GLP-1 / GCG / GIP triple receptor agonist and its use

Abstract

The present invention relates to a triple receptor agonist. The agonist comprises a polypeptide represented by formula (I), X1X2X3GTX6TSDYSIX 13 X 14 DX 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LX 27 X 28 GGPSSGAPPPS (I), X1 is Y or H; X2 is Aib; X3 is Q or H; X6 is an unnatural amino acid; X 13 L or Y; X 14 L or K; X 16 E, K or R; X 17 K, R or I; X 18 A, R or K; X 19 Q or A; X 20 R, K, Q, H or Aib; X 21 D, A or E; X 23 I or V; X 24 E or Q; X 25 W or Y; X 27 I or L; X 28 is E or A. This agonist has strong agonist activity on the three receptors of GLP-1, GCG and GIP, and can be used to treat diseases related to metabolic disorders.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology. Specifically, the present invention relates to a GLP-1 / GCG / GIP triple receptor agonist and its use. More specifically, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition and its use. Background Art

[0002] Diabetes is a metabolic disease closely related to obesity and non-alcoholic steatohepatitis (NASH), and its prevalence and incidence continue to increase worldwide. Although glucagon-like peptide-1 (GLP-1) receptor agonists such as dulaglutide and semaglutide are currently approved for the treatment of type 2 diabetes mellitus (T2DM), metabolic diseases are characterized by complications and heterogeneity, especially type 2 diabetes accompanied by multiple complications such as obesity, and the efficacy of single-target treatment options is limited. Acting on multiple targets can improve the effectiveness of treating such diseases. However, combined administration based on multi-drug combinations, such as compound preparations, will complicate drug development and clinical research, but the development of single-molecule multi-target drugs can effectively avoid such problems.

[0003] Based on the effectiveness and safety of GLP-1 receptor agonists, the current research and development strategy is to develop them into single-molecule, multi-target drugs in combination with other intestinal hormones such as glucagon (GCG) and glucose-dependent incretin (GIP). These drugs act simultaneously on multiple targets, balancing the side effects and shortcomings of different targets while maintaining stable pharmacokinetic characteristics, ultimately resulting in therapeutic effects superior to those achieved with a single target. Summary of the Invention

[0004] The present invention aims to at least partially address one of the technical problems existing in the prior art. To this end, the present invention provides a GLP-1 / GCG / GIP triple receptor agonist that exhibits strong agonist activity at all three receptors: GLP-1, GCG, and GIP.

[0005] The present invention is accomplished based on the following findings of the inventors:

[0006] Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted by intestinal L-cells after a meal. It stimulates pancreatic beta cells to secrete insulin, thereby stabilizing postprandial blood sugar fluctuations. Its blood sugar-lowering effect is glucose concentration-dependent, significantly reducing the risk of hypoglycemia while regulating blood sugar. In recent years, GLP-1-based drugs, such as liraglutide, dulaglutide, and semaglutide, have gradually occupied a very important position in diabetes medications. GLP-1 drugs have the effect of reducing blood sugar and weight loss. The mechanism is that GLP-1 acts on the gastrointestinal tract to delay gastric emptying and intestinal motility, and on the central nervous system to suppress appetite, thereby reducing food intake. However, when used for weight loss, GLP-1 receptor agonists generally require large doses, are prone to gastrointestinal side effects, and have poor tolerability.

[0007] Glucagon (GCG) is a polypeptide hormone secreted by pancreatic α-cells that promotes glycogenolysis and gluconeogenesis, significantly increasing blood sugar. It also activates lipase, promoting fat breakdown, enhancing fatty acid oxidation, and increasing energy expenditure, resulting in fat and weight loss. While its glucose-raising properties make it useful for treating hypoglycemia, this limits its application in obesity weight loss, particularly in obese individuals with type 2 diabetes.

[0008] Glucose-dependent incretin (GIP) is a polypeptide hormone secreted by intestinal K cells. Both GIP and GLP-1 are incretins, both promoting insulin secretion and lowering blood glucose in a glucose-dependent manner, with GIP's blood glucose-lowering effect being stronger than that of GLP-1. However, diabetic patients exhibit insensitivity to GIP, likely due to receptor tolerance caused by hyperglycemia. Consequently, the use of GIP receptor agonists alone in diabetic patients has not achieved the goal of improving blood glucose.

[0009] Studies have found that the causes of metabolic disorder-related diseases (such as diabetes, obesity, and NASH) are complex, and the efficacy of single-target drugs is relatively limited.

[0010] Based on this, in one aspect of the present invention, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof. According to an embodiment of the present invention, the compound represented by formula (I) is X1X2X3GTX6TSDYSIX13X 14 DX 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LX 27 X 28GGPSSGAPPPS (I), wherein X1 is Y or H; X2 is Aib; X3 is Q or H; X6 is an unnatural amino acid; X 13 L or Y; X 14 L or K; X 16 E, K or R; X 17 K, R or I; X 18 A, R or K; X 19 Q or A; X 20 R, K, Q, H or Aib; X 21 D, A or E; X 23 I or V; X 24 E or Q; X 25 W or Y; X 27 I or L; X 28 is E or A; where X 16 When K, X 14 The above-mentioned compound of the present invention or its pharmaceutically acceptable salt or solvate exhibits strong agonist activity on the three receptor targets of GLP-1, GCG and GIP, can effectively control blood sugar and reduce body weight, and can be used to prevent or treat diseases related to metabolic disorders, especially obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.

[0011] In another aspect, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the aforementioned compound or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition of the present invention can effectively prevent or treat diseases related to metabolic disorders, particularly obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome, and non-alcoholic fatty liver disease.

