Polypeptide derivative with GCGR, GIPR and GLP-1R triple targeting agonistic effect

Abstract

The invention discloses a polypeptide derivative with a GCGR, GIPR and GLP-1R triple targeting agonistic effect as well as a preparation method and application of the polypeptide derivative, the polypeptide derivative is shown as a formula (I), (II) is a branched chain modification structure of a peptide chain, and the group definition is detailed in the specification. The polypeptide derivative compound and the pharmaceutically acceptable salt thereof provided by the invention can be used for treating metabolic related diseases such as diabetes mellitus, weight loss, MASH and the like, cardiovascular and cerebrovascular diseases and / or neurodegenerative diseases. Tyr-Aib-Gln-Gly-Thr-Ph-Thr-Ser-Asp-Tyr-Ser-Xaa12-Xaa13-Leu-As-Lys-Xaa17-Ala-Gln-Xaa24-Xaa25-Leu-Leu-Xaa28-Gly-Ala-Pro-Pro-Ser-NH2 (I) # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a polypeptide derivative with triple targeting agonistic effects of GCGR, GIPR and GLP-1R, and a preparation method and use thereof. Background Art

[0002] In contrast to the effects of insulin, glucagon (GCG, Glucagon) is a hormone secreted by the α cells of the pancreas to promote catabolism. Glucagon has a strong effect of promoting glycogenolysis and gluconeogenesis, which significantly increases blood sugar. Glucagon activates the phosphorylase of liver cells through the cAMP-PK system, accelerating glycogenolysis. Gluconeogenesis is enhanced because the hormone accelerates the entry of amino acids into liver cells and activates the enzyme system related to the gluconeogenesis process. Glucagon can also activate lipase to promote fat decomposition, while at the same time enhancing fatty acid oxidation and increasing ketone body production. Glucagon can promote the secretion of insulin and somatostatin. Pharmacological doses of glucagon can increase the cAMP content in myocardial cells and enhance myocardial contraction.

[0003] Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid polypeptide secreted by K cells mainly located in the proximal small intestine. It is the first incretin hormone discovered. In early studies, the insulinotropic effect induced by acute infusion of GIP in patients with T2DM was weakened, limiting its possibility as a drug development target. However, recent studies have found that the insulinotropic effect of GIP can be restored after T2DM patients receive hypoglycemic drug treatment and improve blood sugar control. In addition, GIP can act on bone and adipose tissue, inhibit bone reabsorption, and promote lipid synthesis in adipocytes, thereby affecting lipid metabolism and fat distribution. Its effects are independent of insulin action; GIP may also reduce food intake and reduce weight by activating GIPR+ neurons in the hypothalamus.

[0004] Glucagon-like peptide 1 (GLP-1) is a peptide hormone secreted by human intestinal L cells. It can promote the secretion of insulin and inhibit the secretion of glucagon. It has the effect of lowering blood sugar concentration and is used to treat type II diabetes. GLP-1 exerts its physiological effects by binding to its specific receptors. The receptors of GLP-1 are widely distributed in multiple organs or tissues throughout the body. Evidence-based medicine also confirms that GLP-1R agonists (GLP-1RA) have protective effects on the cardiovascular system, kidneys, and central nervous system in addition to treating diabetes and obesity. GLP-1R is widely distributed and can regulate the metabolism of key target tissues with other receptors. For example, GLP-1 and amylin can slow down gastric emptying, and both can act on receptors on the central nervous system, thereby reducing appetite and ultimately reducing blood sugar and body weight.

[0005] Glucagon can also inhibit food intake and reduce body weight by binding to glucagon receptor (GCGR) and GLP-1R. A preclinical study also suggested that GCG can increase energy expenditure and brown adipose tissue activity in mice through the FGF21 pathway.

[0006] Natural GLP-1 and GIP are unstable in the body and are easily degraded by dipeptidyl peptidase-IV (DPP-IV). The half-life of natural GCG in plasma is 5-10 minutes, and it is mainly inactivated in the liver, and also degraded in the kidneys.

[0007] Researchers around the world are studying potential new drugs that act on these targets, such as CN201380067043, CN201480061187, CN201680082339, CN201780074707, CN201880081212, CN202080008168, etc. Eli Lilly's Retatrutide (LY3437943) has completed Phase II clinical trials and entered Phase III clinical trials, Hanmi's HM15211 (Efocipegtrutide) is in Phase II clinical trials, Novo Nordisk's NN9423, and Sanofi's SAR441255 are both in Phase I clinical trials.

[0008] Existing scientific research and technology show that the rational combination of GCG, GIP and GLP-1 on their receptor target agonist activity is the core of this type of drug. Different active combinations produce different pharmacological effects and adverse reactions. At the same time, different branch chain modifications have different effects on the triple-targeted agonist activity and drug efficacy half-life of this type of GCGR, GIPR and GLP-1R. GCGR, GIPR and GLP-1R multi-receptor targeted agonist peptides have great therapeutic potential in the treatment of diabetes, weight loss, cardiovascular and cerebrovascular diseases such as sudden cardiac death (SCD), heart failure with preserved ejection fraction (HFpEF), myocardial infarction (AMI), metabolic dysfunction-associated fatty hepatitis (MASH, formerly known as NASH), neurodegenerative diseases such as AD and PD, etc., which are worthy of in-depth exploration and research.

