drug

Abstract

The present invention relates to a combination drug. This combination drug comprises (1) a medicinal product, preferably a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist, containing a compound having an anti-obesity effect, and (2) a peptide having myostatin inhibitory activity, wherein reduction in lean body mass caused by the agonist is suppressed by the peptide.

Description

Pharmaceuticals 【0001】 The present invention relates to a pharmaceutical product containing a compound having an anti-obesity effect, preferably a pharmaceutical product that suppresses the reduction of lean body mass by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist, and more particularly to a combination pharmaceutical product. 【0002】 80,000 people worldwide are obese, and in the United States, for example, 42% of adults are obese. 【0003】 The cost associated with obesity is estimated at US$17.3 trillion annually, representing a significant social burden. Obesity is a chronic disease characterized by excess body fat, which is associated with an increased risk of various complications and premature death. Furthermore, obesity, particularly in women, hinders the detection of cancer through preventative screening and increases mortality rates. Weight gain in obese individuals has been reported to improve blood glucose levels, lipid levels, blood pressure, and other complications, highlighting the need for effective treatments (Non-Patent Literature 1). 【0004】 In recent years, glucagon-like peptide-1 receptor agonists (also known as "GLP-1RAs" or "GLP-1 receptor agonists") such as liraglutide and semaglutide, which are used in the treatment of type 2 diabetes, have been shown to have a weight-reducing effect in obesity and have come to be used as a treatment for obesity. Furthermore, it has been shown that agonists for both the GLP-1 receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor (also known as "GIP / GLP-1 receptor agonists," "GIP / GLP-1 receptor agonists," or "GIP / GLP-1 receptor dual agonists") have a greater weight-reducing effect than GLP-1RAs and are being used clinically (Non-Patent Literature 2). Furthermore, in recent years, new drugs containing compounds with anti-obesity effects have been discovered that also act on glucagon receptors, such as GIP / GLP-1 / glucagon receptor agonists (WO2021 / 234984) and GLP-1 / amyrin receptor agonists (WO2023 / 234984). 【0005】However, it has been found that weight loss induced by GLP-1 receptor agonists or GIP / GLP-1 receptor agonists results in a decrease in lean body mass (LBM), calculated by subtracting fat mass from body weight, and this decrease in muscle mass is considered to be the main cause. A decrease in LBM reduces basal metabolic rate, which is a concern in the long-term management of obesity. In addition to protein intake and exercise, the combined use of the anti-type II activin receptor (ActRIIB) antibody bimagrumab, or the anti-myostatin antibody trevogrumab and anti-activin A antibody garetosmab has been proposed to suppress the decrease in LBM caused by GLP-1 receptor agonists or GIP / GLP-1 receptor agonists (Non-Patent Literature 3). 【0006】 Myostatin, also known as growth factor 8 or GDF-8, is a member of the transforming growth factor-β (TGF-β) superfamily. Produced and released by muscle cells, myostatin is an endogenous negative regulator that acts on important autocrine / paracrine pathways in skeletal muscle growth. Myostatin negatively regulates muscle mass by binding to type II activin receptors, activating type I receptors such as ALK4 or ALK5, phosphorylating intracellular SMAD2 / 3, and forming a complex with SMAD4 to express target genes (Non-Patent Literature 4). Negative regulation of muscle hypertrophy is not only mediated by myostatin, but also by GDF-11 and activin A, which also belong to the TGF-β superfamily. ActRIIB also binds to other TGF-β superfamily members besides myostatin, such as activin A (Non-Patent Literature 5) and GDF-11 (Non-Patent Literature 6), and transmits signals. Therefore, the mechanism of action by which it is suitable for improving LBM decline in obesity treatment with GLP-1 receptor agonists is not clear. 【0007】SRK-439, an anti-pro- and latent myostatin antibody that specifically inhibits myostatin signaling, has been reported to improve LBM decline in GLP-1RA-induced obese model mice and maintain weight loss after discontinuation of GLP-1RA administration, demonstrating the therapeutic usefulness of specific myostatin signaling inhibition (Non-Patent Literature 7). However, because SRK-439 is an antibody, it requires subcutaneous injection (Non-Patent Literature 8), which presents challenges for patients due to the risk of infection at the injection site, pain, and prejudice. In contrast, oral formulations have been reported to have the advantage of high patient compliance because they are less burdensome to take and have no risk of infection (Non-Patent Literature 9). 【0008】 WO2021 / 234984WO2023 / 234984 【0009】JAMA. 2023;330(20):2000-15. Int J Mol Sci. 2023;;24(13):10449. doi:10.3390 / ijms241310449 Diabetes Obes Metab 2024;26(Suppl.4):16-27. Doi:10.1111 / dom. 15728 Annu Rev Physiol. 2023;85:269-291. doi:10.1146 / annurev-physiol-012422-112116. Nat Commun 8, 15153 (2017). https: / / doi. org / 10.1038 / ncomms15153Sci Rep. 2020;10:4561. doi:10.1038 / s41598-020-61443-yScholar Rock Press Release June 24, 2024 https: / / investors. scholarrock. com / news-releases / news-release-details / scholar-rock-announces-new-srk-439-preclinical-data-showing / Scholar Rock Press Release February 6, 2024 https: / / investors. scholarrock. com / news-releases / news-release-details / scholar-rock-presents-new-preclinical-data-demonstrating / Adv Mater 2024;36(6):e2306081. doi. org / 10.1002 / adma. 202306081 【0010】 There is a need for pharmaceuticals containing compounds with anti-obesity effects, particularly pharmaceuticals that effectively suppress the reduction of lean body mass caused by GLP-1 receptor agonists or GIP / GLP-1 receptor agonists. As a result of diligent research, the present inventors have discovered that combining an orally administered myostatin inhibitor peptide with a pharmaceutical containing a GLP-1 receptor agonist such as semaglutide or a GIP / GLP-1 receptor agonist improves the reduction of lean body mass, leading to the present invention. 【0011】The present invention includes, but is not limited to, the following embodiments: [1] A combination pharmaceutical comprising (1) a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist; and (2) a peptide having myostatin inhibitory activity, wherein the peptide suppresses the reduction of lean body mass caused by the agonist. [2] The combination pharmaceutical according to [1], wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, and dulaglutide. [3] The peptide having myostatin inhibitory activity has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and [1] or [2] is a combination pharmaceutical according to [1] or [2], wherein the peptide contains an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4). [4] A combination pharmaceutical according to any one of [1] to [3], wherein the agonist and / or the peptide having myostatin inhibitory activity is administered orally. [5] A combination pharmaceutical according to any one of [1] to [3], wherein the peptide having myostatin inhibitory activity is administered orally. [6] A pharmaceutical comprising a peptide having myostatin inhibitory activity, used together with a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist, wherein the peptide suppresses the reduction of lean body mass caused by the agonist.[7] The pharmaceutical product according to [6], wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, and dulaglutide. [8] The peptide having myostatin inhibitory activity has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and A pharmaceutical product according to [6] or [7], comprising an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4). [9] A pharmaceutical product according to any one of [6] to [8], wherein the agonist and / or the peptide having myostatin inhibitory activity is administered orally.

[10] A pharmaceutical product according to any one of [6] to [8], wherein the peptide having myostatin inhibitory activity is administered orally.

[11] A pharmaceutical product comprising a peptide having myostatin inhibitory activity, for suppressing the reduction of lean body mass caused by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist.

[12] The pharmaceutical product according to

[11] , wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, and dulaglutide.

[13] The peptide having myostatin inhibitory activity has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and A pharmaceutical product according to

[11] or

[12] , comprising a peptide containing an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4).

[14] A pharmaceutical product according to any one of

[11] to

[13] , wherein the agonist and / or the peptide having myostatin inhibitory activity is administered orally.

[15] A pharmaceutical product according to any one of

[11] to

[13] , wherein the peptide having myostatin inhibitory activity is administered orally.

[16] Use of a peptide having myostatin inhibitory activity for the manufacture of a pharmaceutical product for suppressing the reduction of lean body mass caused by a pharmaceutical product containing an obesity-causing compound.

[17] The pharmaceutical product comprising the compound having the obesity effect is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide and dulaglutide, as described in

[16] . 【0012】

[18] The peptide having myostatin inhibitory activity has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and The use according to

[16] or

[17] , wherein the peptide comprises an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4).

[19] The use according to any one of

[16] -

[18] , wherein the pharmaceutical product containing the compound having an obesity effect and / or the peptide having myostatin inhibitory activity is administered orally.

[20] The use according to any one of

[16] -

[18] , wherein the peptide having myostatin inhibitory activity is administered orally.

[21] A method for suppressing the reduction of lean body mass caused by the agonist with the peptide, comprising administering the peptide having myostatin inhibitory activity to a subject receiving a pharmaceutical product containing a compound having an obesity effect.