[0012] In another aspect of the present invention, the present invention provides a use of the aforementioned compound or its pharmaceutically acceptable salt or solvate or the aforementioned pharmaceutical composition in the preparation of a medicament for treating or preventing diseases related to metabolic disorders.

[0013] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments with reference to the following drawings, in which:

[0015] Figure 1 The blood glucose and AUC of each group in Example 4 of the present invention are 0～90min The test results;

[0016] Figure 2 The blood glucose and AUC of each group in Example 5 of the present invention are 0～90min The test results;

[0017] Figure 3 The blood glucose test results of each group in Example 6 of the present invention are shown below:

[0018] Figure 4 The test results of glycated hemoglobin for each group in Example 6 of the present invention are as follows;

[0019] Figure 5 The results of the weight change rates of the groups in Example 7 of the present invention are shown below:

[0020] Figure 6 This is the test result of the cumulative food intake of each group in Example 7 of the present invention. DETAILED DESCRIPTION

[0021] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0022] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0023] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0024] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0025] As used herein, the term "solvate" refers to a complex of defined stoichiometry formed between a solute (here, a compound according to the present invention or a pharmaceutically acceptable salt thereof) and a solvent. The solvent may be water, ethanol, or other pharmaceutically acceptable small organic molecule representative thereof, including, but not limited to, acetic acid or lactic acid. When the solvent is water, such a solvate is generally referred to as a hydrate.

[0026] In this document, amino acids are referred to using the conventional single-letter and three-letter codes for natural amino acids, as well as the commonly accepted three-letter codes for other α-amino acids, for example, α-aminoisobutyric acid can be represented by both codes Aib and B. Unless otherwise specified, all amino acid residues in the present invention are preferably in the L-configuration.

[0027] Among them, the structural formula of Aib or B is

[0028] In this document, the terms "(L)-α-Me-(2-F)-Phe" and "αMeF(2F)" refer to α-methyl 2-fluorophenylalanine, the structural formula of which is

[0029]

[0030] In this article, the sequence structure "-NH2" refers to the amidation of -COOH on the C-terminus of the amino acid to -CONH2, for example, in Y-Aib-QGTX6TSDYSIL-K ({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-C 18 -CO2H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH2 "-NH2" indicates that the free carboxyl group -COOH in the C-terminal serine S is amidated to -CONH2.

[0031] As used herein, the term "OEG" refers to {[2-(2-amino-ethoxy)-ethoxy]-acetyl, the structural formula of which is shown below:

[0032]

[0033] As used herein, the term "agonist" refers to a substance (ligand) that activates the receptor type in question.

[0034] As used herein, the term "treatment" refers to any process used to obtain a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in individuals who are susceptible to the disease but have not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a drug or compound to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering a drug containing a compound described herein to an individual in need.

[0035] In this article, the term "non-alcoholic fatty liver disease (NAFLD)" generally refers to a clinical pathological syndrome characterized by excessive fat deposition in hepatocytes, excluding alcohol and other clear liver-damaging factors. It is an acquired metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, including but not limited to simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH) and its related cirrhosis.

[0036] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition and uses thereof, which are described in detail below.

[0037] A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof

[0038] In one aspect of the present invention, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof. According to an embodiment of the present invention, the compound represented by formula (I) is X1X2X3GTX6TSDYSIX 13 X 14 DX16X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LX 27 X 28 GGPSSGAPPPS (I), wherein X1 is Y or H; X2 is Aib; X3 is Q or H; X6 is an unnatural amino acid; X 13 L or Y; X 14 L or K; X 16 E, K or R; X 17 K, R or I; X 18 A, R or K; X 19 Q or A; X 20 R, K, Q, H or Aib; X 21 D, A or E; X 23 I or V; X 24 E or Q; X 25 W or Y; X 27 I or L; X 28 is E or A; where X 16 When K, X 14The compound of the present invention, or its pharmaceutically acceptable salt or solvate (or agonist), exhibits strong agonist activity against the three receptor targets of GLP-1, GCG, and GIP. By optimizing the activity of each receptor, it can avoid the side effects caused by excessive activity of one or more receptors, resulting in good activity of each receptor, effective blood sugar control, and weight loss. Furthermore, it has strong in vivo stability, which can prolong the duration of drug action and achieve a once-weekly dosing frequency. Therefore, the agonist can be used to prevent or treat diseases related to metabolic disorders, especially obesity, diabetes, diseases related to dyslipidemia, fatty liver disease, metabolic syndrome, and non-alcoholic fatty liver disease.

[0039] According to an embodiment of the present invention, X1 is Y; X2 is Aib; X3 is Q or H; X6 is αMeF(2F); 13 L; X 14 L or K; X 16 E or K; X 17 K or I; X 18 A or R; X 19 Q; X 20 R, Q or Aib; X 21 A or E; X 23 I; X 24 E; X 25 W or Y; X 27 L; X 28 is E or A; where X 16 When K, X 14 is K. Thus, the agonist activity on the three receptor targets of GLP-1, GCG and GIP can be further enhanced.