[0009] Although most of the GCGR, GLP-1R and GIPR triple-targeted agonists under development have reached a dosing frequency of once a week for humans, for many chronic patients who are naturally afraid of injections but need long-term dosing, oral or longer-acting injectable peptide drugs (such as once a month) are more conducive to solving the problem of clinical compliance. Therefore, the field still longs for peptides with dual targeting agonism of GLP-1R and GIPR, especially ultra-long-acting peptide drugs, which have great therapeutic potential in the treatment of diabetes, weight loss, cardiovascular and diabetes, metabolic dysfunction-related fatty hepatitis (MASH, formerly known as non-alcoholic fatty hepatitis NASH), neurodegenerative diseases such as AD and PD, cardiovascular and cerebrovascular diseases such as sudden cardiac death (SCD), heart failure with preserved ejection fraction (HFpEF), myocardial infarction (AMI), stroke (CIS), etc. Summary of the invention

[0010] The present invention provides a polypeptide derivative with triple targeting agonism of GCGR, GIPR and GLP-1R or a pharmaceutically acceptable salt thereof, wherein the main peptide chain of the polypeptide derivative with triple targeting agonism of GCGR, GIPR and GLP-1R is represented by formula (I), the side chain is represented by formula (II), and Xaa in the main chain is 17 is Lys, and its side chain ε-amino group is connected to X1 in the branched chain formula (II) in the form of an amide bond;

[0011] Tyr-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Xaa 12 -Xaa 13 -Leu-Asp-Lys-Xaa 17 -Ala-Gln-Xaa 20 -Ala-Phe-Xaa 23 -Xaa 24 -Xaa25-Leu-Leu-Xaa28 -Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

[0012]

[0013] Among them, Aib is aminoisobutyric acid, α-Me-L is 2-methyl-leucine (or α-methyl-leucine), and it is connected to the preceding and following amino acids by an amide bond (peptide bond);

[0014] XA 12 Selected from Ile or Lys;

[0015] XA 13 Selected from Aib or Tyr or α-Me-L;

[0016] XA 20 Selected from Lys or Aib;

[0017] XA 23 From Val or Ile;

[0018] XA 24 Selected from Glu or Gln;

[0019] XA 25 Selected from Trp or Tyr;

[0020] XA 28 Selected from Ala or Glu

[0021] Alternatively, in formula (II), n is 8 or 9; X2 is At the same time, X1 is

[0022]

[0023] Preferably, when Xaa 23 When it is Val, Xaa 24 is Gln; when Xaa 23 When it is Ile, Xaa 24 In one embodiment of the present invention, in the polypeptide derivative, n in formula (II) is 8.

[0024] In one embodiment of the present invention, in the polypeptide derivative, n is 9 in formula (II).

[0025] In one embodiment of the present invention, the polypeptide derivative is of the following formula (1):

[0026]

[0027] In one embodiment of the present invention, the polypeptide derivative is of the following formula (2):

[0028]

[0029] In one embodiment of the present invention, the polypeptide derivative is of the following formula (3):

[0030]

[0031] In one embodiment of the present invention, the polypeptide derivative is of the following formula (4):

[0032]

[0033] In one embodiment of the present invention, the polypeptide derivative is of the following formula (5):

[0034]

[0035] In one embodiment of the present invention, the polypeptide derivative is the following formula (6):

[0036]

[0037] In one embodiment of the present invention, the polypeptide derivative is the following formula (7):

[0038]

[0039] In one embodiment of the present invention, the polypeptide derivative is the following formula (8):

[0040]

[0041] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. All of these isomers and their mixtures are included within the scope of the present invention. In an embodiment of the present invention, as a preferred embodiment of the present invention, the amino acids in the polypeptide derivatives are preferably L-type amino acids.

[0042] Throughout the entire specification of the present invention, not only the conventional single-letter and three-letter codes for naturally occurring amino acids are used, but also those three-letter codes that are generally allowed for other amino acids (such as α-aminoisobutyric acid (Aib)) are used. In addition, the naming rules of IUPAC-IUB for referring to natural amino acids in the present invention are abbreviated as follows:

[0043] Alanine (Ala, A) Arginine (Arg, R) Asparagine (Asn, N) Aspartic acid (Asp, D)

[0044] Cysteine ​​(Cys, C) Glutamic acid (Glu, E) Glutamine (Gln, Q) Glycine (Gly, G)

[0045] Histidine (His, H) Isoleucine (Ile, I) Leucine (Leu, L) Lysine (Lys, K)

[0046] Methionine (Met, M) Phenylalanine (Phe, F) Proline (Pro, P) Serine (Ser, S)

[0047] Threonine (Thr, T) Tryptophan (Trp, W) Tyrosine (Tyr, Y) Valine (Val, V).

[0048] In another aspect, the present invention provides a method for preparing the above polypeptide derivative, the preparation method comprising the following step A:

[0049] 1) Synthesis of branched fragments by solid or liquid phase method;

[0050] 2) Solid phase method for peptide chain synthesis;

[0051] 3) coupling the branched fragment to the peptide resin;

[0052] 4) Cleavage and removal of the protecting group and the resin mounting to obtain the polypeptide derivative.

[0053] The present invention provides another method for preparing the above polypeptide derivative, the preparation method comprising the following step B:

[0054] 1) Solid phase method for peptide chain synthesis;

[0055] 2) The solid phase method is used to couple each branch chain module to the peptide resin one by one;

[0056] 3) Cleavage and removal of the protecting group and the resin mounting to obtain the polypeptide derivative.

[0057] In some embodiments, the scheme for synthesizing the branched fragment in step A is as follows:

[0058] Will and Condensation coupling is carried out under weak organic base conditions, and Boc protection is removed by TFA; Fmoc-Glu-OtBu is condensed and coupled with the product of the previous step, and Fmoc protection is removed by Pip solution or other alkaline solution; the long fatty diacid with single protection of tBu group is condensed and coupled to the amino position of Glu in the previous step; finally, the benzyl ester is removed by hydrogen hydrolysis under the catalysis of palladium carbon to expose the side chain carboxyl group that needs to be combined with the peptide chain.

[0059] 2) Solid phase method for peptide chain synthesis;

[0060] In some embodiments, the scheme for synthesizing the backbone is as follows:

[0061] According to the amino acid sequence of the molecular structure of the present invention, the Fmoc-protected amino acids are coupled to the solid phase synthesis resin in reverse order, and the Fmoc is deprotected by Pip solution or other alkaline solution, and the cycle is repeated until all the main chain amino acids of the peptide chain are completed; wherein the Lys of the side chain fragment to be connected is protected by Alloc (optionally, using the raw material Fmoc-Lys(Alloc)-OH) or Dde (optionally, using the raw material Fmoc-Lys(Dde)-OH) or ivDde (optionally, using the raw material Fmoc-Lys(ivDde)-OH); the terminal of the molecular structure of the present invention is serine amide, and a resin such as Rink Amide-AM resin, Rink Amide-MBHA resin, Sieber resin, PAM resin, Rink Amide resin, etc. can be used to construct an amide-type polypeptide.

