected from Ile, Pro or deletion; R4 is selected from amino; When R3 is absent, R2 is a palmitoyl group.

2. The disulfide cyclic peptide compound according to claim 1, characterized in that The disulfide cyclic peptide compound has the following structural formula: wherein R1, R2, R3 and R4 are as defined in claim 1.

3. The disulfide cyclic peptide compound according to claim 1 or 2, characterized in that The disulfide cyclic peptide compound is selected from at least one of the following compounds: 。 4. A method for preparing the disulfide cyclic peptide compound according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: Step 1: Select a resin and remove the Fmoc protecting group to obtain a resin from which the Fmoc protecting group has been removed; Step 2: Weigh Fmoc-R3-OH or Fmoc-Cys(Trt)-OH and PyBop, and perform a coupling reaction on the resin with the Fmoc protecting group removed to obtain a coupled resin; Step 3: According to the peptide sequence, the coupling resin is coupled from the C-terminus to the N-terminus to obtain a linear peptide resin; Step 4: reacting the cleavage solution with the linear peptide resin to remove the protecting group and obtain a polypeptide; Step 5: dissolving the polypeptide in water, adjusting the pH and adding H2O2 to react to obtain the disulfide cyclic peptide compound.

5. Use of the disulfide cyclic peptide compound according to any one of claims 1 to 3 or the disulfide cyclic peptide compound prepared by the method according to claim 7 in the preparation of a drug, characterized in that: The medicaments include those for treating or preventing acute or chronic inflammatory diseases, autoimmune diseases, transplant rejection, metabolic diseases associated with weight gain, metabolic diseases associated with weight loss, diabetes, diabetic complications, cancer, cancerous hyperplasia, reproductive system diseases, peripheral or central nervous system diseases, cardiovascular diseases or respiratory system diseases.

6. The use according to claim 5, characterized in that The application is achieved by combining the disulfide cyclic peptide compound with the melanocortin receptor.

7. The use according to claim 6, characterized in that The melanocortin receptors include at least one of MC1R, MC3R, MC4R and MC5R.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the disulfide cyclic peptide compound or an analog thereof according to any one of claims 1 to 7, wherein the analog comprises a derivative of the disulfide cyclic peptide compound, a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient.

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