[0040] According to an embodiment of the present invention, the compound represented by formula (I) has at least one of the following structures:

[0041] Y-Aib-QGTX6TSDYSILLDEKAQRDFIEWLLEGPGPSSGAPPPS;

[0042] Y-Aib-HGTX6TSDYSILLDEKAQRDFIEWLLAGPGPSSGAPPPS;

[0043] Y-Aib-HGTX6TSDYSILLDEIAQKDFIEWLLEGPSSGAPPPS;

[0044] H-Aib-QGTX6TSDYSILLDEIAQKDFIEWLLEGPGPSSGAPPPS;

[0045] Y-Aib-QGTX6TSDYSILLDEKAQQAFIEYLLEGGPSSGAPPPS;

[0046] Y-Aib-QGTX6TSDYSILLDEKAQQDFIEWLIAGGPSSGAPPPS;

[0047] Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLLEGGPSSGAPPPS;

[0048] Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLIAGGPSSGAPPPS;

[0049] Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLAGGPSSGAPPPS;

[0050] Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS;

[0051] Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLEGGPSSGAPPPS;

[0052] Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLAGGPSSGAPPPS;

[0053] Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLEGGPSSGAPPPS;

[0054] Y-Aib-HGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS;

[0055] Y-Aib-HGTX6TSDYSILLDEKAQQAFIEYLLAGGPSSGAPPPS;

[0056] Y-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS;

[0057] Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLEGGPSSGAPPPS;

[0058] Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLEGGPSSGAPPPS;

[0059] Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLEGGPSSGAPPPS;

[0060] Y-Aib-QGTX6TSDYSILLDEKRARAFIEYLLAGGPSSGAPPPS;

[0061] Y-Aib-HGTX6TSDYSILLDEKRAREFIEWLLEGGPSSGAPPPS;

[0062] Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS;

[0063] Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLIAGGPSSGAPPPS;

[0064] Y-Aib-QGTX6TSDYSILLDEKAQQAFVQWLIAGGPSSGAPPPS;

[0065] Y-Aib-QGTX6TSDYSILLDEKRAQAFIEYLLEGGPSSGAPPPS;

[0066] Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS;

[0067] Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLLAGGPSSGAPPPS;

[0068] Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLIAGGPSSGAPPPS;

[0069] Y-Aib-QGTX6TSDYSILLDEIAQKAFVQWLIAGGPSSGAPPPS;

[0070] Y-Aib-HGTX6TSDYSILLDEKAQ-Aib-EFIEWLLAGGPSSGAPPPS;

[0071] Y-Aib-QGTX6TSDYSILLDEKAQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0072] Y-Aib-HGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS;

[0073] Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS;

[0074] Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0075] Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLEGGPSSGAPPPS;

[0076] Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLEGGPSSGAPPPS;

[0077] Y-Aib-HGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS;

[0078] Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS;

[0079] Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS;

[0080] Y-Aib-HGTX6TSDYSILLDEKRQKAFIEYLLAGGPSSGAPPPS;

[0081] Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLAGGPSSGAPPPS;

[0082] Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS;

[0083] Y-Aib-QGTX6TSDYSILLDRIRQKEFIEWLLAGGPSSGAPPPS;

[0084] Y-Aib-QGTX6TSDYSILLDRIRQKAFIEYLLEGGPSSGAPPPS;

[0085] Y-Aib-QGTX6TSDYSILLDRKRQQEFIEWLLAGGPSSGAPPPS;

[0086] Y-Aib-QGTX6TSDYSILLDRKRQQAFIEYLLAGGPSSGAPPPS;

[0087] Y-Aib-QGTX6TSDYSILLDEKKQ-Aib-EFIEWLLAGGPSSGAPPPS;

[0088] Y-Aib-QGTX6TSDYSILLDEKKQKAFIEYLLAGGPSSGAPPPS;

[0089] H-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS;

[0090] Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS;

[0091] Y-Aib-QGTX6TSDYSILLDEKRQRAFVEYLLAGGPSSGAPPPS;

[0092] Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLAGGPSSGAPPPS;

[0093] Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLEGGPSSGAPPPS;

[0094] Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0095] Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLAGGPSSGAPPPS;

[0096] Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLEGGPSSGAPPPS;

[0097] Y-Aib-QGTX6TSDYSILKDRIAQRAFIEYLLEGGPSSGAPPPS;

[0098] Y-Aib-QGTX6TSDYSILKDKIRQQAFIEYLLEGGPSSGAPPPS;

[0099] Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLEGGPSSGAPPPS;

[0100] Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0101] Y-Aib-QGTX6TSDYSILKDRIRQQAFIEYLLEGPGPSSGAPPPS;

[0102] Y-Aib-QGTX6TSDYSILKDRIRQQAFIEYLLAGGPSSGAPPPS;

[0103] Y-Aib-QGTX6TSDYSILKDRRAQQAFVEYLLAGGPSSGAPPPS;

[0104] Y-Aib-QGTX6TSDYSILKDRRAQQAFVEYLLEGGPSSGAPPPS;

[0105] H-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS;

[0106] H-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLAGGPSSGAPPPS;

[0107] H-Aib-HGTX6TSDYSILLDRKAQHAFIEYLLEGPGPSSGAPPPS;

[0108] H-Aib-HGTX6TSDYSILLDRKAQQAFIEYLLAGGPSSGAPPPS;

[0109] H-Aib-HGTX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;

[0110] H-Aib-QGTX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;

[0111] H-Aib-QGTX6TSDYSILLDRKAQHEFIEWLLEGPGPSSGAPPPS;

[0112] Wherein, X6 is αMeF(2F).

[0113] It should be noted that the "-" between amino acids in the polypeptide of the above compound represents an amide bond. For example, the "-" in "H-Aib-Q" represents an amide bond.

[0114] According to an embodiment of the present invention, the compound represented by formula (I) or its pharmaceutically acceptable salt or solvate further comprises a modifying group, wherein the modifying group is 14 、X 17 and X 20 At least one of the amino acids is connected.

[0115] According to an embodiment of the present invention, X 14 、X 17 and X 20 At least one of them is K, and the modifying group and X 14 、X 17 and X 20 The ε-amino group of at least one of the K side chains is connected via an amide bond.

[0116] According to an embodiment of the present invention, X 14 and / or X 17 is K, the modifying group and X 14 and / or X 17 The ε-amino group of the K side chain is connected via an amide bond.