[22] (1) A pharmaceutical product comprising a compound having an anti-obesity effect; and (2) A combination pharmaceutical product comprising a peptide having myostatin inhibitory activity, wherein the reduction of lean body mass caused by the agonist is suppressed by the peptide. 【0013】The object of the present invention is to provide a method for improving the decrease in LBM (Lean Body Mass) caused by the administration of a pharmaceutical product containing a compound having anti-obesity effects, by administering a peptide having myostatin inhibitory activity, and to provide a pharmaceutical product for this purpose. In particular, the combined use of a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist with a peptide having myostatin inhibitory activity is useful for improving the decrease in LBM. Furthermore, the pharmaceutical product of the present invention is useful as a preventive and / or therapeutic agent for the decrease in LBM caused by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist. 【0014】Figure 1 is a graph showing the lean body mass (LBM) of obesity-induced C57BL6 / J mice after 4 weeks of simultaneous administration of semaglutide and / or the peptide Myostatin_99_v424 of the present invention at each dose once daily. The vertical axis shows the percentage change in LBM compared to one week before the start of administration. Gray indicates C57BL6 / J mice without obesity induction that were administered only the solvent, and white indicates C57BL6 / J mice with obesity induction that were administered the solvent. Furthermore, the black areas represent obesity-induced C57BL6 / J mice treated with a solvent and Semaglutide (0.12 mg / kg / day), the shaded areas represent obesity-induced C57BL6 / J mice treated with Myostatin_99_v424 (0.5 mg / kg / day) and Semaglutide (0.12 mg / kg / day), and the vertical stripes represent obesity-induced C57BL6 / J mice treated with Myostatin_99_v424. Figure 2 shows the results of administering Myostatin_99_v424 (1.5 mg / kg / day) and Semaglutide (0.12 mg / kg / day) to obese C57BL6 / J mice, respectively. Figure 2 is a graph showing the lean body mass (LBM) of obese C57BL6 / J mice after 4 weeks of administration of semaglutide once daily and / or the respective doses of the peptide Myostatin_99_v424 of the present invention once weekly. The vertical axis shows the percentage change in LBM compared to one week before the start of administration. Gray indicates C57BL6 / J mice without obesity induction that were administered the solvent, and white indicates C57BL6 / J mice with obesity induction that were administered the solvent. Black indicates C57BL6 / J mice with obesity induction that were administered the solvent and Semaglutide (0.12 mg / kg / day), windowpane checks indicate C57BL6 / J mice with obesity induction that were administered Myostatin_99_v424 (3 mg / kg / day) and Semaglutide (0.12 mg / kg / day), and dots indicate C57BL6 / J mice with obesity induction. The images show the results of administering Myostatin_99_v424 (10 mg / kg / day) and Semaglutide (0.12 mg / kg / day) to mice, and the vertical stripes show the results of administering Myostatin_99_v424 (30 mg / kg / day) and Semaglutide (0.12 mg / kg / day) to obesity-induced C57BL6 / J mice.Figure 3 is a graph showing the changes in body weight of obese-induced C57BL6 / J mice administered semaglutide and / or the peptide Myostatin_99_v424 of the present invention at each dose once daily. The vertical axis shows the percentage change in body weight compared to day 0. Gray circles represent the no-administration group, white squares represent the solvent-only administration group, black squares represent the solvent and semaglutide administration group, white diamonds represent the 0.5 mg / kg / day Myostatin_99_v424 administration group, black and white hexagons represent the 1.5 mg / kg / day Myostatin_99_v424 administration group, and black and white diamonds represent the 4.5 mg / kg / day Myostatin_99_v424 administration group. Figure 4 is a graph showing the changes in body weight of obesity-induced C57BL6 / J mice administered semaglutide once daily and / or the peptide Myostatin_99_v424 of the present invention at each dose once weekly. The vertical axis shows the percentage change in body weight compared to day 0. Gray circles represent the no-administration group, white squares represent the solvent-only administration group, black squares represent the solvent and semaglutide administration group, X represents the Myostatin_99_v424 administration group at 3 mg / kg / week, * represents the Myostatin_99_v424 administration group at 10 mg / kg / week, and + represents the Myostatin_99_v424 administration group at 30 mg / kg / week. Figure 5 is a graph showing the lean body mass (LBM) of obesity-induced C57BL6 / J mice after 4 weeks of administration of semaglutide once daily and / or the respective doses of the peptides of the present invention, Myostatin_99_v424 (Peptide No. 1), Myostatin_99_v483 (Peptide No. 2), Myostatin_99_v488 (Peptide No. 3), or Myostatin_99_v489 (Peptide No. 4). The vertical axis shows the percentage change in LBM compared to 6 days before the start of administration. Gray indicates C57BL6 / J mice without obesity induction that were administered the solvent, and white indicates C57BL6 / J mice with obesity induction that were administered the solvent.Additionally, black mice were given a solvent and Semaglutide (0.12 mg / kg / day), vertical stripes were given Myostatin_99_v424 (30 mg / kg / week) and Semaglutide (0.12 mg / kg / day), and diagonal stripes were given Myostatin_99_v483 (30 mg / kg / week) and Semaglutide (0.12 mg / kg / day) to obesity-induced C57BL6 / J mice. The brick pattern shows the results of administering Myostatin_99_v488 (30 mg / kg / week) and Semaglutide (0.12 mg / kg / day) to obese-induced C57BL6 / J mice, while the checkerboard pattern shows the results of administering Myostatin_99_v489 (30 mg / kg / week) and Semaglutide (0.12 mg / kg / day) to obese-induced C57BL6 / J mice. Figure 6 is a graph showing the lean body mass (LBM) of obesity-induced C57BL6 / J mice after 4 weeks of administration of semaglutide once daily or with a solvent, and the peptides Myostatin_99_v483 and Myostatin_99_v488 of the present invention or a solvent at each dose once weekly. The vertical axis shows the percentage change in LBM compared to 4 days before the start of administration. From left to right, white indicates C57BL6 / J mice without obesity induction that were administered with a solvent, and black square grids indicate C57BL6 / J mice with obesity induction that were administered with a solvent. Furthermore, the vertical stripes indicate that obesity-induced C57BL6 / J mice were administered Myostatin_99_v483 (30 mg / kg / week) with a solvent instead of semaglutide, while the gray checkerboard pattern indicates that obesity-induced C57BL6 / J mice were administered Myostatin_99_v488 (30 mg / kg / week) with a solvent instead of semaglutide.Furthermore, the dot pattern shows the results of administering semaglutide (0.12 mg / kg / day) and a solvent instead of a myostatin inhibitor peptide to obese-induced C57BL6 / J mice; the gray and black patterns show the results of administering semaglutide (0.12 mg / kg / day) and Myostatin_99_v483 (3 mg or 30 mg / kg / week) to obese-induced C57BL6 / J mice; and the light gray and white checkerboard patterns show the results of administering semaglutide (0.12 mg / kg / day) and Myostatin_99_v488 (3 mg or 30 mg / kg / week) to obese-induced C57BL6 / J mice. Figure 7 is a graph showing the percentage change in fat mass after 4 weeks in obesity-induced C57BL6 / J mice that were administered semaglutide once daily or with a solvent, and the peptides Myostatin_99_v483 and Myostatin_99_v488 of the present invention or with a solvent at each dose once weekly. The vertical axis shows the percentage change in fat mass compared to four days before the start of administration. From left to right, the dot pattern shows the results of administering semaglutide (0.12 mg / kg / day) and a solvent instead of a myostatin inhibitor peptide to obese-induced C57BL6 / J mice; the gray and black lines show the results of administering semaglutide (0.12 mg / kg / day) and Myostatin_99_v483 (3 mg or 30 mg / kg / week) to obese-induced C57BL6 / J mice; and the light gray and white checkerboard lines show the results of administering semaglutide (0.12 mg / kg / day) and Myostatin_99_v488 (3 mg or 30 mg / kg / week) to obese-induced C57BL6 / J mice. Figure 8A is a graph showing the body weight of obesity-induced C57BL6 / J mice from 5 days prior to administration to 18 days prior to administration, administered semaglutide once daily or with a solvent, and the peptides Myostatin_99_v483 and Myostatin_99_v488 of the present invention at their respective doses once weekly.Black circles indicate the group receiving no treatment, white squares indicate the group receiving only the solvent, black triangles indicate the group receiving 30 mg / kg / week of Myostatin_99_v483 alone, white inverted triangles indicate the group receiving 30 mg / kg / week of Myostatin_99_v488 alone, black squares indicate the group receiving semaglutide alone, white triangles indicate the group receiving semaglutide and 3 mg / kg / week of Myostatin_99_v483, white circles indicate the group receiving semaglutide and 30 mg / kg / week of Myostatin_99_v483, X indicates the group receiving semaglutide and 3 mg / kg / week of Myostatin_99_v488, and black diamonds indicate the group receiving semaglutide and 30 mg / kg / week of Myostatin_99_v483. The vertical axis of the graph represents body weight (g). Figure 8B is a graph showing the percentage change in body weight from 5 days before administration to 18 days after administration of obesity-induced C57BL6 / J mice that were administered semaglutide once daily or with a solvent, and the peptides Myostatin_99_v483 and Myostatin_99_v488 of the present invention at their respective doses once a week. Black circles indicate the group receiving no treatment, white squares indicate the group receiving only the solvent, black triangles indicate the group receiving 30 mg / kg / week of Myostatin_99_v483 alone, white inverted triangles indicate the group receiving 30 mg / kg / week of Myostatin_99_v488 alone, black squares indicate the group receiving semaglutide alone, white triangles indicate the group receiving semaglutide and 3 mg / kg / week of Myostatin_99_v483, white circles indicate the group receiving semaglutide and 30 mg / kg / week of Myostatin_99_v483, X indicates the group receiving semaglutide and 3 mg / kg / week of Myostatin_99_v488, and black diamonds indicate the group receiving semaglutide and 30 mg / kg / week of Myostatin_99_v483. The vertical axis of the graph shows the percentage change in weight. 【0015】 The present invention includes, but is not limited to, the following embodiments. Unless otherwise specified herein, the technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. The substances, materials and examples disclosed herein are illustrative and not intended to limit them. Where the phrase "in one embodiment" is used herein, it means that the invention is not limited to that embodiment, i.e., it is not limited to that embodiment. 【0016】 1. Abbreviations In this specification, unless otherwise specified, the following abbreviations shall have the meanings set forth below. 【0017】 Abbreviations (common): Å: angstrom (unit); ClAc: chloroacetyl; DCM: dichloromethane; tBu: tert-butyl; DMSO: dimethyl sulfoxide; Trt: trityl; Boc: tert-butyl carbonyl; DMF: N,N-dimethylformamide; DIEA or DIPEA: N,N-diisopropylethylamine; DIPCI or DIC: N,N'-diisopropylcarbodiimide; Oxyma pure: cyano(hydroxyimino)ethyl acetate; DODT: 3,6-dioxa-1,8-octan-dithiol; Fmoc: 9-fluorenylmethyloxycarbonyl; g: gram (unit); HATU: O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HPLC: High-performance liquid chromatography; LC-MS or LC / MS: Liquid chromatography-mass spectrometry; mL: Milliliter; M: Molar; μL: Microliter; mM: Millimolar; μM: Micromolar; mmol: Millimole; mg: Milligram; MeCN or CH ３ CN: Acetonitrile; min: Minute; mm: Millimeter; μm: Micrometer; nm: Nanometer; nM: Nanomolar; OSu: Succinimide; PEG: Polyethylene glycol; rpm: Revolutions per minute; TFA: Trifluoroacetic acid; TIS: Triisopropylsilane; Trt or Tr: Trityl group; AA: Amino acid; PyAOP: 7-(azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Fmoc-OSu: N-(9-Fluorenylmethoxycarbonyloxy)succinimide; THF: Tetrahydrofuran; Pd ２ (dba) ３ CHCl３ : Tris(dibenzylideneacetone)dipalladium(0)-chloroform complex; SPhos: 2-dicyclohexylphosphin-2',6'-dimethoxybiphenyl; Pd(PPh ３ ) ４ : Tetrakis(triphenylphosphine)palladium(0); ClAcOH: Chloroacetic acid; conc: Concentration; HFIP: 1,1,1,3,3,3-Hexafluoro-2-propanol; Pbf: 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl; Alloc: Allyloxycarbonyl; TEAA: Triethylammonium acetate. 【0018】 Abbreviations (Non-natural amino acids) The following abbreviations for non-natural amino acids include those in which the amino group of the main chain is protected by common protecting groups such as Boc groups and Fmoc groups. 【0019】 MeA: (2S)-2-(methylamino)propanoic acid (CAS No. 3913-67-5) W6H1Ph4COO: (S)-4-(3-(2-amino-2-carboxyethyl)-6-hydroxy-1H-indole-1-yl)benzoic acid 【0020】 MeF: (2S)-2-(methylamino)-3-phenylpropanoic acid (CAS No. 2566-30-5) dp: D-proline (CAS No. 344-25-2) F4COO: (S)-4-(2-amino-2-carboxyethyl)benzoic acid (CAS No. 126109-42-0) MeF4am: (S)-3-(4-(aminomethyl)phenyl)-2-(methylamino)propanoic acid 【0021】 Ano: (S)-2-aminononanoic acid (CAS No. 133444-84-5) dc: D-cysteine ​​(CAS No. 921-01-7) F3aao: (S)-2-amino-3-(3-(carboxymethoxy)phenyl)propanoic acid 【0022】 da: D-alanine (CAS No. 338-69-2) CrpG: 4-((carboxymethyl)amino)butanoic acid (CAS No. 4386-04-3) Pip4mAc: 3-(piperidine-4-yl)propanoic acid (CAS No. 1822-32-8) CeG: 3-((carboxymethyl)amino)propanoic acid (CAS No. 505-72-6) MeDap: (S)-3-amino-2-(methylamino)propanoic acid (CAS No. 904832-42-4) MeG: 2-(methylamino)acetic acid (CAS No. 107-97-1) 【0023】 2. Combination Pharmaceuticals In one embodiment of the present invention, the present invention relates to a combination pharmaceutical comprising a compound having an anti-obesity effect and a peptide having myostatin inhibitory activity. The combination pharmaceutical of the present invention suppresses the reduction of lean body mass caused by the pharmaceutical containing the compound having an anti-obesity effect with the peptide. 【0024】 In one embodiment, a pharmaceutical product containing a compound having an anti-obesity effect is a pharmaceutical product containing a compound having an appetite-suppressing effect. Furthermore, "a pharmaceutical product containing a compound having an anti-obesity effect" may be one or more drugs, and is not limited to one drug. 【0025】 In one embodiment, a pharmaceutical product containing a compound having an anti-obesity effect may be a pharmaceutical product containing a compound having an anti-obesity effect that has the potential to reduce lean body mass (LBM). 【0026】 "Lean body mass" (hereinafter sometimes referred to as "LBM" in this specification) is the weight obtained by subtracting the amount of fat from body weight, and is the total weight of muscles, bones, internal organs, and water such as blood. It is generally used as an indicator of muscle mass. Among anti-obesity drugs, it is known that LBM decreases in patients receiving treatment with drugs containing compounds that have an appetite-suppressing effect, particularly GLP-1 receptor agonists and GIP / GLP-1 receptor agonists (Non-Patent Literature 3). In particular, a decrease in muscle mass is considered to be the main cause of the decrease in LBM. 【0027】In one aspect, a pharmaceutical product containing a compound having an anti-obesity effect is a glucagon-like peptide-1 receptor agonist (also referred to as "GLP-1 receptor agonist", "GLP-1 receptor agonist", or "GLP-1 RA"), an agonist for both GLP-1 receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor (also referred to as "GIP / GLP-1 receptor agonist", "GIP / GLP-1 RA", "GIP / GLP-1 receptor dual agonist"), a GIP / GLP-1 / glucagon receptor agonist (also referred to as "GIP / GLP-1 / glucagon agonist (GGG)" or "triple agonist"), or a GLP-1 / amylin receptor agonist. In the present specification, a glucagon-like peptide-1 receptor agonist may be referred to as "GLP-1 receptor agonist", and an agonist for both GLP-1 receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor may be referred to as "GIP / GLP-1 receptor agonist". 【0028】 In one aspect, the present invention relates to a combined pharmaceutical product comprising: (1) a pharmaceutical product containing a compound having an anti-obesity effect; and (2) a peptide having myostatin inhibitory activity, wherein the decrease in fat-free body weight caused by the agonist is suppressed by the peptide. 【0029】 In one aspect, the present invention relates to a combined pharmaceutical product comprising: (1) a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist; and (2) a peptide having myostatin inhibitory activity, wherein the decrease in fat-free body weight caused by the agonist is suppressed by the peptide. 【0030】In one aspect, a pharmaceutical product containing a compound having an anti-obesity effect is, without limitation, a glucagon-like peptide-1 receptor agonist, also known as a GLP-1 receptor agonist or an incretin mimetic, or a pharmaceutical product containing the same. A GLP-1 receptor agonist is a hormone that is present in the body, binds to the GLP-1 receptor, activates the receptor, and has a hypoglycemic effect by promoting insulin secretion according to blood glucose levels. It is a general term for compounds that bind to the GLP-1 receptor and have a hypoglycemic effect by promoting insulin secretion according to blood glucose levels, similar to GLP-1. Since GLP-1 receptor agonists exhibit a hypoglycemic effect, they are used as therapeutic agents for diabetes. GLP-1 receptor agonists are generally considered to be more potent than dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors) that inhibit the degradation of GLP-1. In one aspect, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, and dulaglutide. 【0031】 In one aspect, a pharmaceutical product containing a compound having an anti-obesity effect is, without limitation, a GIP / GLP-1 receptor agonist. A GIP / GLP-1 receptor agonist binds to and activates both the glucose-dependent insulinotropic polypeptide (GIP) and the aforementioned GLP-1 receptors, and exhibits a hypoglycemic effect by promoting insulin secretion according to blood glucose levels. In one aspect, the GIP / GLP-1 receptor agonist is tirzepatide. 【0032】 In one aspect, a pharmaceutical product containing a compound having an anti-obesity effect is, without limitation, a GIP / GLP-1 / glucagon receptor agonist. A GIP / GLP-1 / glucagon receptor agonist binds to and activates not only the aforementioned GIP and GLP-1 receptors but also the glucagon receptor, and exhibits a blood glucose control and fat burning promotion effect. In one aspect, the GIP / GLP-1 / glucagon receptor agonist is retatrutide. 【0033】In one embodiment, a pharmaceutical product containing a compound having an anti-obesity effect is, without limitation, a GLP-1 / amyrin receptor agonist. GLP-1 / amyrin receptor agonists exert their anti-obesity effect by contributing to blood glucose control as well as increased satiety. In one embodiment, the GLP-1 / amyrin receptor agonist is amicretin. 【0034】 In this specification, pharmaceuticals containing compounds with anti-obesity effects may be described using GLP-1 receptor agonists or GIP / GLP-1 receptor agonists as examples. 【0035】 In this specification, when referring to a "GLP-1 receptor agonist," it may include GIP / GLP-1 receptor agonists, GIP / GLP-1 / glucagon receptor agonists, and GLP-1 / amyrin receptor agonists, unless it is particularly technically inappropriate. 【0036】 Peptides having myostatin inhibitory activity The present invention is based on the technical idea that (2) a peptide having myostatin inhibitory activity is used in combination with (1) a pharmaceutical product containing a compound having anti-obesity activity, preferably a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist, thereby suppressing the reduction of lean body mass caused by the agonist with the peptide. 