[0062] 3) coupling the branched fragment to the peptide resin;

[0063] In some embodiments, the scheme for coupling the branch chain to the peptide chain is as follows:

[0064] Depeptide resin Lys side chain protection, such as Xaa 17 When the side chain protecting group is Alloc, Alloc protection is removed by using tetrakis(triphenylphosphine)palladium and PhSiH3; 17 When the side chain protecting group is Dde or ivDde, the Dde or ivDde protection is removed by hydrazine hydrate; the side chain fragment is coupled with the peptide resin; and the first amino acid Fmoc protection is removed by Pip solution or other alkaline solution.

[0065] 4) Cleavage to remove the protecting group and resin mounting

[0066] The protecting group and the resin are removed by cleavage to obtain a crude polypeptide derivative.

[0067] In some embodiments, the lysis protocol is as follows:

[0068] Prepare TFA cleavage solution in a certain proportion, add the fully protected peptide resin to the cleavage solution, cut it off from the resin and remove the side chain. Remove TFA by vacuum rotary evaporation, add ether or alkane solvent to the concentrated solution to precipitate a white solid, which is the target product.

[0069] Optionally, further comprising:

[0070] Chromatographic purification: multi-step reverse phase chromatography purification or ion chromatography purification, and finally salt conversion into an aqueous solution containing the active ingredient; and freeze drying.

[0071] In some embodiments, the scheme for synthesizing the main chain in step B is similar to the scheme for synthesizing the main chain in step A, but the α-amino group of the first Tyr at the N-terminus is protected by a Boc group.

[0072] In some embodiments, the solid phase method in step B is to sequentially couple each branched chain module with the peptide resin as follows:

[0073] This step is carried out by solid phase synthesis of polypeptides, and the polypeptide main chain is connected to the resin in reverse order according to the structural sequence of each module of the branch chain of the present invention. 17 The side chain is protected, and the intermediate containing X1 and X2, the Glu side chain and the mono-tert-butyl octadecane dioate or the mono-tert-butyl eicosanedioate are coupled and deprotected in sequence to complete the synthesis of the entire side chain.

[0074] In some embodiments, the lysis, purification, lyophilization, etc. of step B are the same as those of step A.

[0075] The condensation coupling described in the present invention refers to the condensation coupling reaction of carboxylic acid and amino group. According to the specific situation (such as solid phase peptide synthesis), condensation agents used in organic synthesis such as DCC / HOBt, DIC / Cl-HOBt, EDC / HOBt, TBTU / DIEA, HBTU / DIEA, PyBOP / DIEA, HATU / DIEA, T3P / DIEA, DEPBT / DIEA, etc. can be used.

[0076] The definitions of some abbreviations in the present invention are as follows.

[0077] Sieber resin: Rink Amide-AM Resin: Fmoc: fluorenylmethoxycarbonyl

[0078] EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

[0079] DIC: N,N'-diisopropylcarbodiimide

[0080] HOBt: 1-Hydroxybenzotriazole

[0081] DCC: N,N'-dicyclopropylcarbodiimide

[0082] Cl-HOBt: 6-chloro-1-hydroxybenzotriazole

[0083] HBTU: O-Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0084] TBTU: O-Benzotriazol-N,N,N',N'-tetramethyluronium tetrafluoroborate PyBop: Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

[0085] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate TIS: triisopropylsilane

[0086] DIEA: Diisopropylethylamine

[0087] Pip:piperidine

[0088] OtBu: tert-butyl ester

[0089] DCM: dichloromethane

[0090] MTBE: Methyl tert-butyl ether

[0091] Et2O: ether

[0092] NMP: N-methylpyrrolidone

[0093] Bzl: benzyl

[0094] TEA: triethylamine

[0095] Dde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl

[0096] T3P: 1-propylphosphoric anhydride

[0097] Alloc: Allyloxycarbonyl

[0098] tBu: tert-butyl

[0099] Pd[P(C6H5)3]4:Tetrakis(triphenylphosphine)palladium

[0100] PhSiH3: Phenylsilane

[0101] DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one

[0102] NMM: N-methylmorpholine

[0103] The present invention discloses a pharmaceutical composition, which comprises the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, and a pharmaceutically acceptable carrier.

[0104] The pharmaceutically acceptable salts of the polypeptide derivatives of the present invention include, in a preferred embodiment, the free compounds of the present invention, conventional non-toxic salts of the compounds of the present invention formed by reaction of inorganic acids or organic acids, and conventional non-toxic salts of the compounds of the present invention formed by reaction of inorganic bases or organic bases. For example, salts obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., and salts obtained from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. For another example, salts obtained from inorganic bases such as sodium, potassium, calcium, magnesium, zinc, iron, etc., and salts obtained from organic bases such as ammonia water, arginine, lysine, citrulline, histidine, etc. The salts described in the present invention include acid or base salts formed by reacting a small amount of acid or base compounds used for pharmaceutical purposes. Pharmaceutically acceptable salts are preferably sodium salts.

[0105] One of the objectives of the present invention is to develop a clinically available pharmaceutical preparation based on the polypeptide derivative of the present invention. The preparation may further contain a buffer, a preservative, an isotonic agent, a cosolvent, a tonicity agent, a chelating agent, a stabilizer, an antioxidant, a surfactant, an acid-base regulator, etc. The concentration is usually 0.01 mg / ml to 50 mg / ml, wherein the preparation has a pH of 3.0 to 9.0.

[0106] In one embodiment of the invention, the pharmaceutical formulation is an aqueous formulation, ie an aqueous solution, typically a solution, emulsion or suspension.

[0107] In another embodiment, the pharmaceutical preparation is a lyophilized preparation, and a solvent and / or a diluent is added thereto to fully dissolve the preparation before use.

[0108] In another embodiment, the pharmaceutical preparation is a ready-to-use dry preparation that does not require pre-dissolution, such as a lyophilized powder for spray inhalation.