[0117] According to an embodiment of the present invention, the modifying group has the following structure: {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -CO2H, wherein a is any integer from 1 to 3, b is any integer from 1 to 3, and c is any integer from 14 to 20.

[0118] In some alternative embodiments of the present invention, a is 1. In some alternative embodiments of the present invention, a is 2. In some alternative embodiments of the present invention, a is 3.

[0119] In some optional embodiments of the present invention, b is 1. In some optional embodiments of the present invention, b is 2. In some optional embodiments of the present invention, b is 3.

[0120] In some optional embodiments of the present invention, c is any integer from 14 to 20. For example, c is 14, 15, 16, 17, 18, 19 and 20 or a range value with two values ​​therebetween as endpoint values, such as 14 to 18, 16 to 18 or 16 to 20.

[0121] It should be noted that the “-” in the above-mentioned modifying groups represents a chemical bond connecting chemical groups; for example, “[2-(2-amino-ethoxy)-ethoxy]-acetyl” is synonymous with “OEG”; the “-” in “CO-CH2” represents a chemical bond connecting chemical groups; a, b and c represent the number of different groups; “Glu” and “E” are synonymous, both referring to glutamic acid; and “CO2H” refers to the COOH group.

[0122] According to an embodiment of the present invention, the modifying group has at least one of the following structures:

[0123]

[0124] According to an embodiment of the present invention, the C-terminus of the amino acid S at position 39 of the compound represented by formula (I) is amidated.

[0125] It should be noted that amidation means that the -OH in the -COOH of serine S in the compound represented by formula (I) is replaced by an amino group -NH2, that is, the -COOH of serine S in the compound represented by formula (I) is amidated to -CONH2.

[0126] According to an embodiment of the present invention, the compound represented by formula (I) has at least one of the following structures:

[0127] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRDFIEWLLEGPSSGAPPPS;

[0128] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRDFIEWLLAGPGPSSGAPPPS;

[0129] Y-Aib-HGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)DFIEWLLEGGPSSGAPPPS;

[0130] H-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)DFIEWLLEGGPSSGAPPPS;

[0131] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQAFIEYLLEGPGPSSGAPPPS;

[0132] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQDFIEWLIAGGPSSGAPPPS;

[0133] Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)EFIEWLLEGGPSSGAPPPS;

[0134] Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)EFIEWLIAGGPSSGAPPPS;

[0135] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQREFIEWLLAGPGPSSGAPPPS;

[0136] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLAGPGPSSGAPPPS;

[0137] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQREFIEWLLEGPSSGAPPPS;

[0138] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2)16 -CO2H)RQREFIEWLLAGPGPSSGAPPPS;

[0139] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLLEGPGPSSGAPPPS;

[0140] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQQEFIEWLLEGPGPSSGAPPPS;

[0141] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQQEFIEWLLAGPGPSSGAPPPS;

[0142] Y-Aib-HGTX6TSDYSILLDE-K(-{[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQAFIEYLLAGPGPSSGAPPPS;

[0143] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLEGPGPSSGAPPPS;

[0144] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLAGPGPSSGAPPPS;

[0145] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLEGPGPSSGAPPPS;

[0146] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLEGPGPSSGAPPPS;

[0147] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS;

[0148] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQREFIEWLLEGPSSGAPPPS;

[0149] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RARAFIEYLLAGPGPSSGAPPPS;

[0150] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RAREFIEWLLEGPSSGAPPPS;

[0151] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLLAGPGPSSGAPPPS;

[0152] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLIAGGPSSGAPPPS;

[0153] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18-CO2H)AQQAFVQWLIAGGPSSGAPPPS;

[0154] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQQAFIEYLLEGPGPSSGAPPPS;

[0155] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RAQAFIEYLLEGPGPSSGAPPPS;

[0156] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLAGPGPSSGAPPPS;

[0157] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQREFIEWLLAGPGPSSGAPPPS;

[0158] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLEGPGPSSGAPPPS;

[0159] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)AFIEYLLAGGPSSGAPPPS;

[0160] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)AFIEYLIAGGPSSGAPPPS;

[0161] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)AFVQWLIAGGPSSGAPPPS;

[0162] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQ-Aib-EFIEWLLAGPGPSSGAPPPS-NH2;

[0163] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2;

[0164] Y-Aib-HGTX6TSDYSILLDEK({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQ-Aib-EFIEWLLAGPGPSSGAPPPS-NH2;

[0165] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQ-Aib-EFIEWLLAGPGPSSGAPPPS-NH2;

[0166] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2;

[0167] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQQAFIEYLLEGPGPSSGAPPPS-NH2;

[0168] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQ-Aib-AFIEYLLEGPSSGAPPPS-NH2;

[0169] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLEGPGPSSGAPPPS;

[0170] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS;

[0171] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLEGPGPSSGAPPPS;

[0172] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQKAFIEYLLAGPGPSSGAPPPS-NH2;

[0173] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQQAFIEYLLAGGPSSGAPPPS-NH2;

[0174] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLEGPGPSSGAPPPS;

[0175] Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2)16 -CO2H)EFIEWLLAGGPSSGAPPPS;

[0176] Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AFIEYLLEGGPSSGAPPPS;

[0177] Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQQEFIEWLLAGPGPSSGAPPPS;

[0178] Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQQAFIEYLLAGPGPSSGAPPPS;

[0179] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)KQ-Aib-EFIEWLLAGPGPSSGAPPPS-NH2;

[0180] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)KQKAFIEYLLAGPGPSSGAPPPS-NH2;

[0181] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)KQKAFIEYLLAGPGPSSGAPPPS-NH2;

