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WO2024067662A1 - Glp-1/gcg/gip三受体激动剂及其用途 - Google Patents

Glp-1/gcg/gip三受体激动剂及其用途 Download PDF

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Publication number
WO2024067662A1
WO2024067662A1 PCT/CN2023/121877 CN2023121877W WO2024067662A1 WO 2024067662 A1 WO2024067662 A1 WO 2024067662A1 CN 2023121877 W CN2023121877 W CN 2023121877W WO 2024067662 A1 WO2024067662 A1 WO 2024067662A1
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WIPO (PCT)
Prior art keywords
aib
ethoxy
qgtx
amino
acetyl
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PCT/CN2023/121877
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English (en)
French (fr)
Inventor
蒋鹏
郭林峰
周林俊
孙宁远
肖�琳
余江虹
陈俊英
李利佳
李勇
李明
李晓平
李静
李文佳
Original Assignee
广东东阳光药业股份有限公司
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Priority to AU2023348864A priority Critical patent/AU2023348864A1/en
Priority to KR1020257013861A priority patent/KR20250075689A/ko
Publication of WO2024067662A1 publication Critical patent/WO2024067662A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • 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 uses thereof. 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 uses thereof.
  • Diabetes is a metabolic disease closely related to obesity and non-alcoholic steatohepatitis (NASH), and its prevalence and incidence continue to increase worldwide.
  • GLP-1 glucagon-like peptide-1 receptor agonists
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • T2DM type 2 diabetes
  • a single-target treatment options is limited. Acting on multiple targets can improve the effect of treating such diseases.
  • GLP-1 receptor agonists Based on the effectiveness and safety of GLP-1 receptor agonists, the current research and development idea is to develop them and other intestinal hormones such as glucagon (GCG) and glucose-dependent incretin (GIP) into single-molecule multi-target drugs. They act on multiple targets at the same time, balance the side effects and shortcomings of different targets, and have stable pharmacokinetic characteristics, which can ultimately bring better therapeutic effects than single targets.
  • GCG glucagon
  • GIP glucose-dependent incretin
  • the present invention aims to solve one of the technical problems existing in the prior art to at least a certain extent.
  • the present invention provides a GLP-1/GCG/GIP triple receptor agonist, which can show strong agonist activity on the three receptors of GLP-1, GCG and GIP.
  • Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted by intestinal L-cells after eating. It can stimulate pancreatic ⁇ -cells to secrete insulin, thereby stabilizing postprandial blood sugar fluctuations. Its effect of lowering blood sugar is dependent on glucose concentration. While regulating blood sugar, it greatly reduces the risk of hypoglycemia. In recent years, GLP-1-based drugs, such as liraglutide, dulaglutide and semaglutide, have gradually occupied a very important position in diabetes drugs. GLP-1 drugs also have the effect of weight loss when lowering blood sugar.
  • GLP-1 acts on the gastrointestinal tract to delay gastric emptying and intestinal motility, and acts on the central nervous system to suppress appetite, thereby achieving the purpose of reducing food intake.
  • GLP-1 receptor agonist drugs are used for weight loss, the dose required is generally large, which is prone to gastrointestinal side effects and poor tolerance.
  • Glucagon is a polypeptide hormone secreted by pancreatic ⁇ cells, which can promote glycogenolysis and gluconeogenesis, significantly increase blood sugar; it can also activate lipase, promote fat decomposition, increase fatty acid oxidation, increase energy consumption, and have the effect of reducing fat and weight. Due to its blood sugar-raising effect, although it can be used to treat hypoglycemia, its application in obesity weight loss is limited, especially in obese people with type 2 diabetes.
  • GIP Glucose-dependent incretin
  • GIP and GLP-1 are both incretins, and both can promote insulin secretion and lower blood sugar in a blood sugar concentration-dependent manner, and the blood sugar lowering effect mediated by GIP is stronger than that of GLP-1.
  • diabetic patients are insensitive to GIP, probably due to receptor tolerance caused by hyperglycemia, so the use of GIP receptor agonists alone in diabetic patients does not achieve the purpose of improving blood sugar.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the compound represented by formula (I) is X1X2X3GTX6TSDYSIX13X14DX16X17X18X19X20X21FX23X24X25LX27X28GGPSSGAPPPS (I), wherein X1 is Y or H ; X2 is Aib ; X3 is Q or H ; X6 is a non - natural amino acid ; X13 is L or Y ; X14 is L or K; X16 is E, K or R; X17 is K , R or I; X18 is A, R or K; X19 is Q or A; X20 is R , K, Q, H or Aib; X21 is D, A or E; X23 is I or V; X24 is E or Q; X25 is
  • the above-mentioned compound of the present invention or its pharmaceutically acceptable salt or solvate exhibits strong agonist activity on 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, diseases related to dyslipidemia, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.
  • the present invention provides a pharmaceutical composition.
  • 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, especially obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.
  • 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 drug for treating or preventing diseases related to metabolic disorders.
  • FIG1 is the test results of blood glucose and AUC 0-90min of each group in Example 4 of the present invention.
  • FIG2 is the test results of blood glucose and AUC 0-90min of each group in Example 5 of the present invention.
  • FIG3 is a graph showing the blood sugar test results of each group in Example 6 of the present invention.
  • FIG4 is the test results of glycated hemoglobin in each group in Example 6 of the present invention.
  • FIG5 is a test result of the weight change rate of each group in Example 7 of the present invention.
  • FIG. 6 is the detection results of the cumulative food intake of each group in Example 7 of the present invention.
  • first and second are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as “first” and “second” may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality” is two or more.
  • 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.
  • 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 molecule organic compounds, for example, including but not limited to acetic acid or lactic acid.
  • a solvate is generally referred to as a hydrate.
  • amino acids herein are referred to by the conventional one-letter and three-letter codes for naturally occurring amino acids, as well as the commonly accepted three-letter codes for other ⁇ -amino acids, for example, ⁇ -aminoisobutyric acid can be represented by both codes Aib or B. Unless otherwise specified, all amino acid residues in the present invention are preferably in the L-configuration.
  • sequence structure " -NH2” means that the -COOH on the amino acid C-terminus is amidated to -CONH2 .
  • sequence structure " -NH2” means that the free carboxyl -COOH in the C-terminal serine S is amidated to -CONH2 .
  • OEG refers to ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl, the structural formula of which is shown below:
  • agonist refers to a substance (ligand) which activates the receptor type in question.
  • treatment is used to refer to obtaining 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 may be therapeutic in terms of partially or completely curing a disease and/or the adverse effects caused by the disease.
  • Treatment covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, such as blocking the progression of the disease; or (c) alleviating the disease, such as alleviating symptoms associated with the disease.
  • Treatment covers any medication that administers a drug or compound to an individual to treat, cure, alleviate, improve, mitigate or inhibit an individual's disease, including but not limited to administering a drug containing a compound described herein to an individual in need.
  • non-alcoholic fatty liver disease generally refers to a clinical pathological syndrome characterized by excessive fat deposition in hepatocytes excluding alcohol and other clear liver-damaging factors, and 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.