【0037】 In this specification, when referring to a "peptide," unless otherwise specified, this also includes references to its pharmaceutically acceptable salts or solvates. 【0038】In one embodiment, the peptide having myostatin inhibitory activity used in the present invention is a polypeptide described in PCT / JP2024 / 034645. In one embodiment, the peptide includes the following amino acid sequence: A-R-W-Y-MeF-I-MeG-Y-Y-R-MeF-L-MeA-MeF-C (SEQ ID NO: 5) or an amino acid sequence having substitutions, additions, deletions or insertions in 1 to 14 amino acid residues selected from the group consisting of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 11th, 12th, 13th, 14th, and 15th amino acid residues of the above amino acid sequence. 【0039】 The peptide, in one embodiment, has the following amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 6) where, X1 is any amino acid or peptoid; X2 is any amino acid; X3 is an amino acid having an aromatic ring which may be substituted on its side chain; X4 is an amino acid having an aromatic ring which may be substituted on its side chain; X5 is an amino acid having an aromatic ring which may be substituted on its side chain, or an aromatic ring which may be substituted on its side chain, or an aromatic ring which may be substituted on its side chain; X6 is an amino acid having an alkyl group in its side chain; X7 is any secondary amino acid, N-alkyl amino acid, or peptoid; X8 is any amino acid; X9 is an amino acid containing an aromatic ring which may be substituted on its side chain, or an aromatic group which may be substituted on its side chain, or an aromatic group which may be substituted on its side chain, or an aromatic ring which may be substituted on its side chain; X10 is R; X11 is an amino acid containing an optionally substituted aromatic ring, or an optionally substituted alkyl group or cycloalkyl group in its side chain; X12 is an optionally substituted aliphatic amino acid, or an amino acid having an optionally substituted alkyl chain in its side chain; X13 is any secondary amino acid, N-alkyl amino acid, or peptoid; X14 is an amino acid having an optionally substituted aromatic ring in its side chain; and X15 is any amino acid. 【0040】In one embodiment, in sequence number 6, X3 is not W. In one embodiment, X7 is not MeA. In one embodiment, X3 is not W, and X7 is not MeA. In one embodiment, the peptide has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and This peptide contains an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4). 【0041】 The peptides mentioned above are E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1), A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-daa-MeA (SEQ ID NO: 2), and CrpG-A-W6H1Ph4COO-Y-MeF-I -dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3) and CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4) are peptides that were confirmed to have myostatin inhibitory activity in Example 2 of this specification. 【0042】Furthermore, the amino acid sequence of Sequence ID No. 1 may have substitutions, additions, deletions, or insertions at 1 to 4 amino acid residues selected from the group consisting of the 1st, 11th, 13th, and 15th amino acid residues. The number of substituted, deleted, added, and / or inserted amino acids may be between 1 and 4, with a lower limit of 1. The upper limit is 4, 3, or 2, and the minimum is 1. Preferably, it is an amino acid substitution. Such amino acid substitutions are preferably conservative amino acid substitutions. 【0043】 A "conservative amino acid substitution" refers to a substitution with a functionally equivalent or similar amino acid. Conservative amino acid substitutions in peptides result in static changes to the peptide's amino acid sequence. For example, one or more amino acids with similar polarity act functionally equivalently, resulting in a static change to the peptide's amino acid sequence. Generally, substitutions within a given group can be considered structurally and functionally conservative. However, as is obvious to those skilled in the art, the role of a particular amino acid residue can be determined in terms of its significance in the three-dimensional structure of the molecule containing that amino acid. For example, a cysteine ​​residue can take the less polar oxidized (disulfide) form compared to its reduced (thiol) form. Long aliphatic portions of arginine side chains can constitute structurally and functionally important features. Furthermore, side chains containing aromatic rings (tryptophan, tyrosine, phenylalanine) can contribute to ion-aromatic or cation-pi interactions. In such cases, substituting amino acids with these side chains with amino acids belonging to the acidic or nonpolar group may result in structural and functional conservation. Residues such as proline, glycine, and cysteine ​​(disulfide form) can have a direct effect on the three-dimensional structure of the main chain and often cannot be substituted without structural distortion. 【0044】Conservative amino acid substitutions include specific substitutions based on side chain similarity (e.g., substitutions described in L. Lehninger, Biochemistry, 2nd edition, pp. 73-75, Worth Publisher, New York (1975)) and typical substitutions, as shown below. Furthermore, for example, in groups of natural amino acids divided based on the properties of their common side chains, substitutions to amino acids belonging to the same group to which a given amino acid belongs are preferred. 【0045】 Hydrophobic (also called nonpolar) amino acids: Amino acids that exhibit hydrophobicity (nonpolarity), including alanine ("Ala" or simply "A"), glycine ("Gly" or simply "G"), valine ("Val" or simply "V"), leucine ("Leu" or simply "L"), isoleucine ("Ile" or simply "I"), proline ("Pro" or simply "P"), phenylalanine ("Phe" or simply "F"), tryptophan ("Trp" or simply "W"), tyrosine ("Tyr" or simply "Y"), and methionine ("Met" or simply "M"). 【0046】 Furthermore, hydrophobic amino acids can be further divided into the following groups. 【0047】 Aliphatic amino acids: Amino acids having fatty acids or hydrogen in their side chains, including Al, Gly, Val, Ile, and Leu. 【0048】 Aliphatic branched-chain amino acids: Amino acids having branched fatty acids in their side chains, including Val, Ile, and Leu. 【0049】 Aromatic amino acids: Amino acids having an aromatic ring in their side chain, including Trp, Tyr, and Phe. 【0050】Hydrophilic (also called polar) amino acids: Amino acids that exhibit hydrophilicity (polarity), including serine ("Ser" or simply "S"), threonine ("Thr" or simply "T"), cysteine ​​("Cys" or simply "C"), asparagine ("Asn" or simply "N"), glutamine ("Gln" or simply "Q"), aspartic acid ("Asp" or simply "D"), glutamic acid ("Glu" or simply "E"), lysine (also written as lysine; "Lys" or simply "K"), arginine ("Arg" or simply "R"), and histidine ("His" or simply "H"). 【0051】 Furthermore, hydrophilic amino acids can be further divided into the following groups. 【0052】 Acidic amino acids: Amino acids whose side chains exhibit acidity, including Asp and Glu. 【0053】 Basic amino acids: Amino acids whose side chains are basic, including Lys, Arg, and His. 【0054】 Neutral amino acids: Amino acids whose side chains are neutral, including Ser, Thr, Asn, Gln, and Cys. 【0055】 Furthermore, Gly and Pro can be classified as "amino acids that affect the orientation of the main chain," and amino acids containing sulfur molecules in their side chains, Cys and Met, can be classified as "sulfur-containing amino acids." 【0056】In this specification, "amino acids" include not only natural amino acids but also unnatural amino acids. Unnatural amino acids include, for example, N-alkylated amino acids, which are natural amino acids as described above, and amino acids modified with lower alkyl groups (e.g., C1-C5, preferably C1-C3, more preferably C1) in which the nitrogen forming the peptide bond is branched or unbranched. N-alkyl amino acids are preferably N-ethyl amino acids, N-butyl amino acids, or N-methyl amino acids, and more preferably N-methyl amino acids. Unnatural amino acids also include D-type amino acids (also written as D-amino acids), β-amino acids, γ-amino acids, amino acid mutants, amino acid derivatives, and other chemically modified amino acids, as well as amino acids that do not become building blocks of proteins in living organisms, such as norleucine and ornithine. Furthermore, this includes amino acids in which functional groups have been added to the side chain of a natural amino acid or substituted with other functional groups (for example, amino acids with substitutions or additions to the arylene group, alkylene group, etc. of the side chain; amino acids with an increased number of C groups in the arylene group, alkylene group, or alkyl group of the side chain; amino acids with substitutions in the aromatic ring of the side chain; and heterocyclic or fused amino acids). 【0057】Furthermore, by adding or substituting functional groups or other structures to the side chains of natural amino acids, properties different from those of natural amino acids can be conferred. For example, Dap is an amino acid that has an amino group in the side chain of alanine, but because of the addition of this amino group, it exhibits the properties of a polar amino acid with basicity, unlike alanine which belongs to the nonpolar amino acid group. In other words, the aforementioned groups, which divide natural amino acids based on the properties of their common side chains, can include non-natural amino acids that have similar side chain properties. For example, N-methylarginine (MeR), an amino acid in which the nitrogen atom of the main chain of arginine, which belongs to the basic amino acids, is methylated, is a non-natural amino acid, but because it exhibits basicity, it can be classified as a basic amino acid. In this way, non-natural amino acids that exhibit similar side chain properties to a certain amino acid can also be included as targets for conservative amino acid substitution. Furthermore, D-amino acids such as de (D-glutamic acid) can be classified as D-amino acids, but they can also be classified according to the properties of their side chains, and N-methyl amino acids can be classified as N-alkyl amino acids, or according to the properties of the side chain of the original amino acid that has not been N-methylated. 【0058】 Non-natural amino acids include, but are not limited to, N-methyl amino acids, W6H1Ph4COO, MeF, dp, F3aao, F4COO, MeF4am, Ano, MeA, dc, MeDap, da, MeG, Pip4mAc, etc. 【0059】 In one embodiment, the peptide is a peptide comprising the following amino acid sequence: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1), or an amino acid sequence having four or fewer amino acid substitutions selected from (1-i) to (1-iv) in the above amino acid sequence. 【0060】(1-i) The first amino acid in the sequence number 1 is replaced with A, CrpG, or CeG; (1-ii) The eleventh amino acid in the sequence number 1 is replaced with MeF4am; (1-iii) The thirteenth amino acid in the sequence number 1 is replaced with MeDap; (1-iv) The fifteenth amino acid in the sequence number 1 is replaced with da. 【0061】 Furthermore, if the 15th amino acid in the amino acid sequence described in Sequence ID No. 1 is substituted with da, MeA may be added as the 16th amino acid. 【0062】 Non-limitingly, the peptide may be a peptide comprising an amino acid sequence having four or fewer, three or fewer, two or fewer, or one amino acid substitution selected from (1-i) to (1-iv) in the amino acid sequence described in Sequence ID No. 1. The substitutions (1-i) to (1-iv) include any combination. 【0063】 In one embodiment, the peptide may have 15 or 16 amino acid residues in its cyclic structure (for example, the 15th amino acid may be da, and MeA may be added as the 16th amino acid). 【0064】 In this specification, when referring to a "peptide," unless otherwise specified, it also includes references to its pharmaceutically acceptable salts. “Its pharmaceutically acceptable salt” means a salt of any peptide. Examples of pharmaceutically acceptable salts include salts with mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid; salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, and benzenesulfonic acid; salts with amines such as trimethylamine and methylamine; or salts with metal ions such as sodium ions, potassium ions, and calcium ions. For compounds that have acquired water over time, such water is also included in the pharmaceutically acceptable salts. 【0065】 In one embodiment, the peptide may preferably contain a linker at its C-terminus. 【0066】The peptide may, in no particular way, further contain additional amino acids such as G (glycine) at its C-terminus. 【0067】 In one embodiment, the peptide is a cyclic peptide. A "cyclic peptide" refers to a peptide in which two amino acids are linked together, and all or part of it is cyclic. The peptide also includes those in which amino acids in the peptide form a cross-linking structure, those in which a cyclic structure is formed by lactam ring formation or macrocyclization reaction, and those having a lasso-peptide-like structure. In other words, the cyclic peptide only needs to have a part of it that forms a cyclic structure, and may also have a linear portion. 【0068】 Peptides generally have poor metabolic stability in vivo and their large size makes them difficult to permeate cell membranes. To address these challenges, methods such as cyclization of peptides have been employed. Cyclization of peptides has been shown to improve protease resistance and metabolic stability, and to restrict conformational changes, thereby increasing rigidity and improving membrane permeability and affinity to target proteins. 【0069】In one embodiment, the peptide has a cyclic structure in which a chloroacetylated amino acid is bonded to a cysteine ​​residue contained in the peptide. In one embodiment, the peptide has a cyclic structure in which an N-terminal amino acid (the first amino acid residue) is bonded to a cysteine ​​residue contained in the peptide. In one embodiment, the peptide has a cyclic structure in which an N-terminal amino acid (the first amino acid residue) is bonded to a 15th cysteine ​​residue contained in the peptide. In one embodiment, the peptide has a cyclic structure in which a chloroacetylated N-terminal amino acid (the first amino acid residue) is bonded to a 15th cysteine ​​residue contained in the peptide. "Chloroacetylation" may also be "halogen acetylation" with other halogens. Also, "acetylation" may also be "acylation" with acyl groups other than acetyl groups. In one embodiment, the peptide may have a structure in which the amino acid sequence described in any of Sequence IDs 1-XX is bonded to cysteine ​​contained in the peptide or its substitution via an acetyl group. In other words, in this specification, for example, "cyclic peptide consisting of SEQ ID NO: XX" also includes a cyclic structure in which the amino acid sequence represented by SEQ ID NO: XX is bonded to an acetyl group attached to the first amino acid in the amino acid sequence, and to a sulfur atom (S) contained in cysteine ​​or its substitution (including dc, which is D-cysteine). In this specification, some amino acids may be modified for the cyclization of a peptide. Such partially modified amino acids are also included. For example, as described above, there are cases in which a chloroacetyl group is added to the N-terminal amino acid and bonded to a cysteine ​​residue in the peptide to form a cyclization. Various (natural / unnatural) amino acids to which such chloroacetyl groups have been added are also included in the amino acids of this application. 【0070】In one embodiment, the peptide has a cyclic structure in which an N-terminal amino acid (the first amino acid residue; X1) is bonded to a C-terminal amino acid (the 15th amino acid residue; X15). In one embodiment, the peptide has a cyclic structure in which the amino group of the N-terminal amino acid (the first amino acid residue) is bonded to the carboxyl group of the 15th amino acid contained in the peptide. In one embodiment, the peptide may have a cyclic structure in which the amino group of the first amino acid residue contained in the peptide is bonded to the carboxyl group of the 15th amino acid residue. In another embodiment, an additional amino acid is added to the 15th amino acid residue, and the peptide may have a cyclic structure in which an additional amino acid residue is added to the N-terminal amino acid (the first amino acid residue) and, for example, the 16th amino acid residue is bonded to the 15th. In one embodiment, the peptide has a cyclic structure in which the amino group of the first amino acid residue contained in the peptide is bonded to the carboxyl group of the 16th amino acid residue. 【0071】 In one embodiment, the peptide having a cyclic structure may further have cross-linking structures between amino acid residues included in the cyclic structure. In one embodiment, the side chain of an amino acid residue included in the cyclic structure is linked to the side chain of another amino acid residue included in the cyclic structure, forming a cross-linking structure. For example, non-limitingly, the amino group at the end of the side chain of amino acid residue K included in the cyclic structure may be linked to the carboxyl group at the end of the side chain of another amino acid residue MeE included in the cyclic structure, forming a cross-linking structure within the cyclic structure. Also, in one embodiment, there is a cross-linking structure between the N-terminal amino acid residue (the first amino acid residue) and the 11th or 13th amino acid residue. In the peptide having a cyclic structure with further cross-linking structures, there may be one or more cross-linking structures. For example, a peptide having a cyclic structure with one further cross-linking structure is also called a bicyclic peptide. 【0072】In one embodiment, the peptide having a cyclic structure further cross-linked has a cross-linked structure in which the N-terminal amino acid residue and the side chain of the 11th amino acid residue are linked. In another embodiment, it has a cross-linked structure in which the N-terminal amino acid residue and the side chain of the 13th amino acid residue are linked. 【0073】 In one embodiment, the peptide having a cyclic structure further having a crosslinking structure may be a peptide having a cyclic structure that further has a crosslinking structure in which the side chain of either amino acid E or CeG is linked to the side chain of either amino acid MeF4am or MeDap. 【0074】 Examples of peptides having a cross-linking structure within the ring include, or consist of, the amino acid sequence described in SEQ ID NO: 1 or 4. 【0075】 The peptide is either a peptide consisting of the amino acid sequence described in SEQ ID NO: 1 or 4, or a peptide consisting of an amino acid sequence in which one to four (preferably one to four, one to three, two, or one) amino acid residues are substituted, deleted, inserted, or added. In the case of sequences with added amino acid residues, many more amino acid residues (e.g., one to fourteen residues) may be added, provided the added portion is a linker. Furthermore, peptides consisting of these amino acid sequences with substituted, deleted, inserted, or added amino acid residues are preferably those that have, for example, myostatin inhibitory activity. 【0076】 The peptide may further contain additional amino acid residues. In addition to the amino acid sequences described in Sequence IDs 1-4, the peptide may also contain additional amino acid residues. 【0077】 The "additional amino acid residues" may be contained within a cyclic peptide, or further amino acid residues may be added to the cyclic peptide in a linker-like manner. The number of amide bonds (number and length of amino acids) in the peptide and peptide moiety are not particularly limited. 