[0182] Y-Aib-QGTX6TSDYSILLDEKKQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AFIEYLLAGPGPSSGAPPPS-NH2;

[0183] H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS;

[0184] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS;

[0185] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFVEYLLAGGPSSGAPPPS;

[0186] Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLAGPGPSSGAPPPS;

[0187] Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLEGPGPSSGAPPPS;

[0188] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2;

[0189] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2;

[0190] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16-CO2H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH2;

[0191] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQKAFIEYLLEGPGPSSGAPPPS-NH2;

[0192] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRIAQRAFIEYLLEGPGPSSGAPPPS;

[0193] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIRQQAFIEYLLEGPGPSSGAPPPS-NH2;

[0194] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIRQ-Aib-AFIEYLLEGPSSGAPPPS-NH2;

[0195] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIRQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2;

[0196] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRIRQQAFIEYLLEGPGPSSGAPPPS;

[0197] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRIRQQAFIEYLLAGGPSSGAPPPS;

[0198] Y-Aib-QGTX6TSDYSIL-K(-{[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRRAQQAFVEYLLAGGPSSGAPPPS;

[0199] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRRAQQAFVEYLLEGPGPSSGAPPPS;

[0200] H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLEGPGPSSGAPPPS;

[0201] H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLAGPGPSSGAPPPS;

[0202] H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQHAFIEYLLEGPGPSSGAPPPS;

[0203] H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQQAFIEYLLAGPGPSSGAPPPS;

[0204] H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQHAFIEYLLAGPGPSSGAPPPS;

[0205] H-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16-CO2H)AQHAFIEYLLAGPGPSSGAPPPS;

[0206] H-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQHEFIEWLLEGPSSGAPPPS;

[0207] Wherein, X6 is αMeF(2F).

[0208] It should be noted that the “-” between amino acids in the polypeptide of the above compound represents an amide bond; for example, the “-” in “H-Aib-Q” represents an amide bond. The “-” in the above modification group represents a chemical bond connecting chemical groups; for example, “{[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-C 18 In "-CO2H", "-" represents the chemical bond between chemical groups.

[0209] Pharmaceutical composition

[0210] In another aspect, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the aforementioned compound or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition of the present invention can effectively prevent or treat diseases related to metabolic disorders, particularly obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome, and non-alcoholic fatty liver disease.

[0211] According to an embodiment of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable excipient.

[0212] use

[0213] In another aspect of the present invention, the present invention provides a use of the aforementioned compound or its pharmaceutically acceptable salt or solvate or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing or treating diseases related to metabolic disorders.

[0214] According to an embodiment of the present invention, the metabolic disorder-related diseases include obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.

[0215] Method for preventing or treating diseases related to metabolic disorders

[0216] In another aspect, the present invention provides a method for preventing or treating metabolic disorder-related diseases. According to an embodiment of the present invention, the method comprises: administering a pharmaceutically acceptable amount of the aforementioned compound, or a pharmaceutically acceptable salt or solvate thereof, or the aforementioned pharmaceutical composition to a subject.

[0217] According to an embodiment of the present invention, the metabolic disorder-related diseases include obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.

[0218] It should be noted that a "pharmaceutically acceptable amount" may vary depending on the mode of administration and the severity of the disease to be treated, and is preferably an effective amount. The selection of a pharmaceutically acceptable amount can be determined by a person of ordinary skill in the art based on various factors (e.g., through clinical trials). Such factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, the route of administration, etc. For example, depending on the urgency of the treatment, several divided doses may be administered daily, or the dose may be reduced proportionally.

[0219] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0220] Example 1: Preparation of polypeptide compound

[0221] 1. Human GLP-1, human GCG, human GIP and various polypeptide compounds (triple receptor agonists) were synthesized according to Table 1 below. The specific polypeptide compound structures are shown in Table 1.

[0222] Table 1 Compound structures of three receptor agonists

[0223]

[0224]

[0225]

[0226] Note: The amino acid code "X" in the sequence column of the above table refers to the unnatural amino acid αMeF(2F) mentioned above.

[0227] The specific steps for preparing a fatty acid side chain modified polypeptide compound are as follows:

[0228] 1) Place the resin in a 150ml reactor and add 50ml of dichloromethane (DCM) to soak for 2 hours. Wash the resin with dimethylformamide (DMF) and then drain it. Repeat this process four times and drain the resin. Weigh the first amino acid (protected) at the Fmoc-C terminus, DCM, and N,N-diisopropylethylamine (DIEA) and add them to the reactor. Then place the reactor on a shaker at 30°C and react for 2 hours. Block with methanol solution (methanol:DIEA:DCM = 1:1:2) for half an hour, then wash four times with DMF and drain it. Add 20% piperidine solution to the reactor to remove the Fmoc protecting group. After deprotection, wash the resin four times with DMF and drain it.

[0229] 2) Weigh the second amino acid at the C-terminus of Fmoc (protected), 1-hydroxybenzotriazole (HOBT), and N,N-diisopropylcarbodiimide (DIC) into a reactor and place the reactor on a shaker at 30°C for 1 hour. Test a small amount of resin using the ninhydrin method. If the resin is colored, condensation is incomplete and the reaction should continue. After the reaction is complete, wash the resin four times with DMF and drain. Add a certain amount of 20% piperidine (piperidine / DMF = 1:4) to the reactor and shake on a decolorizing shaker for 20 minutes to remove the Fmoc protecting group from the resin. After deprotection, wash the resin four times with DMF and drain to check for protection.

[0230] 3) Follow the steps to connect amino acids. Use a specially protected Lys residue (the Lys residue attached to the side chain). Protect the N-terminal amino group with Boc anhydride. Remove the special protecting group from the Lys side chain and connect the side chain structure as in step 2. Remove all protecting groups from the peptide using a cleavage reagent and cleave it from the resin for purification.