  • SFL simple fatty liver
  • NASH non-alcoholic steatohepatitis
  • 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 will be described in detail below.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the compound represented by formula (I) is X1X2X3GTX6TSDYSIX13X14DX16X17X18X19X20X21FX23X24X25LX27X28GGPSSGAPPPS (I), wherein X1 is Y or H ; X2 is Aib ; X3 is Q or H ; X6 is a non - natural amino acid ; X13 is L or Y ; X14 is L or K; X16 is E, K or R; X17 is K , R or I; X18 is A, R or K; X19 is Q or A; X20 is R , K, Q, H or Aib; X21 is D, A or E; X23 is I or V; X24 is E or Q; X25 is W or Y
  • the above-mentioned compound of the present invention or its pharmaceutically acceptable salt or solvate (or agonist) exhibits strong agonist activity on the three receptor targets of GLP-1, GCG and GIP. It can optimize the activity of each receptor to avoid the side effects caused by excessive activity of one or more receptors, and has the advantages of good activity of each receptor, effective control of blood sugar and weight loss; at the same time, it has strong stability in the body, which can prolong the drug action time to achieve a frequency of once a week. Therefore, the agonist 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.
  • the agonist activity on the three receptor targets of GLP-1, GCG and GIP can be further enhanced.
  • the compound represented by formula (I) has at least one of the following structures:
  • H-Aib-QGTX 6 TSDYSILLDEIAQKDFIEWLLEGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDEKRQQAFIEYLLAGGPSSGAPPPS;
  • H-Aib-HGTX 6 TSDYSILLDRKAQHAFIEYLLEGGPSSGAPPPS;
  • H-Aib-HGTX 6 TSDYSILLDRKAQQAFIEYLLAGGPSSGAPPPS;
  • H-Aib-HGTX 6 TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDRKAQHEFIEWLLEGGPSSGAPPPS;
  • X6 is ⁇ MeF(2F).
  • the compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof further comprises a modifying group, and the modifying group is connected to at least one of the amino acids X 14 , X 17 and X 20 .
  • At least one of X 14 , X 17 and X 20 is K, and the modifying group is connected to the ⁇ -amino group of the side chain of K of at least one of X 14 , X 17 and X 20 via an amide bond.
  • X 14 and/or X 17 is K
  • the modifying group is connected to the ⁇ -amino group of the K side chain of X 14 and/or X 17 via an amide bond.
  • the modifying group has the following structure: ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ a -( ⁇ Glu) b -CO-(CH 2 ) c -CO 2 H, 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.
  • a is 1. In some optional embodiments of the present invention, a is 2. In some optional embodiments of the present invention, a is 3.
  • 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.
  • c is any integer from 14 to 20.
  • 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.
  • the "-" in the above-mentioned modification groups represents a chemical bond connecting chemical groups; illustratively, “[2-(2-amino-ethoxy)-ethoxy]-acetyl” is synonymous with “OEG”; the “-” in “CO-CH 2 " 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; “CO 2 H” refers to the COOH group.
  • the modifying group has at least one of the following structures:
  • the C-terminus of the amino acid S at position 39 of the compound represented by formula (I) is amidated.
  • amidation means that the -OH in the -COOH of serine S in the compound represented by formula (I) is replaced by an amino group -NH 2 , that is, the -COOH of serine S in the compound represented by formula (I) is amidated to -CONH 2 .
  • the compound represented by formula (I) has at least one of the following structures:
  • H-Aib-QGTX 6 TSDYSILLDEIAQ-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ 2 - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)DFIEWLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AQQAFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AQQDFIEWLIAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)RQQAFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AQQEFIEWLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AQQEFIEWLIAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AQQAFVQWLIAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)RAQAFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)RQRAFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDEIAQ-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ 2 - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AFIEYLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDEIAQ-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ 2 - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AFIEYLIAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDEIAQ-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ 2 - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AFVQWLIAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AQ-Aib-AFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)RQ-Aib-EFIEWLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)RQ-Aib-AFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIAQQAFIEYLLEGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIAQ-Aib-AFIEYLLEGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIAQQAFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)RQRAFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDRIRQ-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)EFIEWLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDRIRQ-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDR-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)RQQEFIEWLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDR-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)RQQAFIEYLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)KQ-Aib-EFIEWLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)KQKAFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)KQKAFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSILLDEKKQ-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AFIEYLLAGGPSSGAPPPS-NH 2 ;
  • H-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)RQRAFIEYLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)RQRAFIEYLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)RQRAFVEYLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSIYLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AQRAFIEYLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSIYLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AQRAFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIAQKAFIEYLLEGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DRIAQRAFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIRQQAFIEYLLEGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIRQ-Aib-AFIEYLLEGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DKIRQ-Aib-AFIEYLLAGGPSSGAPPPS-NH 2 ;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DRIRQQAFIEYLLEGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DRIRQQAFIEYLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSIL-K(- ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DRRAQQAFVEYLLAGGPSSGAPPPS;
  • Y-Aib-QGTX 6 TSDYSIL-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)DRRAQQAFVEYLLEGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)RQQAFIEYLLEGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDE-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)RQQAFIEYLLAGGPSSGAPPPS;
  • H-Aib-HGTX 6 TSDYSILLDR-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AQHAFIEYLLEGGPSSGAPPPS;
  • H-Aib-HGTX 6 TSDYSILLDR-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AQQAFIEYLLAGGPSSGAPPPS;
  • H-Aib-HGTX 6 TSDYSILLDR-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 18 -CO 2 H)AQHAFIEYLLAGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDR-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AQHAFIEYLLAGGPSSGAPPPS;
  • H-Aib-QGTX 6 TSDYSILLDR-K( ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-(CH 2 ) 16 -CO 2 H)AQHEFIEWLLEGGPSSGAPPPS;
  • X6 is ⁇ MeF(2F).
  • the "-" between amino acids in the polypeptide of the above compound represents an amide bond; illustratively, the "-" in “H-Aib-Q” represents an amide bond.
  • the "-” in the above modification group represents a chemical bond connecting chemical groups; illustratively, the "-" in " ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ - ⁇ Glu-CO-C 18 -CO 2 H” represents a chemical bond connecting chemical groups.
  • the present invention provides a pharmaceutical composition.
  • 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, especially obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • 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 drug, wherein the drug is used to prevent or treat diseases related to metabolic disorders.
  • the metabolic disorder-related diseases include obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.
  • the present invention provides a method for preventing or treating diseases related to metabolic disorders.
  • the method comprises: administering a pharmaceutically acceptable amount of the aforementioned compound or its pharmaceutically acceptable salt or solvate or the aforementioned pharmaceutical composition to a subject.
  • the metabolic disorder-related diseases include obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.
  • the "pharmaceutically acceptable amount” may vary with 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). The factors include, but are not limited to: pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc.; 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 situation, several divided doses may be administered daily, or the dose may be reduced proportionally.
  • the present invention provides the compound or its pharmaceutically acceptable salt or solvate or the pharmaceutical composition for use in the individual for treating or preventing metabolic disorder-related diseases.
  • the metabolic disorder-related disease includes at least one of obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.
  • amino acid code "X" in the sequence column of the above table refers to the unnatural amino acid ⁇ MeF(2F) mentioned above.
  • a dose-effect curve was established and its EC 50 was calculated.
  • the specific steps are as follows:
  • HEK293-GLP-1R, HEK293-GCGR and HEK293-GIPR cells After taking out HEK293-GLP-1R, HEK293-GCGR and HEK293-GIPR cells from liquid nitrogen, immediately place them in a 37°C water bath. After they are completely thawed within 1.5 min, add the cells dropwise into a 15 mL centrifuge tube containing 8 mL of warm culture medium in a clean bench, centrifuge at 900 rpm for 5 min, discard the supernatant, resuspend the cells in 1 mL of complete culture medium (pipette 15 times), immediately take 20 ⁇ L of the suspension and mix it with an equal volume of trypan blue, take 20 ⁇ L to count the number of viable cells, and dilute the cells to 4 ⁇ 10 5 cells/mL with complete culture medium;
  • the polypeptide compound of the present invention maintains relatively high agonist activity on GLP-1R, GCGR and GIPR.