[0109] In another embodiment of the present invention, the pH range of the pharmaceutical preparation is very important, which will affect the solubility and stability of such polypeptide derivatives, and under certain specific conditions, the polypeptide will physically aggregate or adsorb. In one embodiment of the present invention, the pH value of the pharmaceutical preparation is 3.0 to 5.0. In one embodiment of the present invention, the pH value of the pharmaceutical preparation is 7.0 to 8.0. In one embodiment of the present invention, the pH value of the pharmaceutical preparation is 7.5 to 8.5. In another embodiment of the present invention, the pH value of the pharmaceutical preparation is 5.0 to 7.5.

[0110] In a further embodiment of the present invention, the buffer is selected from disodium hydrogen phosphate, sodium acetate, etc., the preservative is selected from phenol, o-cresol, m-cresol, p-cresol, etc., the isotonic agent is selected from sodium chloride salts, sugars or sugar alcohols, amino acids, propylene glycol, mannitol, etc., the solubilizing agent is selected from mannitol, propylene glycol, PEG, glycerol, Tween, ethanol, etc., the tonicity agent is selected from sodium chloride salts, propylene glycol, glycerol, mannitol, etc., the chelating agent is selected from EDTA, citrate, etc., the stabilizer is selected from creatinine, glycine, nicotinamide, PEG, etc., the antioxidant is selected from sodium bisulfite, sodium sulfite, cysteine, methionine, etc., the surfactant is selected from polysorbate, glycerol, mannitol, etc., and the acid-base regulator is selected from hydrochloric acid, phosphoric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, etc.

[0111] Other ingredients may be present in the pharmaceutical preparation of the GLP-1 polypeptide derivative of the present invention according to the needs of the pharmaceutical preparation (e.g., long-term stability), including emulsifiers, metal ions, oily carriers, proteins (e.g., human serum albumin, gelatin or protein, etc.), zwitterions (e.g., arginine, glycine, lysine, histidine, betaine and taurine, etc.), and other pharmaceutical preparation additives.

[0112] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, liposomes, etc.

[0113] With respect to drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect.

[0114] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0115] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0116] In the third aspect, the pharmaceutically acceptable salt or free compound of the GCGR, GIPR and GLP-1R triple targeted receptor agonist polypeptide derivatives of the present invention, and its preferred technical scheme, the diseases include metabolic syndrome, obesity, diabetes, obesity-related diseases and diabetes-related diseases, metabolic dysfunction-related fatty hepatitis (MASH, formerly known as non-alcoholic fatty hepatitis NASH), non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), etc. Diabetes includes a group of metabolic diseases characterized by hyperglycemia caused by defects in insulin secretion, insulin action or both. Diabetes is divided into type 1 diabetes, type 2 diabetes and gestational diabetes according to the mechanism of the disease.

[0117] The pharmaceutically acceptable salts or free compounds of the triple-targeted receptor agonist polypeptide derivatives of the present invention can combine the effects of GCG (e.g., effects on fat metabolism, weight loss, and blood sugar), GLP-1 (e.g., effects on blood sugar levels and food intake), GIP (e.g., inhibiting gastric motility and emptying, inhibiting gastric acid secretion, pepsin secretion, stimulating insulin secretion and release, stimulating small intestinal fluid secretion, etc.) and GLP-1 (e.g., promoting insulin secretion, inhibiting glucagon secretion, and having protective effects on the cardiovascular system, kidneys, and central nervous system, etc.). Therefore, it can be used to accelerate the elimination of excess adipose tissue, cause sustained weight loss, and improve blood sugar control. The triple-targeted receptor agonist polypeptide derivatives can also be used to reduce cardiovascular risk factors, such as high cholesterol, such as high LDL cholesterol.

[0118] The pharmaceutically acceptable salts or free compounds of the GCGR, GIPR and GLP-1R triple-targeted receptor agonist polypeptide derivatives of the present invention can also be used to treat insulin resistance, impaired glucose tolerance, prediabetes, elevated fasting blood sugar, type II diabetes, hypertension, dyslipidemia (or a combination of these metabolic risk factors), atherosclerosis, arteriosclerosis, coronary heart disease, peripheral arterial disease and stroke. These are all conditions that may be associated with obesity. However, the effects of the compounds used in the present invention on these conditions may be fully or partially mediated by the effects on body weight, or may be independent of the effects.

[0119] In certain embodiments, the pharmaceutically acceptable salts or free compounds of the GCGR, GIPR and GLP-1R triple targeting receptor agonist polypeptide derivatives of the present invention can play a therapeutic role in obesity-related diseases such as obesity-related inflammation, obesity-related gallbladder disease and obesity-induced sleep apnea.

[0120] Preferably, the invention also includes the use in the preparation of drugs for delaying the efficacy of the treatment of type II diabetes and / or preventing the deterioration of type II diabetes, and a method for improving blood sugar control in adults with type II diabetes, comprising administering an effective amount of the above-mentioned polypeptide derivatives to patients in need as a diet and exercise supplement.

[0121] The pharmaceutically acceptable free compounds or salts of the polypeptide derivatives of the present invention have positive preventive and therapeutic significance for NAFLD and MASH, which are related to multiple metabolism-related factors and have complex pathogenesis. Insulin resistance and fat metabolism disorders constitute early damage to the liver, thereby forming fat accumulation (NAFLD) in liver cells. With the development of the disease, the body's immune regulation is formed, liver cells produce inflammatory reactions, metabolic dysfunction-related fatty liver hepatitis (MASH) occurs, and then promotes the formation of fibrosis, and ultimately leads to end-stage liver disease symptoms such as cirrhosis. The polypeptide derivatives of the GLP-1R / GIPR / GCGR triple-target receptor agonist of the present invention can effectively regulate blood sugar levels and participate in metabolism, and can fully or partially mediate diseases such as NAFLD, MASH, liver fibrosis, and cirrhosis, or can be independent of the above effects.

[0122] The metabolic syndrome described in the present invention may be diabetes or a diabetes-related disease, or obesity or an obesity-related disease, or NAFLD, MASH or a related disease. The connection between obesity and diabetes is well known, so these conditions are not independent or mutually exclusive, but may be combined together. NAFLD, MASH or a related disease may not be independent or mutually exclusive because the mechanism is complex but also involves and is related to obesity and diabetes.