[0231] 2. The target peptides were separated from impurities by reversed-phase liquid chromatography (RPLC). The collected target peptides were lyophilized into powder and then analyzed for purity and mass spectrometry. HPLC analysis showed a purity greater than 95%. Mass spectrometry analysis confirmed that the molecular weights of the peptides were consistent with the theoretical molecular weights.

[0232] Example 2: In vitro cell activity assay

[0233] The peptide, human GLP-1, human GCG and human GIP were respectively used to act on HEK293 cells expressing GLP-1R, GCGR and GIPR, and the cAMP produced by the receptor cells was detected using a cAMP detection kit (Cisbio, 62AM6PEC). The dose-effect curve was established and the EC value was calculated. 50 The specific steps are as follows:

[0234] 1) Prepare assay buffer: Prepare complete culture medium (DMEM + 10% FBS) by adding 4 / 1000 of 500 mM IBMX stock solution, cAMP-d2 working solution, and anti-cAMP-crytate working solution according to the cAMP assay kit instructions.

[0235] 2) Dilute the test sample to a 500 nM stock solution with Assay buffer, and dilute the human control peptides GLP-1, GCG, and GIP to a 200 nM stock solution. Then, add 20 μL to 80 μL of Assay buffer (5-fold dilution) in a gradient dilution, for a total of 8 compound gradients including the stock solution;

[0236] 3) Preparation of cell suspension: After removing HEK293-GLP-1R, HEK293-GCGR, and HEK293-GIPR cells from liquid nitrogen, they were immediately placed in a 37°C water bath. After complete thawing within 1.5 minutes, the cells were added dropwise to a 15 mL centrifuge tube containing 8 mL of warm culture medium in a clean bench. Centrifuge at 900 rpm for 5 minutes, discard the supernatant, and resuspend the cells in 1 mL of complete culture medium (by pipetting 15 times). Immediately, 20 μL of the suspension was mixed with an equal volume of trypan blue. 20 μL was taken to count the number of viable cells, and the cells were diluted to 4 × 10 with complete culture medium. 5 cells / mL;

[0237] 4) Divide a 384-well plate into areas for GLP-1R cells, GCGR cells, and GIPR cells. Use a 12-channel adjustable dispenser to add 5 μL of the cell suspension to the wells in the corresponding areas. Then, use a 12-channel adjustable dispenser to add a gradient dilution of the test sample (the polypeptide compound prepared in Example 1) and the positive control (human GLP-1, human GCG, or human GIP prepared in Example 1) to the 384-well plate corresponding to the cells, 5 μL per well (two replicate wells with the same concentration sample). Negative control: 10 μL assay buffer / well. Set up three wells per 384-well plate, cover with white sealing film, and place in a 37°C constant temperature incubator for half an hour.

[0238] 5) Immediately before use, dilute the cAMP-d2 working solution and anti-cAMP-crytate working solution 20-fold with the lysis buffer provided in the kit. Add 5 μL of lysis buffer and 5 μL of diluted anti-cAMP-crytate working solution to each well of the negative control. Then, mix the diluted cAMP-d2 working solution and anti-cAMP-crytate working solution in a 1:1 ratio. Add 10 μL per well to the sample group wells, cover with a white lid, and incubate at room temperature in the dark for 1 hour or at 4°C overnight.

[0239] 6) Detect the fluorescence values ​​at 665 nm and 620 nm in a multifunctional microplate reader. In GraphPad Prism 6, the signal ratio and sample concentration were nonlinearly fitted using a four-parameter equation to obtain the EC 50 The specific results are shown in Table 2.

[0240] Table 2: In vitro activity test results of different receptor cells

[0241]

[0242]

[0243]

[0244] Experimental conclusion: The polypeptide compound of the present invention maintains high agonist activity on GLP-1R, GCGR and GIPR.

[0245] Example 3: Pharmacokinetic Study in Rats

[0246] Pharmacokinetic studies were conducted on the polypeptide compounds prepared in Example 1 using male Sprague Dawley rats. Three male rats were included in each group. The rats had free access to water and were not fasting. A single subcutaneous injection of 50 nmol / kg (specific polypeptide compounds are shown in Table 3) was administered. Plasma was collected at designated days and time points after administration, and the concentrations of the polypeptide compounds in plasma were determined using LC-MS / MS. Pharmacokinetic parameters were derived from the concentration data to describe the pharmacokinetic properties of the polypeptides in rats following subcutaneous injection. The experimental results are shown in Table 3.

[0247] Table 3: Summary of pharmacokinetic parameters of some triple-target peptides in rats

[0248]

[0249] Note: T max : peak time; C max : Peak concentration; AUC last : Area under the drug-time curve at time 0-t; AUC INF : Area under the drug-time curve from 0 to ∞; T 1 / 2 : Elimination half-life.

[0250] Experimental conclusion: Except for PT-61, which is poorly absorbed in rats, other peptides are well absorbed in rats, with higher blood concentrations and longer half-lives.

[0251] LY3298176 in Examples 4 to 6 below is tirzepatide, a new drug for type 2 diabetes mellitus available on the market. The Vehicle group is injected with the corresponding vehicle, that is, the Vehicle group does not contain the polypeptide compound compared to the polypeptide compound drug group.

[0252] It should be noted that the significance levels in the following Examples 4 to 6 are the significance analysis results of each group (LY3298176 group and other polypeptide compound groups) and the Vehicle group respectively.