  • T max peak time
  • C max peak concentration
  • AUC last area under the drug-time curve at 0-t
  • AUC INF area under the drug-time curve at 0- ⁇
  • T 1/2 elimination half-life.
  • LY3298176 in the following Examples 4 to 6 is tirzepatide, a new drug for type 2 diabetes on the market.
  • the Vehicle group refers to the injection of the corresponding solvent, that is, compared with the polypeptide compound drug group, the Vehicle group only does not contain the polypeptide compound.
  • 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.
  • mice Normal C57BL/6 mice were randomly divided into 8 groups (Vehicle group, LY3298176 group, HEC-PT74 group, HEC-PT75 group, HEC-PT77 group, HEC-PT78 group, HEC-PT80 group, HEC-PT82 group) according to blood sugar and body weight, with 8 mice in each group.
  • LY3298176 group, HEC-PT74 group, HEC-PT75 group, HEC-PT77 group, HEC-PT78 group, HEC-PT80 group and HEC-PT82 group each group of animals was subcutaneously injected with the corresponding drug, and the dosage was 3nmol/kg; for the Vehicle group, the corresponding solvent (i.e., PBS solution) was subcutaneously injected.
  • the corresponding solvent i.e., PBS solution
  • Table 4 Effects of 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
  • each administration group can improve the glucose tolerance of normal C57 mice.
  • HEC-PT75, HEC-PT80 and HEC-PT82 have better effects on improving glucose tolerance than the positive control LY3298176.
  • 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.
  • mice Normal C57BL/6 mice were randomly divided into 8 groups (Vehicle group, LY3298176 group, HEC-PT86 group, HEC-PT96 group, HEC-PT112 group, HEC-PT113 group, HEC-PT114 group, HEC-PT119 group) according to blood sugar and body weight, with 8 mice in each group.
  • LY3298176 group, HEC-PT86 group, HEC-PT96 group, HEC-PT112 group, HEC-PT113 group, HEC-PT114 group, and HEC-PT119 group each group of animals was subcutaneously injected with the corresponding drug, and the dosage was 3nmol/kg; for the control group, the corresponding solvent was subcutaneously injected.
  • Table 5 Effects of 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
  • Example 6 In vivo efficacy evaluation in db/db mouse model
  • This example evaluates the effects of HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86 on blood glucose in db/db mice.
  • mice 7-8 week old db/db mice were randomly divided into 6 groups (Vehicle group, LY3298176 group, HEC-PT74 group, HEC-PT77 group, HEC-PT85 group, HEC-PT86 group) according to blood glucose and body weight values, with 9 mice in each group.
  • LY3298176 group, HEC-PT74 group, HEC-PT77 group, HEC-PT85 group and HEC-PT86 group each group of animals was subcutaneously injected with the corresponding drug, and the dose was 10nmol/kg each time, once every three days; for the Vehicle group, the corresponding solvent was subcutaneously injected. Blood glucose of animals was tested before each administration.
  • HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86 groups were able to significantly reduce blood sugar after administration, and the blood sugar level reached the lowest level at about 24 hours, which was slightly better than the positive control LY3298176 at the same dose.
  • the blood sugar level of mice in the HEC-PT86 group was significantly reduced after long-term repeated administration and remained stable for a long time. Its hypoglycemic effect was better than that of the LY3298176 group.
  • the specific data are shown in Table 6 and Figures 3-4.
  • HEC-PT74, HEC-PT77, HEC-PT85, and HEC-PT86 can significantly improve the blood glucose level of type II diabetes model db/db mice, and the blood glucose lowering level is not inferior to the positive control LY3298176.
  • the blood glucose lowering effect of HEC-PT86 is better than that of LY3298176, and there is a statistical difference.
  • 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.
  • mice C57/BL6 mice were randomly divided into normal group NFD and model group HFD at the fifth week of age.
  • the normal group was fed with ordinary maintenance feed, while the other groups were fed with high-fat feed D12492.
  • the changes in body weight and food intake of mice were monitored every 3 weeks. After 16 weeks of feeding, the body weights of mice in the model group and normal group were (49.0 ⁇ 2.3) g and (31.0 ⁇ 2.0) g, respectively, and the difference between the two groups was statistically significant.
  • the normal group was divided into the Control group, and the mice in the model group with successful modeling were divided into the Vehicle group, Semaglutide group, LY3298176 group, HEC-PT77 group, HEC-PT86 group and HEC-PT112 group, with 10 mice in each group.
  • each group of animals was subcutaneously injected with the corresponding drugs; for the Vehicle group, PBS was subcutaneously injected. After the first administration, the animals were observed for 4 days, and then each group was administered once every 3 days, with the dose of each group being 10 nmol/kg. Body weight and food intake were tested before each administration. After 3 weeks of administration, an intraperitoneal glucose tolerance test was performed. 72 hours after the last administration, the animals were slaughtered and samples were collected, liver weights were recorded, and liver pathological conditions and blood biochemical indicators of each group were tested. The test results are shown in Tables 7-10 and Figures 5-6.
  • Semaglutide is commercially available semaglutide.