[0123] The pharmaceutically acceptable free compounds or salts of the GCGR, GIPR and GLP-1R triple-targeted receptor agonist polypeptide derivatives described in the present invention have active preventive and therapeutic effects on cardiovascular and cerebrovascular diseases with complex pathogenesis and related to multiple metabolism-related factors, such as sudden cardiac death (SCD), heart failure with preserved ejection fraction (HFpEF), myocardial infarction (AMI), stroke (CIS), etc.

[0124] The pharmaceutically acceptable free compounds or salts of the polypeptide derivatives of the present invention have positive preventive and therapeutic significance for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) which are related to multiple metabolism-related factors and have complex pathogenesis.

[0125] In the fourth aspect, the present invention has discovered through research that the GLP-1R / GIPR / GCGR triple-target agonist polypeptide derivative has maintained the efficient activation effect of the triple-target polypeptide derivative on receptors such as GCGR, GIPR and GLP-1R through conservative or non-conservative amino acid replacement and long-acting branched chain structure modification in the prior art, while having a better half-life and other pharmacokinetic properties than the prior art, and can significantly exert a long-acting and highly active effect, thereby improving clinical patients' medication compliance.

[0126] In terms of pharmacokinetics, the polypeptide derivatives of the present invention have significantly better half-life, higher Cmax and AUC area, and lower Cl_F, which means that such polypeptide derivatives may reduce the frequency of clinical medication, reduce the dosage, and thus reduce toxic side effects. In particular, the half-life of the polypeptide derivative formula (5) is nearly twice that of the prior art, the AUC area is more than three times that of the prior art, and the Cl_F value is about 1 / 3 of that of the prior art.

[0127] In terms of pharmacology and efficacy, the polypeptide derivatives of the present invention achieve triple-target agonist activity and hypoglycemic and weight-loss efficacy that are equivalent or similar to those of the prior art, and show better effects than the prior art in reducing TC and TG.

[0128] Some of these experimental results are very surprising, making it possible to inject ultra-long-acting peptide preparations monthly or to take peptide drugs orally with longer intervals, which has extremely important clinical application significance. DETAILED DESCRIPTION

[0129] Example 1 Preparation of polypeptide derivative formula (3)

[0130]

[0131] ESI-MS: [M+6H]817.69, [M+5H]981.11, [M+4H]1226.05

[0132] 1) Branched fragment synthesis

[0133] Will and Isobutyl chloroformate was used for condensation coupling under triethylamine conditions, and Boc protection was removed by TFA; Fmoc-Glu-OtBu was condensed and coupled with the product of the previous step using TBTU / DIEA, and Fmoc protection was removed by 20% Pip / NMP solution; tBu group-monoprotected octadecane dioic acid was condensed and coupled to the amino position of Glu in the previous step; finally, palladium-carbon-catalyzed hydrogen hydrolysis was used to remove the benzyl ester to obtain a branched fragment (as shown in the following formula).

[0134]

[0135] 2) Synthesis of fully protected peptide backbone

[0136] According to the amino acid sequence of the peptide chain of the polypeptide derivative formula (3), the Fmoc-protected amino acids are coupled to the RinkAmide-AM resin in reverse order; the condensation coupling reagent uses PyBOP / DIEA or DIC / Cl-HOBt, and 20% piperidine / DMF solution is used to deprotect Fmoc, and the cycle is repeated until all the amino acids complete the peptide chain; wherein the Lys of the branched chain fragment to be connected is Alloc-protected, i.e., Fmoc-Lys(Alloc)-OH.

[0137] 3) Branched chain coupling on peptide resin

[0138] The Alloc protection of Lys side chain of peptide resin was removed by DMF solution mixed with tetrakis(triphenylphosphine)palladium and phenylsilane; the side chain fragment was coupled with peptide resin by HATU / DIEA; the Fmoc protection of the first amino acid was removed by 20% Pip / DMF solution.

[0139] 4) Cleavage and removal of peptide chains and full side chain protection

[0140] The cleavage solution was prepared in the ratio of TFA:TIS:thioanisole:H2O=96:2:1:1, and the fully protected peptide resin was added to the cleavage solution, the target compound was cleaved from the resin and all the protecting groups were removed. TFA was removed by vacuum rotary evaporation, and MTBE was added to the concentrated solution to precipitate a white solid, which was the crude product of the target product polypeptide derivative formula (3).

[0141] 5) Chromatographic purification

[0142] Perform multi-step reverse phase chromatography purification and finally convert the salt into an acetic acid salt solution;

[0143] 6) Freeze-drying

[0144] After freeze-drying, the acetate polypeptide derivative of formula (3) is obtained as a white or off-white loose solid.

[0145] Example 2 Preparation of polypeptide derivative formula (5)

[0146]

[0147] ESI-MS: [M+6H]813.82, [M+5H]976.41, [M+4H]1220.26

[0148] 1) Liquid phase synthesis of branched fragments;

[0149] Will and Isobutyl chloroformate was used for condensation coupling under triethylamine conditions, and Boc protection was removed by TFA; Fmoc-Glu-OtBu was condensed and coupled with the product of the previous step using TBTU / DIEA, and Fmoc protection was removed with 20% Pip / NMP solution; tBu group-monoprotected eicosanedioic acid was condensed and coupled to the amino position of Glu in the previous step; finally, palladium-carbon-catalyzed hydrogen hydrolysis was used to remove the benzyl ester to obtain a branched fragment intermediate (as shown below).

[0150]

[0151] 2) Solid phase method for peptide chain synthesis;

[0152] Rink Amide-MBHA resin is used to couple the Fmoc protected amino acids to the solid phase synthetic resin in reverse order from C-terminus to N-terminus according to the peptide chain amino acid sequence of the polypeptide derivative formula (5), 20% Pip / NMP solution is used to deprotect Fmoc, TBTU / DIEA or DIC / HOBt is used as a condensation coupling reagent, and the cycle is repeated until all the main peptide chain amino acids are completed; wherein Fmoc-Lys(Dde)-OH is used to condense the Lys of the branched chain fragment to be connected to the peptide resin.