【0078】Furthermore, a linker may be added to the cyclic peptide. Examples of linkers include the aforementioned amino acid linkers (peptide linkers), chemical linkers, fatty acid linkers, nucleic acid linkers, and glycan linkers, and may also be a complex of, for example, a chemical linker and a peptide linker. A chemical linker may be, for example, a PEG linker consisting of 1 to 24 ethylene glycol units. The linker may also be a fatty acid linker containing a divalent chemical moiety derived from a fatty acid. The amino acid (peptide) linker is a linker containing at least one amino acid, and for example, a glycine-rich peptide such as a peptide having the sequence [Gly-Gly-Gly-Gly-Ser]n (wherein n is 1, 2, 3, 4, 5, or 6) as described in U.S. Patent No. 7,271,149, or a serine-rich peptide linker as described in U.S. Patent No. 5,525,491 can be used. In the case of a peptide linker, the bond between amino acids or between amino acids and chemical linkers may be linked via the side chain of the amino acid. In some cases, the addition of a linker can alter the physical properties of a peptide (e.g., solubility). 【0079】 The linker can be attached anywhere. For example, it may be attached to an amino acid located at the C-terminus, or to an amino acid contained in the cyclic peptide. In one embodiment, the peptide contains a linker at its C-terminus. Preferably, it is attached to a Cys located at the C-terminus, or to the side chain of an amino acid contained in the cyclic peptide. 【0080】 Furthermore, the peptide may form a polymer via a linker or the like. The number of peptides contained in the polymer is not limited. In one embodiment, the polymer is a dimer, trimer, tetramer, pentamer, hexamer, octamer, or more. The polymer may contain multiple identical peptides or multiple different peptides. 【0081】 In one embodiment, preferably, the peptide has myostatin inhibitory activity. 【0082】In one embodiment, preferably, the peptide has GDF-8 inhibitory activity. 【0083】 Myostatin is a protein belonging to the TGF-β (Transforming Growth Factor-β) superfamily, also known as GDF-8 (Glow Difference Factor-8). 【0084】 In this specification, the term "myostatin" refers to the naturally occurring myostatin found in mammals, preferably rodents such as mice, and primates such as humans, unless otherwise specified. In this specification, "human myostatin" refers to the naturally occurring myostatin found in humans (e.g., Gene ID: 2660). It is known that the amino acid sequences of human, mouse, and rat myostatin are nearly identical. Unless otherwise specified, in this specification, "myostatin" and "human myostatin" include unprocessed myostatin, processed myostatin, and mutants. Furthermore, myostatin is known to undergo glycosylation and dimerization, and active myostatin (also called mature myostatin) is a homodimer in which two C-terminal growth factor domains are disulfide-linked. 【0085】 Myostatin inhibition refers to the inhibition, blockage, antagonistization, or competitive inhibition of myostatin signaling. Myostatin signaling refers to the process where myostatin binds to the type II activin receptor (ActRI: Gene ID: 92), complexes with the type I activin receptor (ActRI: Gene ID: 90), and transmits signals within the cell. In other words, inhibition of myostatin signaling includes, for example, inhibition of myostatin binding to ActRI by (a peptide) binding to myostatin or ActRI, inhibition of ActRI-ActRI complex formation by binding to ActRI, and inhibition of the signaling pathway from the ActRI-ActRI complex, such as inhibition of signaling pathways mediated by Smad, P13K, Ras, or TAK1. Inhibition of a signaling pathway means reducing, regulating, or inhibiting any of the signaling pathways in question. 【0086】 Myostatin inhibitory activity can be evaluated using known methods. For example, as shown in the examples herein, it can be evaluated using an in vitro myostatin inhibitory activity system with a reporter gene, or by evaluating body weight and muscle strength using mice. Alternatively, myostatin inhibitory activity may be evaluated by methods disclosed in, for example, Japanese Patent Application Publication No. 2020-011965 or Japanese Patent Application Publication No. 2022-101593. 【0087】 Non-limitingly, myostatin inhibitory activity can be expressed by IC50, for example, in an in vitro myostatin inhibitory activity evaluation system using a reporter gene. 【0088】 In one embodiment, the peptide is myostatin-selective (specific). More preferably, the peptide has low inhibitory activity against GDF-11 activity. 【0089】 Many molecules with myostatin inhibitory activity are known to inhibit not only myostatin, i.e., GDF-8, but also the activity of GDF-11, which belongs to the same TGF-8 superfamily. Since the amino acid sequence of GDF-11 is highly identical to that of the active myostatin GDF-11, and furthermore, myostatin, GDF-11, and activin are all signaling molecules that transmit signals via ActR, molecules such as antibodies with myostatin inhibitory activity often inhibit the activity of all three growth factors: myostatin, GDF-11, and activin. However, since GDF-11 has a muscle function-enhancing effect as a rejuvenation factor, it is preferable that it not be inhibited, especially in children and young adults. In one embodiment, a myostatin inhibitor that specifically inhibits only myostatin and does not inhibit other myostatin signaling molecules, such as GDF-11, is preferred. It should be noted that GDF-11 also exhibits high identity among mice, humans, and rats. In this specification, when "GDF-11" is referred to, it preferably means human GDF-11 (Gene ID 10220). 【0090】Furthermore, "not inhibiting GDF-11" means that the inhibitory activity on signal transduction by GDF-11 is lower than that on signal transduction by myostatin. For example, in an in vitro myostatin inhibitory activity evaluation system using a reporter gene, this means that the IC50 of GDF-11 is 2, 3, 4, 5, 10, 20, 30, 40, 50, 100, 200 or more times higher than the IC50 of myostatin. 【0091】 In one embodiment, the peptide has inhibitory activity against myostatins derived from multiple species. Preferably, it has inhibitory activity against human-derived myostatins. 【0092】 The peptide having myostatin inhibitory activity is preferably a peptide that does not inhibit GDF-11 as much as it inhibits myostatin. This is suggested by the fact that, as shown in Example 2 of this specification, for example, the peptide has inhibitory activity against myostatin, but its inhibitory activity against GDF-11 is significantly lower than its myostatin inhibitory activity. 【0093】 Peptides with myostatin inhibitory activity are effective in treating and preventing various diseases involving BMP. Peptides with myostatin inhibitory activity are also effective in various experiments related to various diseases involving myostatin. 【0094】 The peptide having myostatin inhibitory activity can be modified in various ways. For example, polyethylene glycol (PEG) or sugar chains can be added to the polypeptide to increase its blood retention time and reduce its antigenicity. Alternatively, biodegradable polymer compounds such as polylactic acid glycol (PLGA), porous hydroxyapatite, liposomes, surface-modified liposomes, emulsions prepared with unsaturated fatty acids, nanoparticles, nanospheres, etc., may be used as sustained-release bases, and polypeptides may be encapsulated within them. 【0095】The peptide having myostatin inhibitory activity may be an orally administered peptide. Generally, compared to intravenous administration, which allows direct administration into the bloodstream, oral administration is mainly absorbed from the intestinal tract and undergoes the first-pass effect, resulting in a low rate of drug penetration into the body and a long time before the drug takes effect. Therefore, in order to make a pharmacologically active compound orally administrative, it is necessary to take measures to improve the rate of penetration into the body, such as improving the pharmacological effect, modifying the compound to prevent breakdown in the stomach and intestines, improving water solubility, or adding appropriate excipients. In addition, some drugs have side effects such as damaging the stomach wall, so it is necessary to take measures to reduce such side effects. 【0096】 In this specification, "orally administerable" means a peptide that has sufficient myostatin inhibitory activity even when administered orally. A "peptide that has sufficient myostatin inhibitory activity even when administered orally" means, for example, a peptide in which myostatin inhibitory activity and / or water solubility is improved, degradation in the stomach and intestines is reduced, and stability in the body is improved. 【0097】 In one embodiment, whether or not a drug can be administered orally can be expressed by its bioavailability (BA). Bioavailability can be expressed as oral administration AUC (Area Under the blood concentration-time Curve) / intravenous administration AUC × 100. 【0098】 "Peptides that have sufficient myostatin inhibitory activity even when administered orally" may refer to a mixture of peptides with myostatin inhibitory activity and additives that have sufficient myostatin inhibitory activity even when administered orally. The additives may be known additives used for purposes such as enhancing the usefulness of the active ingredient and formulation, improving stability, or promoting absorption from the intestinal tract, or known additives used for oral administration. They may also be lipids, alcohols, sugar alcohols, polyethers, surfactants, or their composites. For example, known additives for oral administration such as salcaprozate sodium and Labrasol (trademark registered) may be used. 【0099】Peptide Production The peptide having myostatin inhibitory activity used in the present invention can be produced by any known method for peptide production, such as the following: 【0100】 Unless otherwise specified, matters described in other sections also apply to this section. 【0101】 Chemical synthesis methods such as liquid-phase methods, solid-phase methods, and hybrid methods combining liquid-phase and solid-phase methods; genetic engineering methods, etc. 【0102】 The solid-phase method involves, for example, esterifying the hydroxyl group of a resin containing a hydroxyl group with the carboxyl group of a first amino acid (usually the C-terminal amino acid of the target peptide) whose α-amino group is protected by a protecting group. Known dehydration condensation agents such as 1-mesitylenesulfonyl-3-nitro-1,2,4-triazole (MSNT), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIC) can be used as esterification catalysts. 【0103】 Next, the protecting group of the α-amino group of the first amino acid is removed, and a second amino acid, in which all functional groups except the carboxyl group of the main chain are protected, is added. The carboxyl group is then activated to bond the first and second amino acids. Furthermore, the α-amino group of the second amino acid is deprotected, and a third amino acid, in which all functional groups except the carboxyl group of the main chain are protected, is added. The carboxyl group is then activated to bond the second and third amino acids. This process is repeated until a peptide of the desired length is synthesized, at which point all functional groups are deprotected. 【0104】 Examples of solid-phase synthesized resins include Merrifield resin, MBHA resin, Cl-Trt resin, SASRIN resin, Wang resin, Rink amide resin, HMFS resin, Amino-PEGA resin (Merck), and HMPA-PEGA resin (Merck). These resins can be used after washing with a solvent (dimethylformamide (DMF), 2-propanol, methylene chloride, etc.). 【0105】Examples of protecting groups for α-amino groups include benzyloxycarbonyl (Cbz or Z) group, tert-butoxycarbonyl (Boc) group, 9-fluorenylmethyloxycarbonyl (Fmoc) group, benzyl group, allyl group, and allyloxycarbonyl (Alloc) group. 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 or pyrrolidine. 【0106】 For example, the α-carboxyl group can be protected using methyl esters, ethyl esters, allyl esters, benzyl esters, tert-butyl esters, cyclohexyl esters, and the like. 【0107】 The carboxyl group can be activated using a condensing agent. Examples of condensing agents include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or WSC), (1H-benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), and 1-[bis(dimethylamino)methyl]-1H-benzotriazolium-3-oxidehexafluorophosphate (HBTU). 【0108】 Peptide chains can be cleaved from resin by treatment with acids such as TFA and hydrogen fluoride (HF). 【0109】 The production of peptides by genetic engineering (translation synthesis system) can be carried out using the nucleic acid encoding the peptide. The nucleic acid encoding the peptide may be DNA or RNA. 【0110】 The nucleic acid encoding the peptide can be prepared by known methods or similar methods. For example, it can be synthesized by an automated synthesis apparatus. Restriction enzyme recognition sites may be added to insert the obtained DNA into a vector. Alternatively, a base sequence encoding an amino acid sequence for cleaving the resulting peptide chain with an enzyme may be incorporated. 【0111】 To suppress degradation by host-derived proteases, a chimeric protein expression method can be used, in which the target peptide is expressed as a chimeric peptide with another peptide. In this case, the nucleic acid used is a nucleic acid that encodes the target peptide and the peptide that binds to it. 【0112】 Next, an expression vector is prepared using the nucleic acid encoding the peptide. The nucleic acid can be inserted downstream of the promoter in the expression vector, either as is, digested with restriction enzymes, or with the addition of a linker. Examples of vectors include E. coli plasmids (pBR322, pBR325, pUC12, pUC13, pUC18, pUC19, pUC118, pBluescript II, etc.), Bacillus subtilis plasmids (pUB110, pTP5, pC1912, pTP4, pE194, pC194, etc.), yeast plasmids (pSH19, pSH15, YEp, YRp, YIp, YAC, etc.), bacteriophages (e-phage, M13 phage, etc.), viruses (retroviruses, vaccinia virus, adenovirus, adeno-associated virus (AAV), cauliflower mosaic virus, tobacco mosaic virus, baculovirus, etc.), and cosmids. 【0113】 The promoter can be appropriately selected depending on the type of host. If the host is animal cells, for example, promoters derived from SV40 (Simian virus 40) or CMV (Cytomegalovarum) can be used. If the host is E. coli, promoters such as the trp promoter, T7 promoter, or lac promoter can be used. 【0114】 Expression vectors can also incorporate nucleic acids that encode, for example, DNA replication start sites (ORI), selection markers (antibiotic resistance, nutritional requirements, etc.), enhancers, splicing signals, poly-A addition signals, and tags (FLAG, HA, GST, GFP, etc.). 【0115】Next, a suitable host cell is transformed with the expression vector. The host can be appropriately selected in relation to the vector. Examples of hosts include Escherichia coli, Bacillus subtilis, Bacillus species, yeast, insects or insect cells, and animal cells. Examples of animal cells include HEK293T cells, CHO cells, COS cells, myeloma cells, HeLa cells, and Vero cells. Transformation can be carried out according to known methods such as lipofection, calcium phosphate, electroporation, microinjection, and particle gun, depending on the type of host. By culturing the transformed cells according to conventional methods, the target peptide is expressed. 【0116】 Peptide purification from transformant cultures involves harvesting the cultured cells, suspending them in a suitable buffer, disrupting the cells by methods such as sonication or freeze-thaw cycles, and obtaining a crude extract by centrifugation or filtration. If peptides are secreted into the culture medium, the supernatant is collected. 【0117】 Purification from the crude extract or culture supernatant can also be carried out by known methods or similar methods (e.g., salting out, dialysis, ultrafiltration, gel filtration, SDS-PAGE, ion exchange chromatography, affinity chromatography, reverse-phase high-performance liquid chromatography, etc.). 【0118】 The obtained peptide may be converted from a free form to a salt, or from a salt to a free form, by known or equivalent methods. 【0119】 In one embodiment, the translation synthesis system may be a cell-free translation system. Generally, with a cell-free translation system, the expression product can be obtained in a highly pure form without purification. The cell-free translation system includes, for example, ribosomal proteins, aminoacyl-tRNA synthetase (ARS), ribosomal RNA, amino acids, rRNA, GTP, ATP, translation initiation factor (IF), elongation factor (EF), termination factor (RF), and ribosomal regeneration factor (RRF), as well as other factors necessary for translation. E. coli extract or wheat germ extract may be added to increase expression efficiency. Alternatively, rabbit red blood cell extract or insect cell extract may be added. 【0120】By continuously supplying energy to a system containing these components using dialysis, proteins can be produced in amounts ranging from several hundred μg to several mg / mL without limitation. The system may also include RNA polymerase to facilitate transcription from gene DNA. Commercially available cell-free translation systems include Roche Diagnostics' RTS-100 (registered trademark), Gene Frontier's PURESYSTEM, and New England Biolabs' PUREexpress In Vitro Protein Synthesis Kit, which are derived from E. coli, and systems from Zoygene and Cellfree Sciences, which can be used. 【0121】 In cell translation systems, artificial aminoacyl-tRNA may be used instead of aminoacyl-tRNA synthesized by natural aminoacyl-tRNA synthetase, by ligating (acylating) a desired amino acid or hydroxy acid to tRNA. Such aminoacyl-tRNA can be synthesized using artificial ribozymes. 【0122】 Examples of such ribozymes include flexizymes (H. Murakami, H. Saito, and H. Suga, (2003), Chemistry & Biology, Vol. 10, 655-662; and WO2007 / 066627, etc.). Flexizymes are also known by the names of the original flexizyme (Fx), and modified versions thereof such as dinitrobenzyl flexizyme (dFx), enhanced flexizyme (eFx), and aminoflexizyme (aFx). 【0123】 By using tRNA linked to a desired amino acid or hydroxy acid, generated by Flexizyme, a desired codon can be translated in association with the desired amino acid or hydroxy acid. Special amino acids may be used as the desired amino acid. For example, unnatural amino acids necessary for the cyclization described above can also be introduced into the bound peptide by this method. 【0124】The chemical synthesis of the peptide can be carried out using various methods commonly used in the art, including, for example, stepwise solid-phase synthesis, semi-synthesis of peptide fragments via conformationally supported re-ligation, and chemical ligation. The synthesis of the peptide is a chemical synthesis using various solid-phase techniques, as described, for example, in K. J. Jensen, P. T. Shelton, S. L. Pedersen, Peptide Synthesis and Applications, 2nd Edition, Springer, 2013. A preferred strategy is based on a combination of an Fmoc group that temporarily protects the α-amino group and allows for selective removal by a base, and a protecting group that temporarily protects the side-chain functional group and is stable under de-Fmoc conditions. Such common peptide side chain selections are found in the aforementioned *Peptide Synthesis and Applications*, 2nd edition, and G. B. Fields, R. L. Noble, *Solid Phase Peptide Synthesis Utilizing 9-Fluorenylmethoxycarbonyl Amino Acids*, Int. J. Peptide Protein Res. As described in 35, 1990, 161-214, preferred peptide side chain protecting groups include, for example, benzyl, tert-butyl, and trityl (Trt) groups for the hydroxyl groups of serine and threonine; 2-bromobenzyloxycarbonyl and tert-butyl groups for the hydroxyl groups of tyrosine; Boc, methyltetrazolethiol (Mtt), Alloc, and ivDde groups for the amino groups of lysine side chains; and for the imidazole group of histidine. Examples include the Trt group and Boc group, the 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) group on the guanidyl group of arginine, the tert-butyl group, allyl group, and 3-methylpentane (Mpe) group on the carboxyl groups of glutamic acid and aspartic acid, the Trt group on the carboxamide group of glutamine and asparagine, and the Trt group and monomethoxytrityl (Mmt) group on the thiol group of cysteine. 