  • Table 7 Effects of long-term administration of HEC-PT77, HEC-PT86 and HEC-PT112 on body weight of DIO mice
  • Table 8 Effects of long-term administration of HEC-PT77, HEC-PT86 and HEC-PT112 on food intake in DIO mice

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Abstract

一种三受体激动剂。激动剂包括式(I)所示的多肽，X 1X 2X 3GTX 6TSDYSIX 13X 14DX 16X 17X 18X 19X 20X 21FX 23X 24X 25LX 27X 28GGPSSGAPPPS(I)，X 1为Y或H；X 2为Aib；X 3为Q或H；X 6为非天然氨基酸；X 13为L或Y；X 14为L或K；X 16为E、K或R；X 17为K、R或I；X 18为A、R或K；X 19为Q或A；X 20为R、K、Q、H或Aib；X 21为D、A或E；X 23为I或V；X 24为E或Q；X 25为W或Y；X 27为I或L；X 28为E或A。该激动剂对GLP-1、GCG和GIP三个受体均有较强的激动活性，可用于治疗代谢紊乱相关疾病。

Description

GLP-1/GCG/GIP三受体激动剂及其用途 技术领域
本发明属于生物医药技术领域，具体地，本发明涉及一种GLP-1/GCG/GIP三受体激动剂及其用途，更具体地，本发明涉及一种具有式(I)所示的化合物或其可药用盐或溶剂化物、药物组合物及其用途。
 背景技术
糖尿病是一种与肥胖和非酒精性脂肪性肝炎(NASH)密切相关的代谢类疾病，其在全球范围内的患病率和发病率持续增加。目前虽有胰高血糖素样肽-1(GLP-1)受体激动剂获批用于治疗2型糖尿病(T2DM)，如度拉糖肽、索马鲁肽等，但因代谢类疾病具有并发性及异质性的特点，尤其是2型糖尿病伴随肥胖等多种并发性疾病，单一靶点治疗方案的疗效有限。而作用于多个靶点，可以提高治疗此类疾病的效果。但基于多药组合的联合给药如复方制剂，会使药物开发和临床研究复杂化，但开发单分子多靶药物可有效避免此类问题。
基于GLP-1受体激动剂的有效性及安全性，目前的研发思路是将其和其他肠道激素如胰高血糖素(GCG)、葡萄糖依赖的肠促胰岛素(GIP)开发成单分子多靶药物。同时作用于多个靶点，平衡不同靶点的的副作用与不足，且具备稳定的药代动力学特征，最终可带来优于单一靶点的治疗效果。
发明内容
本发明旨在至少在一定程度上解决现有技术中存在的技术问题之一。为此，本发明提供了一种GLP-1/GCG/GIP三受体激动剂，该激动剂可对GLP-1、GCG和GIP三个受体都表现出较强的激动活性。
本发明是基于发明人的下列发现而完成的：
胰高血糖素样肽-1(GLP-1)是一种进食后由肠道L-细胞分泌的多肽激素，能刺激胰岛β细胞分泌胰岛素，从而稳定餐后血糖的波动。其降低血糖的作用具有葡萄糖浓度依赖性，在调节血糖的同时，大大降低了低血糖的风险。近年基于GLP-1的药物，如利拉鲁肽、度拉鲁肽及索马鲁肽，逐渐在糖尿病药物中占据了非常重要的地位。GLP-1类药物在降低血糖时还有减重的效果，其机理为GLP-1作用于胃肠道延缓胃排空和肠道蠕动，以及作用于中枢神经系统抑制食欲等，从而达到减少摄食的目的。然而，GLP-1受体激动剂类药物用于减肥时，需要使用的剂量一般较大，易产生胃肠道副作用，耐受性差。
胰高血糖素(GCG)是由胰岛α细胞分泌的一种多肽激素，可促进糖原分解和糖异生，使血糖显著升高；同时还可激活脂肪酶，促进脂肪分解，提高脂肪酸氧化，增加能量消耗，具有减脂和减重的作用。由于其具有升糖作用，虽可用于低血糖方面的治疗，但限制了其在肥胖减肥中的应用，尤其是Ⅱ型糖尿病肥胖者中的应用。
葡萄糖依赖的肠促胰岛素(GIP)是一种由肠道K细胞分泌的多肽激素。GIP和GLP-1同为肠降血糖素，均能以血糖浓度依赖的方式促进胰岛素的分泌和降低血糖，且GIP介导的血糖降低效果强于GLP-1。然而，可能由于高血糖导致的受体耐受，糖尿病患者表现出对GIP不敏感，因而对糖尿病患者单独使用GIP受体激动剂并没有达到改善血糖的目的。
研究发现，代谢紊乱相关疾病(如糖尿病、肥胖症及NASH等)的病因复杂，而单一靶点药物疗效相对有限。
基于此，在本发明的一个方面，本发明提出了一种具有式(I)所示的化合物或其可药用盐或溶剂化物。根据本发明的实施例，所述式(I)所示的化合物为X1X2X3GTX6TSDYSIX13X14DX16X17X18X19X20X21FX23X24X25LX27X28GGPSSGAPPPS(I)，其中，X1为Y或H；X2为Aib；X3为Q或H；X6为非天然氨基酸；X13为L或Y；X14为L或K；X16为E、K或R；X17为K、R或I；X18为A、R或K；X19为Q或A；X20为R、K、Q、H或Aib；X21为D、A或E；X23为I或V；X24为E或Q；X25为W或Y；X27为I或L；X28为E或A；其中，X16为K时，X14为K。本发明的上述化合物或其可药用盐或溶剂化物，对GLP-1、GCG和GIP三个受体靶点均表现出较强的激动活性，可有效地控制血糖和降低体重，可用于预防或治疗代谢紊乱相关疾病，尤其是肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病等疾病。
在本发明的另一方面，本发明提出了一种药物组合物。根据本发明的实施例，药物组合物包括前述的化合物或其可药用盐或溶剂化物。本发明的药物组合物可有效预防或治疗代谢紊乱相关疾病，尤其是肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病等疾病。
在本发明的又一方面，本发明提出了一种前述的化合物或其可药用盐或溶剂化物或前述的药物组合物在制备药物中的用途，所述药物用于治疗或预防代谢紊乱相关疾病。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
 附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1为本发明实施例4中各组的血糖和AUC0～90min的检测结果；
图2为本发明实施例5中各组的血糖和AUC0～90min的检测结果；
图3为本发明实施例6中各组的血糖的检测结果；
图4为本发明实施例6中各组的糖化血红蛋白的检测结果；
图5为本发明实施例7中各组的体重变化率的检测结果；
图6为本发明实施例7中各组的累计摄食量的检测结果。
 具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
需要说明的是，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。进一步地，在本发明的描述中，除非另有说明，“多个”的含义是两个或两个以上。
在本文中，术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本文中，术语“任选地”、“任选的”或“任选”通常是指随后所述的事件或状况可以但未必发生，并且该描述包括其中发生该事件或状况的情况，以及其中未发生该事件或状况的情况。
在本文中，术语“溶剂化物”是指在溶质(这里指的是根据本发明的化合物或其可药用盐)与溶剂之间形成的确定化学计量的复合物。所述溶剂可以是水、乙醇或其他可药用的代表性小分子有机物，例如包括但不限于乙酸或乳酸。当上述溶剂是水时，这样的溶剂化物通常被称为水合物。
在本文中，氨基酸采用天然氨基酸的常规单字母和三字母代码，以及其他α-氨基酸的普遍接受的三字母代码，例如，α-氨基异丁酸可表述为Aib或B两种代码。除非明确指出，否则本发明中的所有氨基酸残基优选为L-构型。
其中，Aib或B结构式为
在本文中，术语“(L)-α-Me-(2-F)-Phe”和“αMeF(2F)”均为α-甲基2-氟苯丙氨酸，其结构式为
在本文中，序列结构“-NH2”是指氨基酸C端上的-COOH酰胺化为-CONH2，例如，在Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-C18-CO2H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH2中“-NH2”表示C末端丝氨酸S中的游离羧基-COOH酰胺化为-CONH2。
在本文中，术语“OEG”是指{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基，其结构式如下所示：
在本文中，术语“激动剂”是指激活所述受体类型的物质(配体)。
在本文中，术语“治疗”是指用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病，例如阻滞疾病发展；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述化合物的药物给予有需要的个体。
在本文中，术语“非酒精性脂肪性肝病(NAFLD)”通常是指除外酒精和其他明确的损肝因素所致的肝细胞内脂肪过度沉积为主要特征的临床病理综合征，与胰岛素抵抗和遗传易感性密切相关的获得性代谢应激性肝损伤，包括但不限于单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化。
本发明提出了一种具有式(I)所示的化合物或其可药用盐或溶剂化物、药物组合物及其用途，下面将分别对其进行详细描述。
具有式(I)所示的化合物或其可药用盐或溶剂化物
在本发明的一个方面，本发明提出了一种具有式(I)所示的化合物或其可药用盐或溶剂化物。根据本发明的实施例，所述式(I)所示的化合物为X1X2X3GTX6TSDYSIX13X14DX16X17X18X19X20X21FX23X24X25LX27X28GGPSSGAPPPS(I)，其中，X1为Y或H；X2为Aib；X3为Q或H；X6为非天然氨基酸；X13为L或Y；X14为L或K；X16为E、K或R；X17为K、R或I；X18为A、R或K；X19为Q或A；X20为R、K、Q、H或Aib；X21为D、A或E；X23为I或V；X24为E或Q；X25为W或Y；X27为I或L；X28为E或A；其中，X16为K时，X14为K。本发明的上述化合物或其可药用盐或溶剂化物(或称激动剂)对GLP-1、GCG和GIP三个受体靶点均表现出较强的激动活性，其可通过优化各受体活性大小，避免一种或多种受体活性过高而带来的副作用，具有各受体活性好以及有效控制血糖和降低体重等优点；同时，其在体内的稳定性强，可延长药物作用时间，以达到每周一次给药的频率。因此，该激动剂可用于预防或治疗代谢紊乱相关疾病，尤其是肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病等疾病。
根据本发明的实施例，X1为Y；X2为Aib；X3为Q或H；X6为αMeF(2F)；X13为L；X14为L或K；X16为E或K；X17为K或I；X18为A或R；X19为Q；X20为R、Q或Aib；X21为A或E；X23为I；X24为E；X25为W或Y；X27为L；X28为E或A；其中，X16为K时，X14为K。由此，可进一步增强对GLP-1、GCG和GIP三个受体靶点的激动活性。
根据本发明的实施例，所述式(I)所示的化合物具有如下结构的至少之一：