[0253] Example 4: Glucose tolerance assessment in normal C57BL / 6 mice

[0254] This example evaluates the effects of HEC-PT74, HEC-PT75, HEC-PT77, HEC-PT78, HEC-PT80, and HEC-PT82 on glucose tolerance in normal C57BL / 6 mice.

[0255] Experimental Methods: Normal C57BL / 6 mice were randomly divided into eight groups (Vehicle, LY3298176, HEC-PT74, HEC-PT75, HEC-PT77, HEC-PT78, HEC-PT80, and HEC-PT82) based on blood glucose and body weight, with eight mice in each group. Animals in the LY3298176, HEC-PT74, HEC-PT75, HEC-PT77, HEC-PT78, HEC-PT80, and HEC-PT82 groups received subcutaneous injections of the corresponding drug at a dose of 3 nmol / kg. The vehicle group received subcutaneous injections of the corresponding vehicle (PBS solution). Twelve hours after a single dose, animals were fasted for 12 hours and had free access to water. Blood was collected from the tail vein to determine the basal blood glucose level of each group of animals. 2g / kg glucose solution was then intraperitoneally injected, and blood glucose was tested at 15, 30, 60, and 90 minutes after glucose administration. Blood glucose concentration-time curves were drawn based on the blood glucose values ​​measured at different time points, and the AUC of each dose group was calculated. 0～90min As shown in Table 4 and Figure 1 shown.

[0256] Table 4: Effects of a single administration of HEC-PT74, HEC-PT75, HEC-PT77, HEC-PT78, HEC-PT80, and HEC-PT82 on glucose tolerance in normal C57 mice 24 hours after administration

[0257]

[0258] Note: Lowercase letters in the same column indicate significant differences compared with the Vehicle group (P<0.05).

[0259] Experimental conclusion: After 24 hours of single administration, all treatment groups can improve the glucose tolerance of normal C57 mice. Among them, HEC-PT75, HEC-PT80, and HEC-PT82 are more effective in improving glucose tolerance than the positive control LY3298176.

[0260] Example 5: Glucose tolerance assessment in normal C57BL / 6 mice

[0261] This example evaluates the effects of HEC-PT86, HEC-PT96, HEC-PT112, HEC-PT113, HEC-PT114, and HEC-PT119 on glucose tolerance in normal C57BL / 6 mice.

[0262] Experimental Methods: Normal C57BL / 6 mice were randomly divided into eight groups (Vehicle, LY3298176, HEC-PT86, HEC-PT96, HEC-PT112, HEC-PT113, HEC-PT114, and HEC-PT119) based on blood glucose and body weight, with eight mice per group. Animals in the LY3298176, HEC-PT86, HEC-PT96, HEC-PT112, HEC-PT113, HEC-PT114, and HEC-PT119 groups received subcutaneous injections of the corresponding drug at a dose of 3 nmol / kg. The control group received subcutaneous injections of the corresponding vehicle. Twelve hours after the single administration, the animals were fasted for 12 hours and had free access to water. Blood was collected from the tail vein to determine the basal blood glucose level of each group of animals. 2g / kg glucose solution was then intraperitoneally injected, and blood glucose was tested at 15, 30, 60, and 90 minutes after glucose administration. Blood glucose concentration-time curves were drawn based on the blood glucose values ​​measured at different time points, and the AUC of each dose group was calculated. 0～90min As shown in Table 5 and Figure 2 shown.

[0263] Table 5: Effects of a single administration of HEC-PT86, HEC-PT96, HEC-PT112, HEC-PT113, HEC-PT114, and HEC-PT119 on glucose tolerance in normal C57 mice 24 hours after administration

[0264]

[0265] Note: Lowercase letters in the same column indicate significant differences compared with the Vehicle group (P<0.05).

[0266] Experimental Conclusion: After 24 hours of single administration, all treatment groups were able to improve the glucose tolerance of normal C57 mice. Among them, HEC-PT112 and HEC-PT113 were superior to the positive control LY3298176.

[0267] Example 6: In vivo efficacy evaluation in the db / db mouse model

[0268] This example evaluates the effects of HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86 on blood glucose in db / db mice.

[0269] Experimental Methods: 7-8-week-old db / db mice were randomly divided into six groups (Vehicle, LY3298176, HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86) based on their blood glucose and body weight, with nine mice per group. Animals in the LY3298176, HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86 groups received subcutaneous injections of the corresponding drug at a dose of 10 nmol / kg every three days. Animals in the Vehicle group received subcutaneous injections of the corresponding vehicle. Blood glucose levels were measured before each administration.

[0270] Experimental results: HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86 groups were able to significantly lower blood sugar levels after administration, with blood sugar levels reaching the lowest level around 24 hours later, and the effect was slightly better than the positive control LY3298176 at the same dose. Compared with Vehicle, the blood sugar levels of mice in the HEC-PT86 group were significantly lower after long-term repeated administration and remained stable for a long time, indicating that its hypoglycemic effect was better than that of the LY3298176 group. Specific data are shown in Table 6 and Figure 3-4 .

[0271] Table 6: Effects of long-term administration of HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86 on blood glucose in db / db mice

[0272]

[0273] Note: The lowercase letters in the same column indicate significant differences compared with the Vehicle group (P<0.05).

[0274] Experimental Conclusion: Long-term administration of HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86 significantly improved blood glucose levels in type II diabetic db / db mice, and the blood glucose-lowering effect was comparable to that of the positive control, LY3298176. HEC-PT86 demonstrated a statistically significant improvement in blood glucose-lowering effect compared to LY3298176.

[0275] Example 7: Studies in diet-induced obese C57BL / 6 mice (DIO)

[0276] This example evaluates the effects of long-term repeated administration of HEC-PT77, HEC-PT86, and HEC-PT112 on body weight and food intake in DIO obese mice.