【0125】The peptide can be synthesized stepwise on the solid-phase resin described above. The α-amino protecting group must be selectively removed from the C-terminal amino acid and all amino acids and peptides used in the synthesis process. Preferably, the solid-phase resin described above is used, and the synthesis is initiated by activating the C-terminal carboxyl group of a peptide whose N-terminus is appropriately protected with an Fmoc group, or the C-terminal carboxyl group of an amino acid protected with an Fmoc group, using an appropriate reagent, and then adding it to an amino group on the solid-phase resin. Subsequent peptide chain extension can be achieved by sequentially repeating the removal of the N-terminal protecting group (Fmoc group) and then the condensation of the protected amino acid derivative, according to the amino acid sequence of the target peptide. In addition, the target peptide can be released in the final stage. For example, as a condition for release, Teixeira, W. E. Benckhuijsen, P. E. de Koning, A. R. P. M. Valentijn, J. W. As cited in Drijfhout, Protein Pept. Lett., 2002, 9, 379-385, etc., TFA can be liberated in a TFA solution containing water / silyl hydride / thiol as a scavenger. A typical example is TFA / Water / TIS / DODT (volume ratio 92.5:2.5:2.5:2.5). 【0126】 The synthesis of the peptides described herein can be carried out using single or multi-channel peptide synthesizers, such as CEM's Liberty Blue synthesizer or Biotage's Syro I synthesizer or their successors. 【0127】 The carboxyl group can be activated using a condensing agent. Examples of condensing agents include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or WSC), (1H-benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), and 1-[bis(dimethylamino)methyl]-1H-benzotriazolium-3-oxidehexafluorophosphate (HBTU). 【0128】 Peptide cyclization can be carried out according to known methods. Non-limitingly, for example, by designing the peptide to contain two or more cysteine ​​residues, a cyclic structure can be formed by disulfide bonds after translation. Alternatively, cyclization can be achieved by synthesizing a peptide having a chloroacetyl group at the N-terminus using genetic code reprogramming techniques according to the method of Goto et al. (Y. Goto, et al. ACS Chem. Biol. 3 120-129 (2008)), and then placing a cysteine ​​residue containing a sulfur molecule within the peptide. In this case, the mercapto group spontaneously nucleophilically attacks the chloroacetyl group after translation, and the peptide is cyclized by thioether bonds. Cyclization may also be achieved by placing other combinations of amino acids that bind to form a ring within the peptide using genetic code reprogramming techniques. Alternatively, cyclization may be achieved by placing an L-2-aminoadipic acid residue within the peptide and binding it with the N-terminal main chain amino group. Thus, any known cyclization method can be used without particular limitation. 【0129】 Peptides may also take on a bicyclic structure formed by cross-linking within the ring. The formation of the bicyclic structure can be carried out by known methods. Although not limited to these methods, for example, a peptide can be obtained that takes on a bicyclic structure by linking the side chains of two amino acids contained in the cyclic structure, with or without the intervening of other amino acids. 【0130】 The peptide having myostatin inhibitory activity of the present invention can be used in combination with a "pharmaceutical containing a compound having anti-obesity effects," such as a GLP-1 receptor agonist, and can suppress the decrease in lean body mass caused by the pharmaceutical containing the compound having anti-obesity effects. 【0131】 In one embodiment, the present invention relates to a combination pharmaceutical product comprising a compound having anti-obesity activity and a peptide having myostatin inhibitory activity. 【0132】In one embodiment, the present invention relates to a combination pharmaceutical product of (1) a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist; and (2) a peptide having myostatin inhibitory activity. 【0133】 In one embodiment, the combination drug is a combination drug for suppressing the decrease in lean body mass. 【0134】 The aforementioned combination pharmaceuticals include, but are not limited to, combination pharmaceutical compositions, therapeutic combination pharmaceuticals, and preventive combination pharmaceuticals. 【0135】 In one embodiment, the present invention relates to a (combination) pharmaceutical composition comprising the GLP-1 receptor agonist or GIP / GLP-1 receptor agonist and the peptide having myostatin inhibitory activity. 【0136】 "Decrease in lean body mass (LBM)" includes a decrease in muscle mass associated with weight loss due to the aforementioned GLP-1 receptor agonist or GIP / GLP-1 receptor agonist. For example, it refers to a decrease in LBM caused by weight loss due to the administration of the aforementioned GLP-1 receptor agonist or GIP / GLP-1 receptor agonist, which may occur in some patients. 【0137】 "Suppressing the decrease in lean body mass caused by an agonist with the peptide" includes embodiments that prevent or treat the decrease in LBM. 【0138】Suppressing the decrease in lean body mass may mean restoring LBM that has already decreased due to some cause, such as a GLP-1 receptor agonist, or preventing the decrease in lean body mass that would normally decrease due to the administration of a GLP-1 receptor agonist or GIP / GLP-1 receptor agonist, or reducing the rate of decrease. Alternatively, suppressing the decrease in lean body mass may mean, for example, comparing the rate of decrease in LBM when only a GLP-1 receptor agonist or GIP / GLP-1 receptor agonist is administered with the rate of decrease in lean body mass when the peptide having the myostatin inhibitory activity is administered, and if a decrease is observed. Preferably, the rate of decrease in lean body mass should be at least 50%, at least 40%, at least 30%, at least 20%, at least 10%, at least 5%, or at least 3%. 【0139】 Lean body mass can be measured by known methods. For example, it can be measured using body composition analyzers that employ bioelectrical impedance analysis, X-ray CT, NMR technology, MRI, etc. 【0140】 In one embodiment, "decrease in lean body mass" may also be viewed as a change in muscle mass. As mentioned above, lean body mass refers to muscle mass, bone mass, blood volume, etc., but when "lean body mass decreases" due to the administration of a GLP-1 receptor agonist or GIP / GLP-1 receptor agonist, it is thought to be mainly due to a decrease in muscle mass. Therefore, for example, in order to confirm whether "decrease in lean body mass" is suppressed, it is sufficient to compare the muscle mass when only a GLP-1 receptor agonist or GIP / GLP-1 receptor agonist is administered with the LBM muscle mass when the peptide having the myostatin inhibitory activity is administered and see if an increase is observed. Muscle mass can be measured by known methods. 【0141】 In one embodiment, the combination drug is for suppressing (including prevention and treatment) the decrease in muscle mass. In one embodiment, the combination drug is for suppressing (including prevention and treatment) the decrease in the amount of muscle fibers. In one embodiment, the combination drug is for increasing the amount of muscle fibers. 【0142】In one embodiment, the combination drug is administered to an individual with obesity symptoms, and to an individual in whom a decrease in lean body mass is expected by administering a drug containing a compound having an anti-obesity effect. The "individual" is preferably a human. 【0143】 The aforementioned combination pharmaceutical may include the pharmaceutical and peptide containing the anti-obesity compound itself, or it may include a pharmaceutically acceptable salt thereof or a solvate thereof. In this specification, "pharmaceutical containing the anti-obesity compound" and "peptide" may include a pharmaceutically acceptable salt thereof or a solvate thereof unless otherwise specified. The aforementioned combination pharmaceutical preferably contains an effective amount of the pharmaceutical containing the anti-obesity compound and the peptide, respectively, as active ingredients. 【0144】 The aforementioned combination pharmaceutical includes embodiments of pharmaceuticals containing the "pharmaceuticals containing compounds having anti-obesity effects" and the "peptides having myostatin inhibitory activity," embodiments in which each compound is used as a combination agent, embodiments in which they are used as a kit, embodiments in which they are administered simultaneously, embodiments in which they are administered at intervals, and embodiments in which one drug is used in combination with another drug. The abbreviation "combination (of)" is sometimes used, but these are synonymous. 【0145】 The aforementioned combination drug may be used in combination with other drugs containing compounds with anti-obesity effects, drugs having myostatin inhibitory activity, or drugs exhibiting other pharmacological effects. 【0146】 The aforementioned combination drug may be a combination formulation prepared by mixing a "pharmaceutical containing a compound having an anti-obesity effect," preferably a "GLP-1 receptor agonist or GIP / GLP-1 receptor agonist," and a "peptide" in any proportion, or it may be formulated separately. Preferably, they are formulated separately. 【0147】Examples of ingredients used in formulation include, but are not limited to, purified water, saline solution, phosphate buffer, dextrose, glycerol, pharmaceutically acceptable organic solvents such as ethanol, animal and vegetable oils, lactose, mannitol, glucose, sorbitol, crystalline cellulose, hydroxypropylcellulose, starch, corn starch, anhydrous silicic acid, aluminum magnesium silicate, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, acacia gum, 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. 【0148】 The aforementioned combination pharmaceutical (a pharmaceutical containing a compound having anti-obesity activity, a peptide having myostatin inhibitory activity, or a pharmaceutical composition containing both) may use the active ingredient as is, or may have additives added for oral formulation. In addition to additives, the aforementioned combination pharmaceutical may also contain pharmaceutically acceptable carriers, excipients, and other additives. Examples of dosage forms include liquids (e.g., injections), dispersants, suspensions, tablets, pills, powders, suppositories, powders, granules, capsules, syrups, lozenges, inhalants, ointments, eye drops, nasal drops, ear drops, and poultices. Formulation can be carried out by conventional methods, for example, by appropriately using excipients, binders, disintegrants, lubricants, solvents, solubilizers, colorants, flavoring and odor-correcting agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. 【0149】The aforementioned combination drug may include an absorption enhancer that improves the absorption of poorly absorbed drugs. Examples of such absorption enhancers include surfactants such as polyoxyethylene lauryl ethers, sodium lauryl sulfate, and saponins; bile salts such as glycocholic 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, and nitric oxide donors. 【0150】 If the aforementioned combination drug is in the form of a pill or tablet, it may be coated with a sugar coating, a gastric-soluble coating, or an enteric-soluble coating. 【0151】 If the aforementioned combination drug is an injectable preparation, it may contain distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, vegetable oil, alcohols, etc. Furthermore, humectants, emulsifiers, dispersants, stabilizers, solvents, solubilizers, preservatives, etc. may be added. 【0152】 Furthermore, the aforementioned combination drug may be intended not only for humans but also for non-human mammals or birds. Examples of non-human mammals include primates other than humans (such as monkeys, chimpanzees, gorillas, etc.), domestic animals (such as pigs, cows, horses, sheep, etc.), or dogs, cats, rats, mice, guinea pigs, rabbits, etc. 【0153】In particular, when administered to humans, the dosage can be defined and selected based on clinically used doses in which the "pharmaceutical containing a compound having anti-obesity effects," preferably "GLP-1 receptor agonist or GIP / GLP-1 receptor agonist" or "peptide" is effective. The dosage will vary depending on the symptoms, the patient's age, sex, weight, sensitivity differences, administration method, administration interval, type of active ingredient, and type of formulation. Non-limitedly, for example, the "pharmaceutical containing a compound having anti-obesity effects" and the "peptide" can be administered in single doses or in divided doses of 30 μg to 100 g, 100 μg to 500 mg, or 100 μg to 100 mg, respectively. In the case of injection administration, depending on the patient's weight, 1 μg / kg to 3000 μg / kg or 3 μg / kg to 1000 μg / kg may be administered in single doses or in divided doses. 【0154】 Dosage Form In this specification, the dosage form of the combination drug (i.e., the "pharmaceutical containing a compound having an anti-obesity effect", the "peptide", or a pharmaceutical composition containing both) is not particularly limited and may be administered orally or parenterally. Preferably, the dosage form of the combination drug is oral administration. Parenteral administrations include, for example, injections such as intramuscular injection, intravenous injection, and subcutaneous injection, transdermal administration, and transmucosal administration (through the nose, through the mouth, through the eye, through the lung, through the vagina, through the rectum). In one embodiment, the dosage forms of the "GLP-1 receptor agonist or GIP / GLP-1 receptor agonist" and the "peptide" may be the same or different. Preferably, the dosage form of the peptide is oral administration. 【0155】 In one embodiment of the present invention, the agonist and / or the peptide having myostatin inhibitory activity is administered orally. 【0156】 In one embodiment of the present invention, the peptide having myostatin inhibitory activity is administered orally. 【0157】The aforementioned combination drug may be administered simultaneously with the "pharmaceutical containing a compound having anti-obesity activity" (including "GLP-1 receptor agonist," "GIP / GLP-1 receptor agonistide," "GIP / GLP-1 / glucagon receptor agonist," or "GLP-1 / amyrin receptor agonist," preferably including "GLP-1 receptor agonist or GIP / GLP-1 receptor agonist") and the "peptide having myostatin inhibitory activity," or administered at different times. Preferably, the peptide is administered in such a manner that the effect of suppressing the reduction of lean body mass is maximized. 【0158】 When administering sequentially, the order of administration does not matter. When administering sequentially, it is sufficient that the time difference is within a range in which the "peptide having myostatin inhibitory activity" can exert its effect on the reduction of lean body mass caused by the pharmaceutical drug containing the compound having anti-obesity activity. Non-limitingly, it is preferable to administer both the "pharmaceutical drug containing the compound having anti-obesity activity" and the "peptide having myostatin inhibitory activity" within 2 hours, 1 hour, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes. As one form of administration with a time interval, the administration may be carried out on different days. For example, the pharmaceutical drug containing the compound having anti-obesity activity may be administered once a day, and the peptide may be administered once a week. Also, even when both are administered once a week, they may be administered on different days of the week. 【0159】 Matters described in other sections of this specification shall also apply to section 2, "Combination Medicines," unless there is a technical inconsistency. 【0160】 3. In one embodiment of the pharmaceutical invention, the present invention relates to a pharmaceutical product comprising a peptide having myostatin inhibitory activity, which is used in conjunction with a pharmaceutical product comprising a compound having an anti-obesity effect, wherein the peptide suppresses the reduction of lean body mass caused by the agonist. 【0161】In one embodiment, the present invention relates to a pharmaceutical product comprising a peptide having myostatin inhibitory activity, used in conjunction with a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist, wherein the peptide suppresses the reduction of lean body mass caused by the agonist. 【0162】 "Used in conjunction with a pharmaceutical product containing a compound having anti-obesity effects" and "Used in conjunction with a GLP-1 receptor agonist or GIP / GLP-1 receptor agonist" mean, as explained in "Dosage Form" under section "2. Combination Pharmaceuticals," that a pharmaceutical product containing a peptide having myostatin inhibitory activity is used within a time lag that allows it to exert an effect of suppressing the reduction of lean body mass caused by a pharmaceutical product containing a compound having anti-obesity effects (including "GLP-1 receptor agonist," "GIP / GLP-1 receptor agonist," "GIP / GLP-1 / glucagon receptor agonist," or "GLP-1 / amyrin receptor agonist." Preferably, it includes "GLP-1 receptor agonist or GIP / GLP-1 receptor agonist"). 【0163】 In one embodiment, the present invention relates to a pharmaceutical product comprising a peptide having myostatin inhibitory activity, for suppressing the reduction of lean body mass caused by a pharmaceutical product comprising a compound having anti-obesity activity. 【0164】 In one embodiment, the present invention relates to the use of a peptide having myostatin inhibitory activity for the manufacture of a pharmaceutical product comprising a compound having an anti-obesity effect, preferably a pharmaceutical product for inhibiting the reduction of lean body mass by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist. 【0165】The aforementioned pharmaceutical treatment and / or prevention of lean body mass loss by suppressing the loss of lean body mass caused by pharmaceuticals containing compounds having anti-obesity effects (including "GLP-1 receptor agonists," "GIP / GLP-1 receptor agonists," "GIP / GLP-1 / glucagon receptor agonists," or "GLP-1 / amyrin receptor agonists," preferably "GLP-1 receptor agonists or GIP / GLP-1 receptor agonists"). The embodiment of the aforementioned pharmaceutical treatment is for a subject who is currently being administered or is scheduled to be administered pharmaceuticals containing compounds having anti-obesity effects (including "GLP-1 receptor agonists or GIP / GLP-1 receptor agonistides"). 【0166】 The definitions of terms such as "pharmaceuticals containing compounds with anti-obesity effects," "GLP-1 receptor agonists or GIP / GLP-1 receptor agonists," "peptides with myostatin inhibitory activity," and "reduction of lean body mass by agonists" are as explained in section 2, "Combination Pharmaceuticals." 【0167】 Matters described in other sections of this specification shall also apply to section 3, "Medicines," unless there is a technical inconsistency. 【0168】 4. Method, Use, etc. In one embodiment, the present invention relates to a method for suppressing (including treatment and / or prevention) the reduction of lean body mass caused by an agonist by a peptide, which includes administering a peptide having myostatin inhibitory activity to a subject who is being administered a pharmaceutical product containing a compound having an anti-obesity effect. 【0169】 In one embodiment, the present invention relates to a method for suppressing the reduction of lean body mass caused by an agonist, comprising administering a peptide having myostatin inhibitory activity to a subject receiving a pharmaceutical product containing a compound having an anti-obesity effect, preferably a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist. 【0170】 In this specification, "administering" includes being actually administered or being scheduled to be administered. 