Y-Aib-QGTX6TSDYSILLDEKAQRDFIEWLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKAQRDFIEWLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEIAQKDFIEWLLEGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDEIAQKDFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQQDFIEWLIAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLIAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKAQQAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKRARAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKRAREFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLIAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQQAFVQWLIAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKRAQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLIAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEIAQKAFVQWLIAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKAQ-Aib-EFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKAQ-Aib-AFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-AFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEKRQKAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDRIRQKEFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDRIRQKAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDRKRQQEFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDRKRQQAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKKQ-Aib-EFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKKQKAFIEYLLAGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEKRQRAFVEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDRIAQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIRQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDRIRQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDRIRQQAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDRRAQQAFVEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILKDRRAQQAFVEYLLEGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLAGGPSSGAPPPS；
H-Aib-HGTX6TSDYSILLDRKAQHAFIEYLLEGGPSSGAPPPS；
H-Aib-HGTX6TSDYSILLDRKAQQAFIEYLLAGGPSSGAPPPS；
H-Aib-HGTX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDRKAQHEFIEWLLEGGPSSGAPPPS；
其中，X6为αMeF(2F)。
需要说明的是，上述化合物的多肽中氨基酸和氨基酸之间的“-”表示酰胺键。示例性地，“H-Aib-Q”中“-”表示酰胺键。
根据本发明的实施例，所述具有式(I)所示的化合物或其可药用盐或溶剂化物进一步包括修饰基团，所述修饰基团与X14、X17和X20中的至少之一位氨基酸相连。
根据本发明的实施例，X14、X17和X20中的至少之一为K，所述修饰基团与X14、X17和X20中的至少之一的K侧链的ε-氨基通过酰胺键相连。
根据本发明的实施例，X14和/或X17为K，所述修饰基团与X14和/或X17的K侧链的ε-氨基通过酰胺键相连。
根据本发明的实施例，所述修饰基团具有如下结构：{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}a-(γGlu)b-CO-(CH2)c-CO2H，其中，a为1～3中的任一整数，b为1～3中的任一整数，c为14～20中的任一整数。
在本发明的一些可选实施例中，a为1。在本发明的一些可选实施例中，a为2。在本发明的一些可选实施例中，a为3。
在本发明的一些可选实施例中，b为1。在本发明的一些可选实施例中，b为2。在本发明的一些可选实施例中，b为3。
在本发明的一些可选实施例中，c为14～20中的任一整数。示例性地，c为14、15、16、17、18、19和20或者它们之间的两个值作为端点值的范围值，如14～18、16～18或16～20。
需要说明的是，上述修饰基团中的“-”表示化学基团之间连接的化学键；示例性地，“[2-(2-氨基-乙氧基)-乙氧基]-乙酰基”与“OEG”同义；“CO-CH2”中“-”表示化学基团之间连接的化学键；a、b和c代表不同基团的个数；“Glu”和“E”同义，均指谷氨酸；“CO2H”是指COOH基团。
根据本发明的实施例，所述修饰基团具有如下结构的至少之一：
根据本发明的实施例，所述式(I)所示的化合物的第39位的氨基酸S的C末端酰胺化。
需要说明的是，酰胺化是指式(I)所示的化合物的丝氨酸S的-COOH中的-OH被氨基-NH2取代，即为式(I)所示的化合物的丝氨酸S的-COOH酰胺化为-CONH2。
根据本发明的实施例，所述式(I)所示的化合物具有如下结构的至少之一：
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRDFIEWLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRDFIEWLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)DFIEWLLEGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)DFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQDFIEWLIAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)EFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)EFIEWLIAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQREFIEWLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQREFIEWLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQREFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQEFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQQEFIEWLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQQEFIEWLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K(-{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQREFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RARAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RAREFIEWLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQEFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQEFIEWLIAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQAFVQWLIAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RAQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQREFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)AFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)AFIEYLIAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)AFVQWLIAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-HGTX6TSDYSILLDEK({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQQAFIEYLLEGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQKAFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQQAFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)EFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQQEFIEWLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQQAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)KQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)KQKAFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)KQKAFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSILLDEKKQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AFIEYLLAGGPSSGAPPPS-NH2；
H-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFVEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQRAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQKAFIEYLLEGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRIAQRAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIRQQAFIEYLLEGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIRQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIRQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRIRQQAFIEYLLEGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRIRQQAFIEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIL-K(-{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRRAQQAFVEYLLAGGPSSGAPPPS；
Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRRAQQAFVEYLLEGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQQAFIEYLLEGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQQAFIEYLLAGGPSSGAPPPS；
H-Aib-HGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQHAFIEYLLEGGPSSGAPPPS；
H-Aib-HGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQQAFIEYLLAGGPSSGAPPPS；
H-Aib-HGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQHAFIEYLLAGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQHAFIEYLLAGGPSSGAPPPS；
H-Aib-QGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQHEFIEWLLEGGPSSGAPPPS；
其中，X6为αMeF(2F)。
需要说明的是，上述化合物的多肽中氨基酸和氨基酸之间的“-”表示酰胺键；示例性地，“H-Aib-Q”中“-”表示酰胺键。上述修饰基团中的“-”表示化学基团之间连接的化学键；示例性地，“{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-C18-CO2H”中“-”表示化学基团之间连接的化学键。
药物组合物
在本发明的另一方面，本发明提出了一种药物组合物。根据本发明的实施例，药物组合物包括前述的化合物或其可药用盐或溶剂化物。本发明的药物组合物可有效预防或治疗代谢紊乱相关疾病，尤其是肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病等疾病。
根据本发明的实施例，药物组合物进一步包括药学上可接受的辅料。
用途
在本发明的又一方面，本发明提出了一种前述的化合物或其可药用盐或溶剂化物或前述的药物组合物在制备药物中的用途，所述药物用于预防或治疗代谢紊乱相关疾病。
根据本发明的实施例，所述代谢紊乱相关疾病包括肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病。
预防或治疗代谢紊乱相关疾病的方法
在本发明的又一方面，本发明提出了一种预防或治疗代谢紊乱相关疾病的方法。根据本发明的实施例，所述方法包括：向受试者施用药学上可接受量的前述的化合物或其可药用盐或溶剂化物或前述的药物组合物。
根据本发明的实施例，所述代谢紊乱相关疾病包括肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病。
需要说明的是，“药学上可接受量”可随给药的模式和待治疗的疾病的严重程度等而变化，优选为有效量。药学上可接受量的选择可以由本领域普通技术人员根据各种因素来确定(例如通过临床试验)。所述的因素包括但不限于：所述的活性成分的药代动力学参数例如生物利用率、代谢、半衰期等；患者所要治疗的疾病的严重程度、患者的体重、患者的免疫状况、给药的途径等。例如，由治疗状况的迫切要求，可每天给予若干次分开的剂量，或将剂量按比例地减少。
在本发明的另一方面，本发明提出了所述的化合物或其可药用盐或溶剂化物或所述的药物组合物用于所述的个体治疗或预防代谢紊乱相关疾病。
根据本发明的实施例，所述代谢紊乱相关疾病包括肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病中的至少之一。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1：多肽化合物的制备
1、按照下表1合成人GLP-1、人GCG、人GIP以及各多肽化合物(三受体激动剂)等，具体多肽化合物结构见表1。
表1三受体激动剂的化合物结构



备注:上表序列栏中的氨基酸代号“X”，即为前述中的非天然氨基酸αMeF(2F)。
制备脂肪酸侧链修饰的多肽化合物的具体步骤如下：
1)将树脂放入150ml反应器中，并加入50ml二氯甲烷(DCM)浸泡2小时。用二甲基甲酰胺(DMF)洗涤树脂，然后抽干，如此重复四次，将树脂抽干。称取Fmoc-C端第一个氨基酸(带保护)、DCM和N,N-二异丙基乙胺(DIEA)加入到反应器中，然后将反应器置于30℃的摇床中反应2小时。用甲醇溶液封闭(甲醇：DIEA：DCM＝1：1：2)半小时，然后用DMF洗涤四次，抽干。向反应器中加入20％哌啶溶液，脱去Fmoc保护基团。脱完保护后用DMF洗涤四次，然后抽干。
2)称取Fmoc-C端第二个氨基酸(带保护)、1-羟基苯并三唑(HOBT)和N,N-二异丙基碳二亚胺(DIC)加入到反应器中，然后将反应器置于30℃的摇床中反应1小时。取少量树脂检测，用茚三酮法检测，若树脂有颜色，说明缩合不完全，继续反应。待反应完全后，用DMF洗涤树脂四次，然后抽干。向反应器中加入一定量的20％哌啶(哌啶/DMF＝1:4)，放在脱色摇床上摇晃20min,以此来脱去树脂上的Fmoc保护基团。脱完保护后用DMF洗涤四次，然后抽干检测保护是否脱去。
3)按照步骤依次连接氨基酸，其中一个Lys使用特殊保护的原料(接侧链的Lys)。加Boc酸酐保护N端氨基。脱去Lys侧链的特殊保护基团，参照步骤2连接侧链结构。用切割试剂将多肽保护基团全部切除，并从树脂上切割下来，送纯化。
2、通过反相液相色谱纯化将目标肽段与杂质分离，将所收集的目标肽冻干成粉末，并进行纯度与质谱鉴定。经HPLC检测，纯度都大于95％。质谱鉴定多肽分子量都与理论分子量一致。
实施例2：体外细胞活性测定
通过将多肽、人GLP-1、人GCG以及人GIP分别作用表达GLP-1R、GCGR与GIPR的HEK293细胞，并用cAMP检测试剂盒(Cisbio，62AM6PEC)检测受体细胞所产生的cAMP，建立量效曲线，计算其EC50。具体步骤如下：
1)配制Assay buffer：取完全培养液(DMEM培养基+10％FBS)，再加入4/1000的500mM IBMX母液，cAMP-d2工作液和anti-cAMP-crytate工作液按cAMP检测试剂盒说明书进行配制；
2)用Assay buffer将待测样品稀释成500nM母液、人源对照多肽GLP-1、GCG及GIP，稀释成200nM的母液，然后按20μL加入到80μL Assay buffer(稀释5倍)的梯度逐级稀释，包括母液共计8个化合物梯度；
3)细胞悬液制备：液氮中取出细胞HEK293-GLP-1R、HEK293-GCGR及HEK293-GIPR后，立即37℃水浴，1.5min内完全融化后，于超净台将细胞逐滴加入至装有8mL温热培养基的15mL离心管中，900rpm离心5min，弃上清，1mL完全培养液将细胞重悬后(吹打15次)，立即取20μL悬液与等体积的台盼蓝混合，取20μL计算活细胞数后，用完全培养基将细胞稀释至4×105cells/mL；
4)将384孔板划分为GLP-1R细胞、GCGR细胞及GIPR细胞区域，用12道变道可调分液器按每孔5μL将细胞悬液加入相应区域的孔中，再用12道变道可调分液器将供试品(实施例1制得的多肽化合物)和阳性对照品(实施例1制备的人GLP-1、人GCG或人GIP)梯度稀释液加入对应细胞的384孔板中，每孔5μL(相同浓度样品平行2个复孔)；阴性对照：10μL assay buffer/每孔，每块384孔板设置3个孔，盖上白色封板膜，放入37℃恒温培养箱，半小时后取出；
5)临用前用试剂盒中lysis buffer将cAMP-d2工作液和anti-cAMP-crytate工作液稀释20倍后，阴性对照每孔加入5μL lysis buffer和5μL稀释后的anti-cAMP-crytate工作液，随后将稀释的cAMP-d2工作液和anti-cAMP-crytate工作液1:1混合均匀，按每孔10μL加入样品组孔，盖上白色盖子，于室温避光放置1h或4℃放置过夜；
6)在多功能酶标仪中检测665nm、620nm的荧光值。在GraphPad Prism 6中将信号比值与样品浓度使用四参数方程进行非线性拟合，得出EC50值，具体结果如表2所示。
表2：不同受体细胞的体外活性检测结果

实验结论：本发明的多肽化合物对GLP-1R、GCGR及GIPR都保持较高的激动活性。
实施例3：大鼠中药代动力学研究
采用雄性Sprague Dawley大鼠对实施例1制得的各多肽化合物进行药代动力学研究。每组3只雄性大鼠，动物自由饮水不禁食，剂量为50nmol/kg，单次皮下注射给药(具体多肽化合物参见表3)，给药后在既定天数和时间点采集血浆后采用LC-MS/MS方法检测血浆中的各多肽化合物的浓度，根据浓度数据求得药代动力学参数，用于描述多肽经皮下注射给药后药物在大鼠体内的药代动力学性质。实验结果如表3所示：
表3：部分三靶多肽在大鼠体内的药代动力学参数总结

注：Tmax：达峰时间；Cmax：达峰浓度；AUClast：0-t时刻药时曲线下面积；AUCINF：0-∞时刻药时曲线下面积；T1/2：消除半衰期。
实验结论：除PT-61在大鼠体内的吸收较差之外，其他多肽在大鼠的体内吸收均较好，血药浓度较高，半衰期较长。
下述实施例4～6中的LY3298176为市售的2型糖尿病新药tirzepatide。Vehicle组为指注射相应的溶媒，即Vehicle组与多肽化合物药物组相比，仅不含多肽化合物。
需要说明的是，下述实施例4～6中的显著性水平标注均为各组(LY3298176组和其他多肽化合物组)分别与Vehicle组的显著性分析结果。
实施例4：在正常C57BL/6小鼠中糖耐量评估
本实施例评估HEC-PT74、HEC-PT75、HEC-PT77、HEC-PT78、HEC-PT80、HEC-PT82对正常C57BL/6小鼠糖耐量的影响。
实验方法：正常C57BL/6小鼠按照血糖和体重随机分为8组(Vehicle组、LY3298176组、HEC-PT74组、HEC-PT75组、HEC-PT77组、HEC-PT78组、HEC-PT80组、HEC-PT82组)，每组8只。对于LY3298176组、HEC-PT74组、HEC-PT75组、HEC-PT77组、HEC-PT78组、HEC-PT80组及HEC-PT82组，每组动物皮下注射给予相应的药物，给药剂量均为3nmol/kg；对于Vehicle组，皮下注射相应的溶媒(即为PBS溶液)。单次给药12h后动物禁食12h、自由饮水。于尾静脉取血测定各组动物血糖基础值，随后腹腔注射给予2g/kg的葡萄糖溶液，并于给糖后15、30、60、90min的时间点进行血糖检测。根据不同时间点测定的血糖值绘制血糖浓度-时间曲线，计算各剂量组AUC0～90min如表4和图1所示。
表4：HEC-PT74、HEC-PT75、HEC-PT77、HEC-PT78、HEC-PT80、HEC-PT82单次给药24h后对正常C57小鼠糖耐量的影响
注：同列肩标小写字母表示与Vehicle组相比差异显著(P<0.05)。
实验结论：单次给药24h后，各给药组均可改善正常C57小鼠糖耐量状态。其中，HEC-PT75、HEC-PT80和HEC-PT82改善糖耐量的效果优于阳性对照LY3298176。
实施例5：在正常C57BL/6小鼠中糖耐量评估