[0277] Experimental Methods: C57 / BL6 mice were randomly divided into a normal (NFD) group and a model (HFD) group at five weeks of age. The normal group was fed a standard maintenance diet, while the other groups were fed a high-fat diet, D12492. Body weight and food intake of the mice were monitored every three weeks. After 16 weeks of feeding, the body weights of the model and normal groups were (49.0±2.3) g and (31.0±2.0) g, respectively, with statistically significant differences between the two groups. The normal group was divided into a control group, and the successfully established model mice were divided into a vehicle group, a semaglutide group, a LY3298176 group, a HEC-PT77 group, a HEC-PT86 group, and a HEC-PT112 group, with 10 mice in each group. Semaglutide, LY3298176, HEC-PT77, HEC-PT86, and HEC-PT112 groups were subcutaneously injected with the corresponding drug; the vehicle group was subcutaneously injected with PBS. After the first dose, the animals were observed for 4 days. Each group was then dosed once every 3 days, with the dose for each group being 10 nmol / kg. Body weight and food intake were measured before each dose. After 3 weeks of dosing, an intraperitoneal glucose tolerance test was performed. 72 hours after the last dose, the animals were slaughtered and samples collected. Liver weights were recorded, and liver pathology and blood biochemical indicators were measured for each group. The test results are shown in Tables 7-10 and Figure 5 -6.

[0278] Semaglutide is commercially available semaglutide.

[0279] Table 7: Effects of long-term administration of HEC-PT77, HEC-PT86, and HEC-PT112 on body weight in DIO mice

[0280]

[0281] Note: Lowercase letters in the same column indicate significant differences compared with the Vehicle group (P<0.05).

[0282] Table 8: Effects of long-term administration of HEC-PT77, HEC-PT86, and HEC-PT112 on food intake in DIO mice

[0283]

[0284]

[0285] Note: Lowercase letters in the same column indicate significant differences compared with the Vehicle group (P<0.05).

[0286] Table 9: Effects of long-term administration of HEC-PT77, HEC-PT86, and HEC-PT112 on body weight and liver index in DIO mice

[0287] Group Body mass / g Liver / g Liver index / % Control <![CDATA[29.7±1.8 a ]]> <![CDATA[1.1±0.1 a ]]> <![CDATA[3.8±0.0 a ]]> Vehicle 48.1±2.6 2.2±0.4 4.6±0.0 Semaglutide <![CDATA[38.3±2.9 a ]]> <![CDATA[1.1±0.1 a ]]> <![CDATA[3.0±0.0 a ]]> LY3298176 <![CDATA[32.6±3.9 a ]]> <![CDATA[1.0±0.1 a ]]> <![CDATA[3.0±0.0 a ]]> HEC-PT77 <![CDATA[31.5±3.2 a ]]> <![CDATA[0.9±0.1 a ]]> <![CDATA[2.7±0.0 a ]]> HEC-PT86 <![CDATA[32.3±4.4 a ]]> <![CDATA[0.9±0.1 a ]]> <![CDATA[2.7±0.0 a ]]> HEC-PT112 <![CDATA[29.7±2.5 a ]]> <![CDATA[0.9±0.1 a ]]> <![CDATA[3.0±0.0 a ]]>

[0288] Note: Lowercase letters in the same column indicate significant differences compared with the Vehicle group (P<0.05).

[0289] Table 10: Effects of long-term administration of HEC-PT77, HEC-PT86, and HEC-PT112 on liver function and blood lipids in DIO mice

[0290]

[0291] Note: Lowercase letters in the same column indicate significant differences compared with the Vehicle group (P<0.05).

[0292] Experimental results: After four weeks of administration, HEC-PT77 and HEC-PT86 demonstrated comparable weight loss and food intake suppression effects to the same dose of the active drug LY3298176, and were superior to the active drug semaglutide. HEC-PT112 significantly outperformed LY3298176 in weight loss and also exhibited some advantages in food intake suppression. HEC-PT77, HEC-PT86, and HEC-PT112 also significantly improved liver function and blood lipids in DIO mice, with effects similar to those of LY3298176.

[0293] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0294] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is composed of a compound represented by formula (I) and a modifying group, and the compound represented by formula (I) is selected from the following structures: Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLAGGPSSGAPPPS; or Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-AFIEYLLAGGPSSGAPPPS; or Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS; Wherein, X6 is αMeF(2F); The modifying group is connected to the 17th amino acid; The modifying group is {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -CO2H, Wherein, a is any integer from 1 to 3, b is any integer from 1 to 3, and c is any integer from 14 to 20.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The modifying group is connected to the ε-amino group of the K side chain at position 17 via an amide bond.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The modifying group is the following structure: (II); or (III); or (IV); or （V）。 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The C-terminus of the amino acid S at position 39 of the compound represented by formula (I) is amidated.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound represented by formula (I) is selected from the following structures: Y-Aib-HGTX6TSDYSILLDE-K ({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQREFIEWLLAGGPSSGAPPPS; or Y-Aib-QGTX6TSDYSILLDE-K ({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLAGGPSSGAPPPS; or Y-Aib-HGTX6TSDYSILLDE-K ({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQREFIEWLLAGGPSSGAPPPS; or Y-Aib-QGTX6TSDYSILLDE-K ({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2; or Y-Aib-QGTX6TSDYSILLDE-K ({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS; Wherein, X6 is αMeF(2F).

6. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, characterized in that Further includes pharmaceutically acceptable excipients.

8. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 6 to 7, in the preparation of a medicament for treating or preventing a disease related to a metabolic disorder; The metabolic disorder-related disease is at least one of obesity and diabetes.

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