【0171】In one embodiment, the present invention relates to the use of a peptide having myostatin inhibitory activity to suppress the reduction of lean body mass by a pharmaceutical product containing a compound having anti-obesity activity. 【0172】 In one embodiment, the present invention relates to the use of a peptide having myostatin inhibitory activity, comprising a compound having anti-obesity activity, preferably for suppressing the reduction of lean body mass by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist. 【0173】 In one embodiment, the present invention relates to the use of a peptide having myostatin inhibitory activity for the manufacture of a pharmaceutical product for inhibiting the reduction of lean body mass by a pharmaceutical product containing a compound having an anti-obesity effect. 【0174】 In one embodiment, the present invention relates to the use of a peptide having myostatin inhibitory activity for the manufacture of a pharmaceutical product comprising a compound having an anti-obesity effect, preferably a pharmaceutical product for inhibiting the reduction of lean body mass by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist. 【0175】 In one embodiment, the present invention relates to a peptide having myostatin inhibitory activity, which is used to suppress the reduction of lean body mass caused by pharmaceuticals containing compounds having anti-obesity effects. 【0176】 In one embodiment, the present invention relates to a pharmaceutical product comprising a compound having an anti-obesity effect, preferably a peptide having myostatin inhibitory activity used to suppress the reduction of lean body mass by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist. 【0177】 The definitions of terms such as "pharmaceuticals containing compounds with anti-obesity effects," "GLP-1 receptor agonists or GIP / GLP-1 receptor agonists," "peptides with myostatin inhibitory activity," and "reduction of lean body mass by agonists" are as explained in section 2, "Combination Pharmaceuticals." 【0178】Matters described in other sections of this specification shall also apply to section 4, "Methods and Use," unless there is a technical contradiction. 【0179】 The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Those skilled in the art can easily modify and change the present invention based on the description herein, and such modifications fall within the technical scope of the present invention. The compound names shown in the following reference examples and examples do not necessarily follow IUPAC nomenclature. Abbreviations may be used for simplification of the description, but these abbreviations are as described above. 【0180】 The raw materials, building blocks, reagents, acids, bases, solid-phase resins, and solvents used in the chemical synthesis of the compounds were either commercially available or synthesized using organic chemical methods, as otherwise stated. Furthermore, commercially available amino acids containing protecting groups were used as is. 【0181】 For counting peptide residues, the amino acid residue that undergoes ClAc conversion is counted as the first residue, and then the residues are counted as the second, third, and so on towards the resin. The common amino acids used are listed below, with side chain protecting groups indicated in parentheses. 【0182】 Fmoc-Phe-OH; Fmoc-Val-OH; Fmoc-Trp(Boc)-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Ala-OH H ２ O; Fmoc-Gly-OH; Fmoc-N-Me-Tyr(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OMpe)-OH; Fmoc-(Dmb)Gly-OH (CAS number 166881-42-1); Fmoc-D-Pro-OH; Fmoc-Cys(Trt)-OH; Fmoc-Lys(Boc)-OH. 【0183】 Furthermore, the non-natural amino acids used were those listed below and those with abbreviations. 【0184】Fmoc-dp-OH; Fmoc-MeF-OH; Fmoc-MeA-OH; Fmoc-W6H(Boc)1Ph4COO(tBu)-OH; Fmoc-W6H(Boc, Boc)-OH; Fmoc-MeDap(alloc)-OH (CAS:2973753-13-6); Fmoc-MeF4am(alloc)-OH (CAS:2973754-55-9); Fmoc-CeG(allyl)-OH (CAS:174800-18-1); Fmoc-Ano-OH (CAS:1262886-65-6); Fmoc-F4COO(tBu)-OH (CAS: 183070-44-2); Fmoc-F3aao(tBu)-OH (CAS: 2973753-95-4); Fmoc-CrpG(tBu)-OH (CAS: 174799-90-7); Fmoc-da-OH (CAS:79990-15-1); Fmoc-CrpG(allyl)-OH (CAS:1403683-46-4); Fmoc-Pip4mAc-OH (CAS:154938-68-8); Fmoc-Ape-OH (CAS:123622-48-0); Fmoc-dcaa-OtBu. 【0185】 The structure of chemically synthesized peptides was determined by calculating the molecular weight, considering the amino acids used according to the target sequence and the building blocks used as needed, and confirming this by ESI-MS(+) in mass spectrometry. "ESI-MS(+)" refers to electrospray ionization mass spectrometry performed in positive ion mode. The detected mass was reported in "m / z" units. Compounds with molecular weights greater than approximately 1000 were frequently detected as divalent or trivalent ions. 【0186】 Example 1 In this example, the following peptides or linker-granting peptides were synthesized. 【0187】 Example 1-1 Synthesis of Myostatin_99_v424 (SEQ ID NO: 1) 【0188】 One equivalent of Cl-Trt(2-Cl)resin (Watanabe Chemical, 0.79 mmol / g, 5.7 g), swollen with DCM, was mixed with 0.66 equivalents of Fmoc-dcaaa-OtBu in DCM solution and 1.7 equivalents of DIEA, and the mixture was shaken at room temperature for 60 minutes. An excess amount of methanol was added, and the mixture was shaken for 10 minutes. The solid phase resin was washed with DMF, DCM, and diethyl ether, and then dried under reduced pressure. A portion of the obtained solid phase resin (0.79 mmol / g, 1.04 g) was used to synthesize the target peptide. A CEM Liberty Blue was used as the solid phase synthesizer, and the synthesis was carried out according to the manufacturer's manual. The reaction was carried out once at 40°C for 30 minutes using 0.21 M Fmoc-AA (in DMF) / 1 M DIC (in DMF) / 0.5 M Oxyma pure (in DMF) (5.1 equivalents / 9.8 equivalents / 4.9 equivalents). However, for residues 4, 6, 7, 10, 12, and 13, the reaction was carried out twice at 40°C for 30 minutes each. Fmoc-E(allyl)-OH was used for the reaction at residue 1, and Fmoc-MeF4am(alloc)-OH was used for the reaction at residue 11. For the third residue, a reaction was carried out once at 40°C for 30 minutes using 0.15 M Fmoc-W6H(Boc)1Ph4COO(tBu)-OH (in NMP) / 1 M DIC (in DMF) / 0.5 M Oxyma pure (in DMF) (3.6 equivalents / 9.8 equivalents / 4.9 equivalents), followed by washing the resin with DMF. Fmoc removal was performed by reacting the resin twice with a 10% pyrrolidine DMF solution at 25°C for 5 minutes each. 【0189】 To cleave the solid phase resin, the obtained resin was first washed five times with DMF and three times with methylene chloride, then washed with diethyl ether and dried under reduced pressure. Next, a reaction cocktail (40 mL, a mixture of HFIP / DCM in a volume ratio of 20 / 80) was added to the reaction vessel containing the solid phase resin, and the mixture was shaken at room temperature for 60 minutes. The reaction solution was filtered and recovered through the frit. The solid phase resin remaining in the reaction vessel was shaken again with the cleavage cocktail, the solution components were recovered through the frit, and mixed with the aforementioned filtrate. The resulting filtrate was concentrated under reduced pressure using Genevac EZ-II Elite, and when diisopropyl ether was added, a white precipitate was formed. 【0190】The mixture was centrifuged (9000 rpm, 0°C, 2 min), and the solution was decanted. The resulting solid was washed with a small amount of diethyl ether cooled again to 0°C, and then dried under reduced pressure. The resulting solid (peptide) was used in the following cyclization reaction. The peptide was dissolved in DMF to a final concentration of 1.5 mM based on the number of moles of the solid phase resin, 1.1 equivalents of HATU and 5 equivalents of DIEA were added, and after stirring at room temperature for 30 minutes, acetic acid was added to quench the reaction. The reaction solution was concentrated under reduced pressure using Genevac HT-12. 【0191】 The resulting mixture was dissolved in 3% HFIP-containing DMF, and 0.02 equivalents of Pd(PPh3)4 and 20 equivalents of phenylsilane were added. After shaking for 60 minutes, diisopropyl ether was added. The resulting precipitate was centrifuged (9000 rpm, 0°C, 2 min), and the solution was decanted. The resulting solid was washed with a small amount of diethyl ether cooled again to 0°C, and then dried under reduced pressure. 【0192】 The obtained solid (peptide) was used in the following cyclization reaction. The peptide was dissolved in DMF to a final concentration of 1.5 mM based on the number of moles of the solid phase resin. 1.1 equivalents of HATU and 5 equivalents of DIEA were added, and the mixture was stirred at room temperature for 30 minutes. Acetic acid was then added to quench the reaction. The reaction solution was concentrated under reduced pressure using Genevac EZ-II Elite, and then diisopropyl ether was added, resulting in the formation of a white precipitate. This mixture was centrifuged (9000 rpm, 0°C, 2 min), and the solution was decanted. The obtained solid was washed with a small amount of diethyl ether cooled again to 0°C, and then dried under reduced pressure. 【0193】 The resulting solid was cooled on ice to obtain a reagent cocktail (20 mL, TFA / H ２ The solution was dissolved in a mixture of O / TIS / DODT in a volume ratio of 92.5 / 2.5 / 2.5 / 2.5 and shaken at 0°C for 20 minutes. Diethyl ether was added, and the resulting white precipitate was centrifuged (9000 rpm, 0°C, 2 minutes), and the solution was decanted. The obtained solid was washed with a small amount of diethyl ether cooled again to 0°C, and then dried under reduced pressure. 【0194】The obtained crude product was purified using the following conditions (column: Agela Claricep Spiral AQ C18 20-35um 100Å 120g; mobile phase: A = 0.1% TFA (in water), B = 0.1% TFA (in MeCN); temperature: 25°C; gradient (%B): 32-32% over 1 minute, 32-47% over 24 minutes, 47-95% over 10 minutes, 95-95% over 5 minutes; flow rate: 10-50 mL / min over 1 minute, then 50 mL / min). After freeze-drying, the following conditions were used for purification: (Column: Waters Xselect® CSH C18 5μm OBD 50x250mm; Mobile phase: A = 1.0% AcOH (in water), B = 1.0% AcOH (in MeCN), C = 0.2M TEAA (in water), D = acetonitrile; Temperature: 50°C; Gradient (%A): 0.1-0.1% over 5 minutes, 0.1-66.7% over 0.1 minutes, then 100-%B; Gradient (%B): 0-0% over 5 minutes, 0-33.3% over 0.1 minutes, then 33.3-34.7% over 1.9 minutes, then 34.7%-34.7% over 3 minutes, then 34.7%-39.8% over 15.5 minutes, then 1 39.8–60% over 5 minutes, then 60–90% over 4 minutes; Gradient (%C): 66.6–66.6% over 5 minutes, 66.6–0% over 0.1 minutes, then 0%; Gradient (%D): 33.3–33.3% over 5 minutes, 33.3–0% over 0.1 minutes, then 0%; Flow rate: 20–20 mL / min over 5.1 minutes, 20–120 mL / min over 1.9 minutes, then 120 mL / min). 【0195】 The purity of the target substance was calculated from the area ratio of the LC / MS (UV wavelength 225 nm) chromatogram under the analytical conditions. The purity of the target substance was 95.3%. 【0196】Analysis conditions: retention time = 5.07 minutes; column: Kinetex EVO C18 2.6 μm 2.1x150 mm, 100 Å; mobile phase: A = 0.025% TFA (in water), B = 0.025% TFA (in MeCN); temperature: 60 °C; gradient (% B conc): from 20 - 60% over 7.15 minutes, then from 60 - 95% over 0.3 minutes, then from 95 - 95% over 1.55 minutes; flow rate: 0.5 mL / min ESI-MS(+) observed value m / z = 1181.18 (M + 2H) ２＋ 【0197】 Example 1 - 2 Synthesis of Myostatin_99_v483 (SEQ ID NO: 2) 【0198】 The target peptide was synthesized using H-A-Trt(2-Cl) resin (Watanabe Chemical, 1.08 mmol / g, 0.23 g). At that time, CEM's Liberty Blue was used as a solid-phase synthesizer and the synthesis was carried out according to the manufacturer's manual. For the introduction of each residue, 0.21 M Fmoc-AA (in DMF) / 1 M DIC (in DMF) / 0.5 M Oxyma pure (in DMF) (4.2 equivalents / 8 equivalents / 4 equivalents) was used per 1 equivalent of resin. 【0199】 The deprotection of the Fmoc group was carried out using a 10% pyrrolidine solution in DMF. Furthermore, the peptide was elongated according to the conditions described in Table 1 below. 【0200】 For cleavage from the solid-phase resin, first the obtained resin was washed 5 times with DMF and 3 times with methylene chloride, then washed with diethyl ether and dried under reduced pressure. Subsequently, to the reaction vessel containing the solid-phase resin, a reagent cocktail (10 mL, a mixture of HFIP / DCM with a volume ratio of 20 / 80) was added and shaken at room temperature for 60 minutes. The reaction solution was filtered and collected through a frit. The solid-phase resin remaining in the reaction vessel was shaken again with the cleavage cocktail, and the solution components were collected through the frit and mixed with the aforementioned filtrate. When diethyl ether was added to the mixture obtained by concentrating the filtrate under reduced pressure, a white turbid precipitate formed. 【0201】The mixture was centrifuged (9000 rpm, 0°C, 2 min), and the solution was decanted. The resulting solid was washed with a small amount of diethyl ether cooled again to 0°C, and then dried under reduced pressure. The resulting solid (peptide) was used in the following cyclization reaction. The peptide was dissolved in DMF to a final concentration of 7 mM based on the number of moles of the solid phase resin. Then, 1.1 equivalents of HATU and 5 equivalents of DIEA were added, and after stirring at room temperature for 30 minutes, acetic acid was added to quench the reaction and carry out the cyclization reaction of the peptide. The reaction solution was concentrated under reduced pressure using Genevac HT-12. 【0202】 The resulting residue is a reagent cocktail (4 mL, TFA / TIS / H ２ The solution was dissolved in a mixture of 0 / thioanisole in a volume ratio of 70 / 2.5 / 2.5 / 25 and shaken at room temperature for 55 minutes. The resulting reaction mixture was added to diethyl ether, and a precipitate was formed. This mixture was centrifuged (9000 rpm, 0°C, 2 min), and the solution was decanted. The resulting solid was washed with a small amount of diethyl ether cooled again to 0°C, and then dried under reduced pressure. The obtained crude product was purified using the following conditions (column: Waters Xbridge® C18 5 μm 50 x 150 mm; mobile phase: A = 0.1% TFA (in water), B = 0.1% TFA (in MeCN); temperature: 40°C; gradient (%B): 19-19% over 2 minutes, 19-44% over 1 minute, 44-49% over 8 minutes, 49-60% over 1 minute; flow rate: 20-20 mL / min over 1 minute, 20-120 mL / min over 1 minute, then 120 mL / min). 【0203】 The purity of the target substance was calculated from the area ratio of the LC / MS (UV wavelength 225 nm) chromatogram under the analytical conditions. The purity of the target substance was 96.0%. 【0204】Analysis conditions: Retention time = 6.13 min; Column: Kinetex EVO C18 2.6 μm 2.1 x 150 mm, 100 Å; Mobile phase: A = 0.025% TFA (water), B = 0.025% TFA (MeCN); Temperature: 60°C; Gradient (% B conc): 20-60% over 7.15 minutes, then 60-95% over 0.3 minutes, then 95-95% over 1.55 minutes; Flow rate: 0.5 mL / min; ESI-MS(+) Observed value m / z = 1144.14 (M + 2H) ２＋ 【0205】 Example 1-3 Synthesis of Myostatin_99_v488 (SEQ ID NO: 3) 【0206】 One equivalent of Sieber amide resin (Watanabe Chemical, 1 mmol / g, 0.70 g) was washed with DMF to remove the Fmoc group using the general method described above, and then the resulting solid phase resin was mixed with 4.2 equivalents of a DMF solution of Fmoc-Pip4mAc-OH, 4 equivalents of HATU, and 8 equivalents of DIEA, and shaken at room temperature for 60 minutes. The solid phase resin was washed with DMF, DCM, and diethyl ether, and then dried under reduced pressure. A portion of the obtained solid phase resin (0.60 mmol / g, 0.42 g) was used to synthesize the target peptide, starting with the removal of the Fmoc group using the general method described above. In this process, CEM's Liberty Blue was used as the solid phase synthesizer, and the synthesis was carried out according to the manufacturer's manual. To introduce each residue, 0.21 M Fmoc-AA (in DMF) / 0.5 M HATU (in DMF) / 1 M DIEA (in DMF) (4.2 equivalents / 4 equivalents / 8 equivalents) were used per equivalent of resin. The reaction was carried out once for 3 minutes at 90°C. However, for the 4th and 13th residues, the reaction was carried out twice for 10 minutes at 90°C. For the 10th and 15th residues, the reaction was carried out twice for 15 minutes at 50°C. For the 12th residue, the reaction was carried out twice for 30 minutes at 75°C. In addition, Fmoc removal was carried out by reacting a 10% pyrrolidine DMF solution once for 1 minute at 90°C. However, for the 4th, 6th, 10th, 12th, 13th, and 15th residues, the reaction was carried out twice for 1 minute at 25°C. 【0207】To introduce the chloroacetyl group, the Fmoc-protected peptide obtained in the previous step was held in a solid-phase resin. The Fmoc group of the α-amino group was removed using the method described above, the peptide was suspended in DMF, and the mixture was shaken at 25°C for 30 minutes with 5 equivalents of chloroacetic acid, 5 equivalents of HATU, and 8 equivalents of DIEA to introduce the chloroacetyl group. 【0208】 To deprotect the side chains and cleave them from the solid phase resin, the resin obtained after the chloroacetyl group introduction step was first washed five times with DMF and three times with methylene chloride, then washed with diethyl ether and dried under reduced pressure. Subsequently, a reaction cocktail (15 mL, TFA / H) was added to the reaction vessel containing the solid phase resin. ２ A mixture of O / TIS / thioanisole in a volume ratio of 70 / 2.5 / 2.5 / 25 was added and shaken at room temperature for 60 minutes. The reaction mixture was filtered and recovered through the frit. The solid resin remaining in the reaction vessel was shaken again with the cutting cocktail, the solution components were recovered through the frit and mixed with the aforementioned filtrate. When this filtrate was added to an excess diisopropyl ether / hexane (1 / 1) mixed solvent cooled to 0°C, a turbid precipitate was formed. 【0209】 The mixture was centrifuged (9000 rpm, 0°C, 2 min), and the solution was decanted. The resulting solid was washed with a small amount of diethyl ether cooled again to 0°C, and then dried under reduced pressure. The resulting solid (peptide) was used in the following cyclization reaction. The peptide was dissolved in water / acetonitrile (1 / 1) to a final concentration of 2.5 mM based on the number of moles of the solid phase resin. Then, 10 equivalents of triethylamine were added, and after stirring at room temperature for 4 hours, acetic acid was added to quench the reaction and carry out the cyclization reaction of the peptide. The reaction solution was concentrated under reduced pressure using Genevac HT-12. 【0210】The obtained mixture was purified under the following conditions (column: Waters Xselect® CSH Prep C18 5μm 30x150mm; mobile phase: A = 50 mM TEAA (in water), B = acetonitrile; temperature: 50°C; gradient (%B): 6.0–2.2% over 0.1 minutes, 2.2–2.2% over 4.9 minutes, 2.2–6.0% over 1 minute, 6.0–31.6% over 3 minutes, 31.6–36.7% over 9 minutes, 36.7–60% over 1 minute; flow rate: 44–9 mL / min over 0.1 minutes, 9–9 mL / min over 4.9 minutes, 9–44 mL / min over 1 minute, then 44 mL / min). After lyophilization, purification was performed again under the same conditions. After freeze-drying, the material was dissolved in 0.1 TFA-containing water / acetonitrile (a 50 / 50 volume mixture) and freeze-dried again. 【0211】 The purity of the target substance was calculated from the area ratio of the LC / MS (UV wavelength 225 nm) chromatogram under the analytical conditions. The purity of the target substance was 98.3%. 【0212】 Analysis conditions: Retention time = 5.32 min; Column: Kinetex EVO C18 2.6 μm 2.1 x 150 mm, 100 Å; Mobile phase: A = 0.025% TFA (water), B = 0.025% TFA (MeCN); Temperature: 60°C; Gradient (% B conc): 20-60% over 7.15 minutes, then 60-95% over 0.3 minutes, then 95-95% over 1.55 minutes; Flow rate: 0.5 mL / min; ESI-MS(+) Observed value m / z = 1251.85 (M + 2H) ２＋ 【0213】 Example 1-4 Synthesis of Myostatin_99_v489 (SEQ ID NO: 4) 【0214】 The target peptide was synthesized using H-A-Trt(2-Cl) resin (Watanabe Chemical, 1.08 mmol / g, 0.12 g). A CEM Liberty Blue solid-phase synthesizer was used, and the synthesis was carried out according to the manufacturer's manual. To introduce each residue, 0.21 M Fmoc-AA (in DMF) / 1 M DIC (in DMF) / 0.5 M Oxyma pure (in DMF) (4.2 equivalents / 8 equivalents / 4 equivalents) were used per equivalent of resin. 