本实施例评估HEC-PT86、HEC-PT96、HEC-PT112、HEC-PT113、HEC-PT114、HEC-PT119对正常C57BL/6小鼠糖耐量的影响。
实验方法：正常C57BL/6小鼠按照血糖和体重随机分为8组(Vehicle组、LY3298176组、HEC-PT86组、HEC-PT96组、HEC-PT112组、HEC-PT113组、HEC-PT114组、HEC-PT119组)，每组8只。对于LY3298176组、HEC-PT86组、HEC-PT96组、HEC-PT112组、HEC-PT113组、HEC-PT114组、HEC-PT119组，每组动物皮下注射给予相应的药物，给药剂量均为3nmol/kg；对于对照组，皮下注射相应的溶媒。单次给药12h后动物禁食12h、自由饮水。于尾静脉取血测定各组动物血糖基础值，随后腹腔注射给予2g/kg的葡萄糖溶液，并于给糖后15、30、60、90min的时间点进行血糖检测。根据不同时间点测定的血糖值绘制血糖浓度-时间曲线，计算各剂量组AUC0～90min如表5和图2所示。
表5：HEC-PT86、HEC-PT96、HEC-PT112、HEC-PT113、HEC-PT114、HEC-PT119单次给药24h后对正常C57小鼠糖耐量的影响
注：同列肩标小写字母表示与Vehicle组相比差异显著(P<0.05)。
实验结论：单次给药24h后，各给药组均可改善正常C57小鼠糖耐量状态。其中，HEC-PT112和HEC-PT113优于阳性对照LY3298176。
实施例6：在db/db小鼠模型中体内药效评估
本实施例评估HEC-PT74、HEC-PT77、HEC-PT85、HEC-PT86对db/db小鼠血糖的影响。
实验方法：7-8周龄db/db小鼠根据血糖及体重值随机分为6组(Vehicle组、LY3298176组、HEC-PT74组、HEC-PT77组、HEC-PT85组、HEC-PT86组)，每组9只。对于LY3298176组、HEC-PT74组、HEC-PT77组、HEC-PT85组及HEC-PT86组，每组动物皮下注射给予相应的药物，每次给药剂量均为10nmol/kg，每三天给药一次；对于Vehicle组，皮下注射相应溶媒。于每次给药前进行动物血糖检测。
实验结果：HEC-PT74、HEC-PT77、HEC-PT85、HEC-PT86各组在给药后能够明显降低血糖，约在24h时血糖值达到最低水平，效果略优于同剂量阳性对照LY3298176。与Vehicle相比，长期重复给药后HEC-PT86组小鼠血糖值明显降低，并保持长期稳定，其降糖作用优于LY3298176组，具体数据见表6及图3-4。
表6：HEC-PT74、HEC-PT77、HEC-PT85、HEC-PT86长期给药对db/db小鼠血糖的影响

注：同列肩标小写字母表示与Vehicle组相比差异显著(P<0.05)
实验结论：HEC-PT74、HEC-PT77、HEC-PT85、HEC-PT86长期给药可明显改善II型糖尿病模型db/db小鼠的血糖水平，并且降糖水平不劣于阳性对照LY3298176。其中HEC-PT86降糖效果优于LY3298176，并有统计学差异。
实施例7：在饮食诱导的肥胖C57BL/6小鼠(DIO)中的研究
本实施例评估HEC-PT77、HEC-PT86及HEC-PT112长期重复给药对DIO肥胖小鼠体重和摄食的影响。
实验方法：将C57/BL6小鼠于第五周龄时随机分为正常组NFD、模型组HFD，正常组给予普通维持饲料喂养，而其他组均给予高脂饲料D12492饲养。每3周监测小鼠体质量和摄食量的变化。饲养16周后，模型组和正常组小鼠体质量分别为(49.0±2.3)g、(31.0±2.0)g，两组比较差异有统计学意义。将正常组分成Control组，造模成功的模型组小鼠分为Vehicle组、Semaglutide组、LY3298176组、HEC-PT77组、HEC-PT86组及HEC-PT112组，每组10只。对于Semaglutide组、LY3298176组、HEC-PT77组、HEC-PT86组及HEC-PT112组，每组动物皮下注射给予相应的药物；对于Vehicle组，皮下注射PBS。首次给药后观察4天，然后各组每3天给药一次，各组剂量均为10nmol/kg。每次给药前进行体重及摄食量的检测。给药3周后，进行腹腔糖耐量试验。末次给药72h后宰杀收集样本，记录肝脏重量，检测各小组肝脏病理状况和血生化指标。检测结果见表7-10及图5-6。
其中，Semaglutide为市售的索马鲁肽(semaglutide)。
表7：HEC-PT77、HEC-PT86及HEC-PT112长期给药对DIO小鼠体重的影响

注：同列肩标小写字母表示与Vehicle组相比差异显著(P<0.05)。
表8：HEC-PT77、HEC-PT86及HEC-PT112长期给药对DIO小鼠摄食量的影响
注：同列肩标小写字母表示与Vehicle组相比差异显著(P<0.05)。
表9：HEC-PT77、HEC-PT86及HEC-PT112长期给药对DIO小鼠体质量和肝脏指数的影响
注：同列肩标小写字母表示与Vehicle组相比差异显著(P<0.05)。
表10：HEC-PT77、HEC-PT86及HEC-PT112长期给药对DIO小鼠肝功及血脂的影响
注：同列肩标小写字母表示与Vehicle组相比差异显著(P<0.05)。
实验结果：经给药4周，HEC-PT77、HEC-PT86的减重及抑制摄食效果与同剂量阳性药LY3298176相当，优于阳性药Semaglutide。HEC-PT112的减重效果明显优于LY3298176，且在抑制摄食方面也存在一定的优势。HEC-PT77、HEC-PT86及HEC-PT112对DIO小鼠的肝功及血脂也有明显改善，作用效果近似于LY3298176。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
[根据细则26改正 12.10.2023]
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (14)

  1. 具有式(I)所示的化合物或其可药用盐或溶剂化物，其特征在于，
    X1X2X3GTX6TSDYSIX13X14DX16X17X18X19X20X21FX23X24X25LX27X28GGPSSGAPPPS
    (I)，
    其中，X1为Y或H；
    X2为Aib；
    X3为Q或H；
    X6为非天然氨基酸；
    X13为L或Y；
    X14为L或K；
    X16为E、K或R；
    X17为K、R或I；
    X18为A、R或K；
    X19为Q或A；
    X20为R、K、Q、H或Aib；
    X21为D、A或E；
    X23为I或V；
    X24为E或Q；
    X25为W或Y；
    X27为I或L；
    X28为E或A；
    其中，X16为K时，X14为K。
  2. 根据权利要求1所述的化合物或其可药用盐或溶剂化物，其特征在于，X1为Y；
    X2为Aib；
    X3为Q或H；
    X6为αMeF(2F)；
    X13为L；
    X14为L或K；
    X16为E或K；
    X17为K或I；
    X18为A或R；
    X19为Q；
    X20为R、Q或Aib；
    X21为A或E；
    X23为I；
    X24为E；
    X25为W或Y；
    X27为L；
    X28为E或A；
    其中，X16为K时，X14为K。
  3. 根据权利要求1所述的化合物或其可药用盐或溶剂化物，其特征在于，所述式(I)所示的化合物具有如下结构的至少之一：
    Y-Aib-QGTX6TSDYSILLDEKAQRDFIEWLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKAQRDFIEWLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEIAQKDFIEWLLEGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDEIAQKDFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQQDFIEWLIAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLIAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKAQQAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKRARAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKRAREFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLIAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQQAFVQWLIAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKRAQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLIAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEIAQKAFVQWLIAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKAQ-Aib-EFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKAQ-Aib-AFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-AFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEKRQKAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDRIRQKEFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDRIRQKAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDRKRQQEFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDRKRQQAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKKQ-Aib-EFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKKQKAFIEYLLAGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEKRQRAFVEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDRIAQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIRQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDRIRQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDRIRQQAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDRRAQQAFVEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILKDRRAQQAFVEYLLEGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLAGGPSSGAPPPS；
    H-Aib-HGTX6TSDYSILLDRKAQHAFIEYLLEGGPSSGAPPPS；
    H-Aib-HGTX6TSDYSILLDRKAQQAFIEYLLAGGPSSGAPPPS；