[0153] 3) coupling the branched fragment to the peptide resin;

[0154] The Dde protection of the peptide resin in step 2) was removed by using 2% hydrazine hydrate / ethanolamine solution; the intermediate of the branched chain fragment in step 1) was coupled to the peptide resin using condensing agent HATU / DIEA; the first amino acid Fmoc protection was removed by 20% Pip / DMF solution. The peptide resin was washed, shrunk and dried.

[0155] 4) Cleavage to remove the protecting group and resin mounting,

[0156] Prepare a cleavage solution in a certain ratio (TFA:TIS:H2O:EDT=96:2:1:1), add the fully protected peptide resin to the cleavage solution, cut the target compound from the resin and remove the side chain protecting groups. Remove TFA by vacuum rotary evaporation, add Et2O to the concentrated solution to precipitate a white solid, which is the crude target product.

[0157] 5) Chromatographic purification

[0158] Perform multi-step reverse phase chromatography purification or ion chromatography purification, and finally desalt to a free solution;

[0159] 6) Freeze-drying

[0160] After freeze-drying, the sodium-containing polypeptide derivative of formula (5) is obtained as a white or off-white loose solid.

[0161] Example 3 Preparation of polypeptide derivative formula (8)

[0162]

[0163] ESI-MS: [M+6H]818.56, [M+5H]982.08

[0164] 1) Solid phase method for peptide chain synthesis;

[0165] Select Sieber resin to sequentially couple Fmoc-protected amino acids to the solid phase synthetic resin in reverse order from C-terminus to N-terminus according to the peptide chain amino acid sequence of the polypeptide derivative formula (8), deprotect Fmoc with 15% Pip / NMP solution, use DEPBT / DIEA or HBTU / DIEA as condensation coupling reagent, and repeat until all the amino acids in the main peptide chain are completed; wherein Fmoc-Lys(Dde)-OH is selected when condensing the Lys of the branched chain fragment to be connected to the peptide resin, and the α-amino group of the last amino acid Tyr is protected with a Boc group;

[0166] 2) The solid phase method is used to couple each branch chain module to the peptide resin one by one;

[0167] 3,6-dioxanoic acid was preactivated by mixed anhydride method with isobutyl chloroformate and NMM at below 0°C, and then coupled with the main peptide chain resin; Condensation coupling under DIEA catalysis; Fmoc protection is removed with 15% Pip / NMP solution; Fmoc-Glu-OtBu is coupled to the main peptide chain resin using T3P / DIEA condensation; Fmoc protection is removed with 15% Pip / NMP solution; tBu group-monoprotected eicosanedioic acid is coupled to the main peptide chain resin.

[0168] 3) Cleavage and removal of the protecting group and the resin mounting to obtain the polypeptide derivative.

[0169] The cleavage solution was prepared in the ratio of TFA:TIS:phenol:H2O=96:2:1:1, and the fully protected peptide resin was added to the cleavage solution, the target compound was cleaved from the resin and all the protecting groups were removed. TFA was removed by vacuum rotary evaporation, and petroleum ether was added to the concentrated solution to precipitate a white solid, which was the crude product of the target product polypeptide derivative formula (8).

[0170] 4) Chromatographic purification

[0171] Perform multiple steps of reverse phase chromatography purification and finally trans-salt into a sodium-containing aqueous solution;

[0172] 5) Freeze-drying

[0173] After freeze-drying, the sodium-containing polypeptide derivative of formula (8) is obtained as a white or off-white loose solid.

[0174] Example 4

[0175] The compounds described in other inventions were synthesized in Reference Examples 1, 2 and 3 respectively.

[0176] Sulfate peptide derivative formula (1) [M+6H] 803.47, [M+5H] 963.98

[0177] Amine-containing polypeptide derivative formula (2) [M+6H] 822.32, [M+5H] 986.59, [M+4H] 1232.96 Free polypeptide derivative formula (3) [M+5H] 981.11, [M+4H] 1,226.01

[0178] Trifluoroacetic acid peptide derivative formula (4) [M+6H] 806.70, [M+5H] 967.85

[0179] Potassium-containing polypeptide derivative formula (6) [M+6H] 814.06, [M+5H] 976.67, [M+4H] 1220.52

[0180] Phosphopolypeptide derivative formula (7) [M+6H] 817.42, [M+5H] 980.64

[0181] Example 5 Pharmacokinetic experiment of single dose in SD rats

[0182] SD rats, both male and female, were randomly numbered and grouped, with n≥6 animals in each group.

[0183] Preparation method of test solution: Take an appropriate amount of test drug and fully dissolve it with water for injection to obtain a test solution with a concentration of 0.15 mg / mL. Prepare it before administration and store it at 2-8°C.

[0184] The dosage was 0.3 mg / kg, and the dosage volume was 2.0 mL / kg. The drug was administered by subcutaneous injection on the back. 0.1 ml of blood was collected from the eye sockets before administration and 0.5, 2.5, 5.5, 8.0, 12.0, 16.0, 24.0, 32.0, 48.0, 72.0, and 96.0 h after administration, respectively. The blood was placed in an anticoagulant tube containing EDTA-K2 on an ice bath, and centrifuged at 4°C and 5000 rpm for 10 min within 2 h. The plasma was collected and temporarily stored in dry ice and stored in a refrigerator below -60°C within 14 h. The plasma samples were analyzed using the established LC-MS / MS method.

[0185] The original data obtained from the experiment were fitted by the instrument software to obtain the standard curve equation and correlation coefficient, and the drug concentration in the plasma samples at each sampling time point and the concentration of the accompanying quality control samples were calculated.

[0186] SPSS 21.0 was used to analyze the raw data, and WinNonlin 6.4 software was used to calculate the metabolic kinetic parameters of drug concentration and time data according to the non-compartmental model method. The results of the pharmacokinetic experiment are shown in Table 1.

[0187] Table 1: Results of single-dose pharmacokinetic experiments in SD rats

[0188]

[0189]

[0190] Note: The comparative reference (B) in the table is the compound of Example 11 (SEQ ID NO: 16) in patent CN111491658A (application number CN201880081212.3), and the structure is shown below.