【0215】 Deprotection of the Fmoc group was performed using a 10% pyrrolidine DMF solution. Furthermore, the peptide was extended according to the conditions described in Table 2 below. 【0216】 The obtained solid-phase resin was suspended in DCM, 5 equivalents of Fmoc-OSu were added, and the mixture was shaken at 25°C for 1 hour, followed by washing with DMF. The obtained resin was suspended in DCM, 0.2 equivalents of Pd(PPh3)4 and 20 equivalents of phenylsilane were added, and the mixture was shaken at 25°C for 60 minutes, followed by sequential washing with DCM and DMF. The obtained resin was suspended in DMF to a final concentration of 3.5 mM based on the number of moles of the solid-phase resin, 1.01 equivalents of PyAOP and 5 equivalents of DIEA were added, and the mixture was shaken at room temperature for 20 minutes. After washing with DMF, the Fmoc groups were removed by shaking with a 10% pyrrolidine DMF solution at room temperature for 30 minutes. 【0217】 To cleave the solid phase resin, the obtained resin was first washed five times with DMF and three times with methylene chloride, then washed with diethyl ether and dried under reduced pressure. Next, a reaction cocktail (10 mL, a mixture of HFIP / DCM in a volume ratio of 20 / 80) was added to the reaction vessel containing the solid phase resin, and the mixture was shaken at room temperature for 60 minutes. The reaction solution was filtered and recovered through the frit. The solid phase resin remaining in the reaction vessel was shaken again with the cleavage cocktail, the solution components were recovered through the frit, and mixed with the aforementioned filtrate. After concentrating the obtained filtrate under reduced pressure, a white precipitate was formed when diethyl ether was added. The precipitate was centrifuged (9000 rpm, 0°C, 2 min), and the solution was decanted. The obtained solid was washed again with a small amount of diethyl ether cooled to 0°C, and then dried under reduced pressure. 【0218】The obtained solid (peptide) was used in the following cyclization reaction. The peptide was dissolved in DMF to a final concentration of 7 mM based on the number of moles of the solid phase resin. 1.1 equivalents of HATU and 5 equivalents of DIEA were added, and the mixture was stirred at room temperature for 30 minutes. Acetic acid was then added to quench the reaction. The reaction solution was concentrated under reduced pressure using Genevac HT-12. The resulting mixture was cooled on ice to form a reagent cocktail (12 mL, TFA / H). ２ The solution was dissolved in a mixture of O / TIS / thioanisole in a volume ratio of 70 / 2.5 / 2.5 / 25 and shaken at 25°C for 35 minutes. Diethyl ether was added, and the resulting white precipitate was centrifuged (9000 rpm, 0°C, 2 min), and the solution was decanted. The obtained solid was washed with a small amount of diethyl ether cooled again to 0°C, and then dried under reduced pressure. 【0219】 The obtained crude product was purified using the following conditions (column: Waters Xselect® CSH Prep C18 5 μm 30 x 150 mm; mobile phase: A = 50 mM TEAA (in water), B = acetonitrile; temperature: 50°C; gradient (%B): 11.1–7.8% over 0.1 minutes, 7.8–7.8% over 4.9 minutes, 7.8–11.1% over 1 minute, 11.1–36.7% over 3 minutes, 36.7–41.8% over 9 minutes, 41.8–60% over 1 minute; flow rate: 44–9 mL / min over 0.1 minutes, 9–9 mL / min over 4.9 minutes, 9–44 mL / min over 1 minute, then 44 mL / min). After freeze-drying, the material was dissolved in 0.1 TFA-containing water / acetonitrile (a 50 / 50 volume mixture) and freeze-dried again. 【0220】 The purity of the target substance was calculated from the area ratio of the LC / MS (UV wavelength 225 nm) chromatogram under the analytical conditions. The purity of the target substance was 94.1%. 【0221】Analysis conditions: Retention time = 5.77 min; Column: Kinetex EVO C18 2.6 μm 2.1 x 150 mm, 100 Å; Mobile phase: A = 0.025% TFA (water), B = 0.025% TFA (MeCN); Temperature: 60°C; Gradient (% B conc): 20-60% over 7.15 minutes, then 60-95% over 0.3 minutes, then 95-95% over 1.55 minutes; Flow rate: 0.5 mL / min; ESI-MS (+) Observed value m / z = 1171.75 (M + 2H) ２＋ 【0222】 Reference Example 1: Synthesis of Fmoc-W6H(Boc)1Ph4COO(tBu)-OH 【0223】 To a DMSO solution (700 mL) of 1H-indole-6-ol (35.0 g, 263 mmol, CAS: 2380-86-1), tert-butyl 4-iodobenzoate (88 g, 289 mmol, CAS: 120363-13-5), copper(I) bromide (1.9 g, 13.1 mmol, CAS: 7787-70-4), potassium carbonate (109 g, 789 mmol, CAS: 534-17-8), and α-D-galacturonic acid hydrate (5.6 g, 26.3 mmol, CAS: 91510-62-2) were added at room temperature, and the mixture was stirred overnight at 100°C. The mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was mixed and washed with saturated ammonium chloride aqueous solution and saturated brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. 【0224】 The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20). A portion of the obtained product (13.7 g, 44.3 mmol) was dissolved in acetonitrile (140 mL), then DMAP (0.54 g, 4.43 mmol) and Boc₂O (9.7 g, 44.3 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The mixed organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. 【0225】The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 83 / 17). A portion of the obtained mixture (16.2 g, 39.6 mmol) was dissolved in DMF (160 mL), and N-iodosuccinimide (9.8 g, 43.5 mmol, CAS: 516-12-1) was added under ice cooling and stirred for 2 hours. The mixture was quenched with saturated sodium bicarbonate solution under ice cooling and diluted with water. The obtained mixture was extracted with ethyl acetate. The mixed organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain tert-butyl 4-(6-((tert-butylcarbonyl)oxy)-3-iodoindole-1-yl-benzoate. 【0226】 At room temperature, zinc (7.0 g, 106 mmol, CAS: 7440-66-6) was suspended in DMF (400 mL), iodine (2.7 g, 10.6 mmol, CAS: 7790-99-0) was added, and the mixture was stirred at room temperature for 20 minutes. Methyl(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (19 g, 42.6 mmol, CAS: 156017-42-4) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. 【0227】 The resulting mixture contains tert-butyl 4-(6-((tert-butylcarbonyl)oxy)-3-iodoindole-1-yl-benzoate (19 g, 36 mmol), Pd ２ (dba) ３ CHCl ３ (1.82 g, 1.8 mmol, CAS: 52522-40-4) and SPhos (2.91 g, 7.1 mmol, CAS: 657408-07-6) were added at room temperature, and the mixture was stirred at 50°C for 3 hours. The reaction mixture was allowed to return to room temperature, and the reaction was quenched with water. The mixture was filtered, and the solid was washed with ethyl acetate. 【0228】The resulting filtrates were mixed and extracted with ethyl acetate. The mixed organic layers were washed with saturated brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 67 / 33). 【0229】 A mixture of a portion of the obtained product and that from another lot (40 g, 55 mmol) was dissolved in isopropanol (900 mL), and an aqueous solution of calcium chloride (96.9 g, 873 mmol, CAS: 10043-52-4) (240 mL) was added under ice cooling. Then, an aqueous solution of lithium hydroxide (5.24 g, 218 mmol, CAS: 1310-65-2) (60 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred overnight at room temperature. An aqueous solution of sodium dihydrogen phosphate was added to adjust the pH to 4. The reaction mixture was extracted with ethyl acetate, and the mixed organic layer was washed with saturated brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by reverse-phase silica gel column chromatography (C18, gradient: 10 nM ammonium bicarbonate H18 over 40 minutes). ２ O / acetonitrile = 95 / 5 - 0 / 100). The indicated substance was obtained. 【0230】 ESI-MS(+) Observed value m / z = 741.4 (M + Na) ＋ 【0231】 Reference Example 2: Synthesis of Fmoc-dcaaa-OtBu 【0232】 To a THF solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-D-cysteine ​​(14.0 g, 40.8 mmol, CAS: 157355-80-1), an aqueous solution of sodium bicarbonate (6.9 g, 82.0 mmol) (102 mL) and allyl 2-chloroacetate (5.2 mL, 44.9 mmol, CAS: 2916-14-5) were added under ice cooling, and the mixture was stirred at 25°C for 4 hours. 1 M hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted twice with ethyl acetate. The mixed organic layer was washed with saturated saline solution, filtered, and concentrated under reduced pressure. 【0233】The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 90 / 10-20 / 80). A portion of the obtained product (9.0 g, 20.4 mmol) was added to a 102 mL solution of dichloromethane under ice cooling with 20.4 g, 102 mmol, CAS: 71432-55-8, and the mixture was stirred at 40°C for 6 hours. The resulting solid was filtered off and washed with ethyl acetate. The filtrate was washed twice with saturated sodium bicarbonate solution, dried over magnesium sulfate, and then concentrated. 【0234】 The resulting residue was purified by column chromatography (hexane / ethyl acetate = 80 / 20-30 / 70). A portion of the obtained product (4.4 g, 8.8 mmol) was added to a 44 mL solution of dichloromethane under ice cooling, and phenylsilane (2.2 mL, 17.7 mmol) and Pd(PPh3)4 (2.0 g, 1.8 mmol) were added, and the mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure and then purified by silica gel column chromatography (heptane / ethyl acetate = 90 / 10-40 / 60). The indicated substance was obtained. 【0235】 ESI-MS(+) Observed value m / z = 402.0 (M - C4H8 + H) ＋ 【0236】 Example 2 In vitro activity evaluation by myostatin signaling reporter gene assay in HepG2 cell line In this example, the in vitro myostatin inhibitory effect of the peptide synthesized in Example 1 was evaluated using a myostatin signaling reporter gene assay in HepG2 cell line. 【0237】 Evaluation Method: HepG2 cell line (HB-8065, ATCC) cultured in EMEM (055-08975, Wako Industries) containing 10% FBS (10270106, Gibco) and gentamicin 50 μg / mL (11980-14, Nacalai Tesque) was placed in a 96-well plate (167008, Thermo) in a 2.0 x 10⁶ format. ４ Seed cells / wells, CO ２ Incubator (37°C, 5% CO2) ２The cells were cultured for 24 hours. To this, a pGL3 vector (E1751, Promega), which incorporates the luciferase gene downstream of a promoter sequence consisting of 12 linked CAGA repeats, was added: pGL3(CAGA) １２ -The luc plasmid was added at a concentration of 0.04 μg / well along with the transfection reagent (X-treamGENE9 DNA Transfection Reagent, 6365809001, Roche). The cell line was then subjected to CO2 transfer. ２ Incubator (37°C, 5% CO2) ２ The cells were cultured for 24 hours in ) and transfection was performed. The medium was discarded and replaced with 50 μL / well of EMEM containing 0.1% bovine serum albumin (A7030, Sigma) and gentamicin 50 μg / mL, and CO2 was used. ２ Incubator (37°C, 5% CO2) ２ They were cultured for 2 hours. 【0238】 Myostatin (788-G8 / C, R&D systems) or GDF-11 (1958-GD-G8 / CF, R&D systems) was added to achieve a final concentration of 1.5 ng / mL in both cases. 【0239】 The various peptides synthesized in Example 1 were added in a 4-fold serial dilution series to concentrations of 0.006–100 nmol / L (myostatin inhibition) and 0.12–2000 nmol / L (GDF-11 inhibition). Blank wells were also prepared in which none of the myostatin, GDF-11, or peptides were added, and CO2 was added for 20–24 hours. ２ Incubator (37°C, 5% CO2) ２ It was cultured in ). 【0240】 The cell culture medium was removed, and a 1:1 mixture of PBS (14190144, Thermo) and the chromogenic substrate One-Glo Luciferase Assay System (E6120, Promega) was added to each well at a rate of 100 μL / well. This mixture was stirred in a plate shaker for 5 minutes and then transferred to a 384-well plate (3570, Corning) at a rate of 20 μL / well. 【0241】The samples were centrifuged at 1,000 x g for 1 minute, and the luminescence signal (700 nm luminescence) was measured using a plate reader (Envision 2104, PerkinElmer). Based on the measured values, the IC50 values ​​of the peptides were calculated using software (Prism 9, GraphPad). The results are shown in Table 3 below. In Table 3, "@" indicates amino acid residues that form cyclic or cross-linked structures. For example, in the case of SEQ ID NO: 1, as shown in Example 1-1, the chloroacetylated first E and the 15th Cys bond to form a cyclic structure, and further, the side chain end of the first E and the side chain end of the 11th MeF4am bond to form a cross-linked structure. In the case of SEQ ID NO: 2, the amino group of the first unchloroacetylated A and the carboxyl group of the 16th MeA bond to form a cyclic structure. Furthermore, Sequence ID No. 4 shows that the amino group of the first CeG and the carboxyl group of the 16th MeA bond to form a cyclic structure, and that the side chain end of the first CeG and the side chain end of the 13th MeDap bond to form a cross-linked structure. 【0242】 These results demonstrate that each peptide synthesized in Example 1 possesses myostatin inhibitory activity. 【0243】 Example 3 Effect of Oral Administration of Myostatin Inhibitory Peptide on Lean Body Weight in Diet-Induced Obese Mice When Combined with GLP-1 Receptor Agonist The effect of oral administration of myostatin inhibitory peptide on the reduction of lean body weight induced by GLP-1 receptor agonists in C57BL6 / J mice (18 weeks old, male) that were obese by being fed a high-fat diet was evaluated. Semaglutide (0.12 mg / kg, BACHEM) was administered subcutaneously once daily as a GLP-1 receptor agonist, and simultaneously, the peptide Myostatin_99_v424 (SEQ ID NO: 1), synthesized in Example 1, was orally administered once daily (0.5, 1.5, 4.5 mg / kg) or once weekly (3, 10, 30 mg / kg) for 4 weeks at three different doses, either as a solvent or as a myostatin inhibitory peptide, and body composition (lean body weight) and body weight were measured. Furthermore, 100 mM EDTA / DPBS was used as the solvent for the peptide. 【0244】The differences between groups for each item were analyzed using Dunnett's multiple comparison test (GraphPad, Prism) after one-way ANOVA. Data are presented as mean ± standard error. A p-value less than 0.05 was considered statistically significant. Figure 1 shows the change in lean body mass (LBM) with once-daily administration, Figure 2 shows the change in LBM with once-weekly administration, Figure 3 shows the change in body weight with once-daily administration, and Figure 4 shows the change in body weight with once-weekly administration. Peptide No. 1 in the figures refers to Myostatin_99_v424 (Sequence ID 1). 【0245】 Results and data analysis regarding body composition and weight: In the semaglutide monotherapy group, lean body weight decreased, whereas in the myostatin inhibitor peptide therapy group, a dose-dependent increase was observed in both once-daily and once-weekly administration methods, with significant differences observed in the highest dose groups of 4.5 mg / kg and 30 mg / kg, respectively (Figures 1 and 2). Regarding body weight, there was no change in the once-daily administration group, but a dose-dependent increase was observed in the once-weekly administration group with myostatin inhibitor peptide administration, with significant differences observed in the 10 mg / kg and 30 mg / kg dose groups (Figures 3 and 4). 【0246】Example 4 Effect of Oral Administration of Various Myostatin Inhibitory Peptides on Lean Body Weight in Diet-Induced Obese Mice When Used in Combination with GLP-1 Receptor Agonists The effect of oral administration of myostatin inhibitory peptides on the reduction of lean body weight caused by GLP-1 receptor agonists was evaluated in C57BL6 / J mice (18 weeks old, male) that were obese by being fed a high-fat diet. Semaglutide (0.12 mg / kg, BACHEM) was administered subcutaneously once daily as a GLP-1 receptor agonist. Simultaneously, four myostatin inhibitor peptides (Myostatin_99_v424 (Peptide No. 1; SEQ ID NO: 1), Myostatin_99_v483 (Peptide No. 2; SEQ ID NO: 2), Myostatin_99_v488 (Peptide No. 3; SEQ ID NO: 3), or Myostatin_99_v489 (Peptide No. 4; SEQ ID NO: 4), either in solvent or synthesized in Example 1, were orally administered once weekly (30 mg / kg) for 4 weeks. Body composition (lean body weight) was then measured. The solvent for the peptides was 100 mM. EDTA / DPBS was used. Differences between groups for each item were analyzed using Dunnett's multiple comparison test (GraphPad, Prism) after one-way ANOVA. Data are presented as mean ± standard error. A p-value less than 0.05 was considered statistically significant. 【0247】 Regarding body composition, semaglutide significantly decreased lean body mass, while in the myostatin inhibitor peptide administration group, all peptides showed a similar degree of increase (Figure 5). 【0248】Example 5 Effects of Oral Administration of Myostatin Inhibitory Peptide on Body Weight, Lean Body Weight, and Fat Mass in Diet-Induced Obese Mice When Combined with GLP-1 Receptor Agonist or Myostatin Peptide Alone The effects of oral administration of GLP-1 receptor agonist or myostatin peptide alone on body weight, lean body weight, and fat mass were evaluated in C57BL6 / J mice (18 weeks old, male) that were obese by being fed a high-fat diet. Semaglutide (0.12 mg / kg, BACHEM) or a solvent was administered subcutaneously once daily as a GLP-1 receptor agonist, and simultaneously, the peptide Myostatin_99_v483 (SEQ ID NO: 2) or Myostatin_99_v488 (SEQ ID NO: 3), synthesized in Example 1, was orally administered once at two different doses (3 and 30 mg / kg) for 4 weeks, and the percentage change in body weight, lean body weight, and fat mass was measured. 100 mM EDTA / DPBS was used as the solvent for the peptide and semaglutide. The percentage change in fat mass and body weight were expressed as a percentage change, with the fat mass or body weight one day before the start of semaglutide and / or myostatin inhibitor peptide administration set to 0. 【0249】 The analysis was performed in the same manner as in Example 4. Figure 6 shows the change in lean body mass (LBM), Figure 7 shows the rate of change in fat mass, and Figure 8 shows the change in body weight and its rate of change. The rate of change in fat mass in the Myostatin_99_v488 (30 mg / kg / week) group was significantly lower (Student t-test, significance level p < 0.05) compared to the semaglutide (0.12 mg / kg / day) group. 【0250】 Results and data analysis regarding lean body mass: Lean body mass decreased in the semaglutide monotherapy group, while a dose-dependent increase was observed in the myostatin inhibitor peptide group (Figure 6). Furthermore, even in the myostatin inhibitor peptide monotherapy group (non-semaglutide group), an increase in lean body mass was observed with the administration of the myostatin inhibitor peptide. 【0251】Results and data analysis regarding the rate of change in fat mass showed that fat mass decreased in the semaglutide monotherapy group. Furthermore, a similar decrease in fat mass was observed in the myostatin inhibitor peptide administration group (Figure 7). In particular, a significant difference was observed in the Myostatin_99_v488 (30 mg / kg) administration group compared to the semaglutide monotherapy group. This indicates that myostatin inhibitor peptides do not inhibit the fat-reducing effect of semaglutide, regardless of the dose, and furthermore, the fat-reducing effect of semaglutide is enhanced by the administration of myostatin inhibitor peptides. 【0252】 Results and data analysis regarding body weight and rate of weight change: Weight loss was observed in the semaglutide monotherapy group and the semaglutide / myostatin inhibitor peptide group, whereas no weight loss was observed in the myostatin inhibitor peptide monotherapy group (Figure 8). 【0253】 The present invention provides a method for improving the decrease in LBM (Lean Body Mass) caused by the administration of a pharmaceutical product containing a compound having anti-obesity effects, by administering a peptide having myostatin inhibitory activity, and a pharmaceutical product for the same purpose. In particular, the pharmaceutical product of the present invention is useful as a preventive and / or therapeutic agent for LBM reduction caused by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist.