    H-Aib-HGTX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDRKAQHEFIEWLLEGGPSSGAPPPS；
    其中，X6为αMeF(2F)。
  4. 根据权利要求1所述的化合物或其可药用盐或溶剂化物，其特征在于，进一步包括修饰基团，所述修饰基团与X14、X17和X20中的至少之一位氨基酸相连。
  5. 根据权利要求4所述的化合物或其可药用盐或溶剂化物，其特征在于，X14、X17和X20中的至少之一为K，所述修饰基团与X14、X17和X20中的至少之一的K侧链的ε-氨基通过酰胺键相连；
    优选地，X14和/或X17为K，所述修饰基团与X14和/或X17的K侧链的ε-氨基通过酰胺键相连。
  6. 根据权利要求4所述的化合物或其可药用盐或溶剂化物，其特征在于，所述修饰基团具有如下结构：
    {[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}a-(γGlu)b-CO-(CH2)c-CO2H，
    其中，a为1～3中的任一整数，b为1～3中的任一整数，c为14～20中的任一整数；
    优选地，所述修饰基团具有如下结构的至少之一：

  7. 根据权利要求1所述的化合物或其可药用盐或溶剂化物，其特征在于，所述式(I)所示的化合物的第39位的氨基酸S的C末端酰胺化。
  8. 根据权利要求1所述的化合物或其可药用盐或溶剂化物，其特征在于，所述式(I)所示的化合物具有如下结构的至少之一：
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRDFIEWLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRDFIEWLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)DFIEWLLEGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)DFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQDFIEWLIAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)EFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)EFIEWLIAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQREFIEWLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQREFIEWLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQREFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQEFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQQEFIEWLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQQEFIEWLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K(-{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H) AQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQREFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RARAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RAREFIEWLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQEFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQEFIEWLIAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQQAFVQWLIAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RAQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQREFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)AFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)AFIEYLIAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}2-γGlu-CO-(CH2)18-CO2H)AFVQWLIAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-HGTX6TSDYSILLDEK({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQQAFIEYLLEGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H) RQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQKAFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQQAFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16CO2H)EFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQQEFIEWLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQQAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)KQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)KQKAFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)KQKAFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSILLDEKKQ-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AFIEYLLAGGPSSGAPPPS-NH2；
    H-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)RQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQRAFVEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQRAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIAQKAFIEYLLEGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H) DRIAQRAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIRQQAFIEYLLEGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIRQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DKIRQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRIRQQAFIEYLLEGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRIRQQAFIEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIL-K(-{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRRAQQAFVEYLLAGGPSSGAPPPS；
    Y-Aib-QGTX6TSDYSIL-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)DRRAQQAFVEYLLEGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQQAFIEYLLEGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDE-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)RQQAFIEYLLAGGPSSGAPPPS；
    H-Aib-HGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQHAFIEYLLEGGPSSGAPPPS；
    H-Aib-HGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQQAFIEYLLAGGPSSGAPPPS；
    H-Aib-HGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)18-CO2H)AQHAFIEYLLAGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQHAFIEYLLAGGPSSGAPPPS；
    H-Aib-QGTX6TSDYSILLDR-K({[2-(2-氨基-乙氧基)-乙氧基]-乙酰基}-γGlu-CO-(CH2)16-CO2H)AQHEFIEWLLEGGPSSGAPPPS；
    其中，X6为αMeF(2F)。
  9. 一种药物组合物，其特征在于，包括权利要求1～8任一项所述的化合物或其可药用盐或溶剂化物。
  10. 根据权利要求9所述的药物组合物，其特征在于，进一步包括药学上可接受的辅料。
  11. 权利要求1～8任一项所述的化合物或其可药用盐或溶剂化物或权利要求9～10任一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防代谢紊乱相关疾病。
  12. 根据权利要求11所述的用途，其特征在于，所述代谢紊乱相关疾病包括肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病中的至少之一。
  13. 用于治疗或预防代谢紊乱相关疾病的方法，所述的方法包括给予所述个体权利要求1～8任一项所述的化合物或其可药用盐或溶剂化物或权利要求9～10任一项所述的药物组合物；
    所述代谢紊乱相关疾病包括肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病中的至少之一。
  14. 权利要求1～8任一项所述的化合物或其可药用盐或溶剂化物或权利要求9～10任一项所述的药物组合物用于制备治疗或预防所述的个体代谢紊乱相关疾病的药物；
    所述代谢紊乱相关疾病包括肥胖症、糖尿病、血脂异常相关疾病、脂肪肝病、代谢综合征和非酒精性脂肪性肝病中的至少之一。
PCT/CN2023/121877 2022-09-28 2023-09-27 Glp-1/gcg/gip三受体激动剂及其用途 WO2024067662A1 (zh)

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