[0191]

[0192] The experimental results show that the polypeptide derivatives of the present invention are compared with the comparative reference drugs (A) Retatrutide and (B). Under the same dosage conditions, the Cmax and AUC of the compounds (1), (3), (5) and (8) of the present invention are significantly higher than those of the comparative reference drugs, which means that in the study of drug exposure-effect relationship, the compounds of the present invention only need a lower or smaller dose to achieve or reach the drug effect, thereby better ensuring the safety and effectiveness of the drug. In addition, the half-life of the compound (5) of the present invention is significantly prolonged by almost one-fold, and the long-term effect is extremely significant, which provides a guarantee for reducing the number of drug administrations in the future clinical practice and improving the compliance of patients with medication.

[0193] Example 6 Experiment on reducing blood sugar, weight and lipids by multiple administration in hyperglycemic ob / ob mice

[0194] 48 ob / ob mice (6-8 weeks old) with basal (fasting) blood glucose ≥ 10mmoL / mL were randomly divided into 6 groups according to fasting body weight, blood glucose value and fasting serum TC, namely model control group, test sample group (peptide derivative formula (5) group and peptide derivative formula (2) group) and positive control group (Retatrutide), 8 mice in each group. Another 8 mice fed with conventional diet were set as normal control group (solvent).

[0195] The model control group, the normal control group (solvent), and the positive control group were administered subcutaneously once every 3 days, for a total of 9 times (D0, D3, D6, D9, D12, D15, D18, D21, and D24). The model control group and the normal control group were administered with a dose of 0.15 mL / 20 g of normal saline. The test sample groups (the polypeptide derivative formula (5) group and the polypeptide derivative formula (2) group) were administered subcutaneously once every 4 days, for a total of 7 times (D0, D4, D8, D12, D16, D20, and D24). The test sample group and the positive control group were administered with a dose of 0.25 mg / kg.

[0196] 1) Body weight: Body weight was measured once every 12 hours after fasting but not drinking water before grouping. After grouping, body weight was measured once a day starting from D0.

[0197] 2) Lee's index: The body length was measured once before the first administration and once on D26. The body length is the maximum straight line length from the nose tip to the anus. The body position of the mouse was adjusted so that the body was in a stretched state, and the body length of the mouse was read using a ruler.

[0198] Lee's index = [body weight (g) × 103 / body length (cm)] 1 / 3.

[0199] 3) Determination of blood glucose (GLU): Measure once on D13 and D25.

[0200] 4) Blood biochemistry (TG, TC, LDL, HDL): measured before grouping, on D14 and on D26.

[0201] 5) Fat-body weight coefficient: After the mice were euthanized, the abdominal subcutaneous fat, perigonadal fat, and scapular subcutaneous fat were removed and weighed separately to calculate the fat-body weight coefficient.

[0202] 6) Food intake and water intake: starting from D0, the measurements were taken once a day (except when fasting was performed).

[0203] The experimental results are as follows:

[0204] 1) Weight:

[0205] There was no statistical difference in the initial body weight between the peptide derivative formula (2) and formula (5) groups and the model control group and the positive control group. Starting from D1, the body weight of the animals in the peptide derivative formula (2), formula (5) and positive control groups decreased, and the body weight increased slowly during the experiment (D1-D26), which was significantly lower than that of the model control group (p<0.01). The model control group had the fastest weight gain, with an average weight gain of 8.14 g; the normal control group had an average weight gain of 2.27 g; the average weight of the animals in the peptide derivative formula (2) group decreased by 5.41 g; the average weight of the animals in the peptide derivative formula (5) group decreased by 5.62 g; and the average weight of the animals in the Retatrutide group decreased by 5.58 g. Due to the fasting operation, the average weight gain of the animals in each group was calculated by subtracting the average weight on D0 from the average weight on D26.

[0206] 2) Lee's Index

[0207] Lee's index is an effective indicator of the degree of obesity in rats. The Lee's index of all animals increased, and the normal group animals increased the least. Compared with the model control group, the Lee's index of animals in each drug-treated group decreased slightly. The results show that both the test drug and the positive control drug can inhibit the obesity of ob / ob mice. The weight control ability of the test group drug and the positive control drug is similar, with no statistical difference. The specific experimental results of Lee's index are shown in Table 2.

[0208] Table 2: Lee's Index Table for Animals

[0209]

[0210] Note: Compared with the model control group, *p<0.05, **p<0.01; compared with the positive drug, #p<0.05, ##p<0.01.

[0211] 3) Random blood sugar:

[0212] The blood glucose levels of the animals were measured on D13 and D25 after administration, and the results showed that the blood glucose concentrations of the animals in each administration group were well controlled. Compared with the model control group, the blood glucose levels of the animals in the normal control group on D0, D13, and D25 were significantly lower than those of the mice in the model control group, indicating that the basal blood glucose levels of the hyperglycemic ob / ob mice were higher, which was consistent with the characteristics of the model. Compared with the mice in the model control group, both the test drug and the positive control drug had a very significant hypoglycemic effect, close to the level of the normal group. There was no significant difference between the administration group and the positive control drug (polypeptide derivative formula (2) / polypeptide derivative formula (5) / Retatrutide). The specific experimental results of random blood glucose are shown in Table 3.

[0213] Table 3: Blood sugar changes in experimental animals

[0214]

[0215] Note: Compared with the model control group, *p<0.05, **p<0.01; compared with the positive drug, #p<0.05, ##p<0.01.

[0216] 4) Blood biochemistry

[0217] (1) TC: Before the experiment (D0), the initial values ​​of the polypeptide derivative formula (2) and the model group were higher than those of other mouse groups of the same strain. Compared with the different time after the self-administration, the TC of obese mice in the polypeptide derivative formula (2) group, the polypeptide derivative formula (5) group and the Retatrutide group after administration was significantly reduced, indicating that the test drug and the positive control drug can significantly reduce the TC content. From the results of D14 and D26, it can be seen that the ability of the polypeptide derivative formula (5) to reduce TC is similar to that of Retatrutide, and the ability of the polypeptide derivative formula (2) to reduce TC is better than that of Retatrutide, which is statistically significant. Moreover, when the initial value of the polypeptide derivative formula (2) group is higher, the ability to reduce TC is stronger and close to the level of the Retatrutide group at D26, and the statistical significance is significantly improved from #p<0.05 to no statistical difference. The specific experimental results of TC examination are shown in Table 4.