Claims

1. A combination pharmaceutical comprising (1) a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist; and (2) a peptide having myostatin inhibitory activity, wherein the peptide suppresses the reduction in lean body mass caused by the agonist.

2. The combination pharmaceutical according to claim 1, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, and dulaglutide.

3. The peptide having myostatin inhibitory activity has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and The combination pharmaceutical according to claim 1 or 2, comprising a peptide containing an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4).

4. The combination pharmaceutical product according to any one of claims 1 to 3, wherein the agonist and / or the peptide having myostatin inhibitory activity is administered orally.

5. The combination pharmaceutical according to any one of claims 1 to 3, wherein the peptide having myostatin inhibitory activity is administered orally.

6. A pharmaceutical product comprising a peptide having myostatin inhibitory activity, used in conjunction with a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist, wherein the peptide suppresses the reduction of lean body mass caused by the agonist.

7. The pharmaceutical product according to claim 6, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, and dulaglutide.

8. The peptide having myostatin inhibitory activity has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and The pharmaceutical product according to claim 6 or 7, which is a peptide comprising an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4).

9. The pharmaceutical product according to any one of claims 6-8, wherein the agonist and / or the peptide having myostatin inhibitory activity is administered orally.

10. The pharmaceutical product according to any one of claims 6-8, wherein the peptide having myostatin inhibitory activity is administered orally.

11. A pharmaceutical product comprising a peptide having myostatin inhibitory activity, for suppressing the reduction of lean body mass caused by a GLP-1 receptor agonist or a GIP / GLP-1 receptor agonist.

12. The pharmaceutical product according to claim 11, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, and dulaglutide.

13. The peptide having myostatin inhibitory activity has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and The pharmaceutical product according to claim 11 or 12, comprising a peptide containing an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4).

14. The pharmaceutical product according to any one of claims 11-13, wherein the agonist and / or the peptide having myostatin inhibitory activity is administered orally.

15. The pharmaceutical product according to any one of claims 11-13, wherein the peptide having myostatin inhibitory activity is administered orally.

16. Use of a peptide having myostatin inhibitory activity for the manufacture of a pharmaceutical product for suppressing the reduction of lean body mass caused by a pharmaceutical product containing an obesity-causing compound.

17. The use according to claim 16, wherein the pharmaceutical product containing the compound having the obesity effect is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, and dulaglutide.

18. The peptide having myostatin inhibitory activity has the following amino acid sequences: E-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF4am-Ano-MeA-MeF-dc (SEQ ID NO: 1); A-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-da-MeA (SEQ ID NO: 2); CrpG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeA-MeF-dc-Pip4mAc (SEQ ID NO: 3); and The use according to claim 16 or 17, wherein the peptide comprises an amino acid sequence selected from the group consisting of CeG-A-W6H1Ph4COO-Y-MeF-I-dp-F3aao-F4COO-R-MeF-Ano-MeDap-MeF-da-MeA (SEQ ID NO: 4).

19. The use according to any one of claims 16-18, wherein the pharmaceutical product containing the compound having the obesity effect and / or the peptide having myostatin inhibitory activity is administered orally.

20. The use according to any one of claims 16-18, wherein the peptide having myostatin inhibitory activity is administered orally.

21. A method for suppressing the reduction of lean body mass caused by an agonist by a peptide, comprising administering a peptide having myostatin inhibitory activity to a subject receiving a pharmaceutical product containing a compound having an obesity-causing effect.

22. A combination pharmaceutical comprising (1) a compound having an anti-obesity effect; and (2) a peptide having myostatin inhibitory activity, wherein the peptide suppresses the reduction of lean body mass caused by the agonist.

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