[0218] Table 4: Changes in TC content in animal blood

[0219]

[0220] Note: Compared with the model control group, *p<0.05, **p<0.01; compared with the corresponding positive drug, #p<0.05, ##p<0.01.

[0221] (2) TG: From the results of D14 and D26, it can be seen that the TG of obese mice in the polypeptide derivative formula (2) group, the polypeptide derivative formula (5) group and the Retatrutide group decreased significantly after administration, indicating that both the test drug and the positive control drug can significantly reduce the TG content. At D26, the test group had a better effect on reducing TG than the positive control drug, with a significant statistical difference (#p<0.05). The specific experimental results of TG examination are shown in Table 5.

[0222] Table 5: TG content in animal blood

[0223]

[0224] Note: Compared with the model control group, *p<0.05, **p<0.01; compared with the corresponding positive drug, #p<0.05, ##p<0.01.

[0225] (3) LDL: At D14 and D26 after administration, the LDL levels of obese mice in the polypeptide derivative formula (2) group, the polypeptide derivative formula (5) group and the Retatrutide group were significantly reduced and significantly lower than that in the model control group (p<0.01). No statistical difference was found between the polypeptide derivative formula (2) group, the polypeptide derivative formula (5) group and the Retatrutide group. The specific experimental results of LDL examination are shown in Table 6.

[0226] Table 6: Animal Blood LDL Content Table

[0227]

[0228] Note: Compared with the model control group, *p<0.05, **p<0.01; compared with the corresponding positive drug, #p<0.05, ##p<0.01.

[0229] (4) HDL: During the experiment, the HDL levels of mice in the model control group were higher than those in the normal control group. Before administration (D0), the HDL levels of mice of the same strain were relatively close. On D14 and D26 after administration, the HDL levels of the polypeptide derivative formula (2) group, the polypeptide derivative formula (5) group and the Retatrutide group were significantly lower than those of the model control group and there was a statistical difference, but no statistical difference was found between the administration groups. The specific experimental results of the HDL examination are shown in Table 7.

[0230] Table 7: Animal blood HDL content

[0231]

[0232] Note: Compared with the model control group, *p<0.05, **p<0.01; compared with the corresponding positive drug, #p<0.05, ##p<0.01.

[0233] The above results indicate that both the test drugs (peptide derivatives of formula (2) and (5)) and the positive control drug (Retatrutide) can reduce the TG, TC, LDL and HDL of animals.

[0234] 5) Fat-to-weight ratio

[0235] After 26 days of administration, the mice were dissected, fat in different parts was separated, and the fat-body weight coefficient was calculated according to the formula (fat / body weight × 100). The results show that the fat-body weight coefficients of the model control group mice in various parts were significantly higher than those of the normal control group mice. The polypeptide derivative formula (2) and the polypeptide derivative formula (5) can significantly reduce the subcutaneous fat and perigonadal fat of the abdomen of hyperglycemic ob / ob mice, and the effect is not significantly different from that of the positive control drug Retatrutide. In addition, the drug has no effect on the subcutaneous fat-body weight coefficient of the scapula. The specific experimental results of the fat-body weight coefficient are shown in Table 8.

[0236] Table 8: Fat-weight coefficient table

[0237]

[0238] Note: Compared with the model control group, *p<0.05, **p<0.01; compared with the corresponding positive drug, #p<0.05, ##p<0.01.

[0239] 6) Food intake and water intake

[0240] After administration, the animals' food intake decreased significantly, and the overall feeding trend of the animals showed a certain correlation with the frequency of administration, with the lowest food intake on the day of administration. As time went on, the food intake increased slowly, but the overall increase was lower than that of the model control group and the normal control group. In the later stage of the experiment, the overall food intake of the animals increased, which may be related to the age and weight gain of the animals. The experimental results show that both the test drug and the positive control drug have a significant effect on controlling food intake.

[0241] The drinking water of each group of experimental animals was quite different, and the drinking water of the drug-treated group was lower than that of the normal group and the model control group. It can be clearly observed that the amount of water consumed by animals after drug administration decreased, and the effect was most obvious after the first administration. The drinking water of mice in subsequent groups increased, and the overall drinking trend of animals showed a certain correlation with the frequency of drug administration. The experimental results show that both the test drug and the positive control drug have obvious drinking water control effects.

[0242] Based on the results of the above experiments on hypoglycemic, weight-reducing and lipid-lowering effects of multiple administration of the drug to hyperglycemic ob / ob mice, the polypeptide derivatives of the present invention have achieved the same or similar triple-target agonist activity and hypoglycemic and weight-reducing effects as Retatrutide, and have shown a more superior effect in reducing TC and TG.

Claims

1. A polypeptide derivative with triple targeting agonism of GCGR, GIPR and GLP-1R or a pharmaceutically acceptable salt thereof, wherein the main peptide chain of the polypeptide derivative with triple targeting agonism of GCGR, GIPR and GLP-1R is represented by formula (I), the side chain is represented by formula (II), and Xaa in the main chain is 17 is Lys, and its side chain ε-amino group is connected to X1 in the branched chain formula (II) in the form of an amide bond; Tyr-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Xaa 12 -No 13 -Leu-Asp-Lys-Xa 17 -Ala-Gln-Xa 20 -Ala-Phe-Xaa 23 -No 24 -No 25 -Leo-Leo-Xia 28 -Gly-Gly-Pro-Ser-Ser-G ly-Ala-Pro-Pro-Pro-Ser-NH2 (Ⅰ) XA 12 Selected from Ile or Lys; XA 13 Selected from Aib or Tyr or α-Me-L; XA 20 Selected from Lys or Aib; XA 23 From Val or Ile; XA 24 Selected from Glu or Gln; XA 25 Selected from Trp or Tyr; XA 28 Selected from Ala or Glu; in, Aib is aminoisobutyric acid, α-Me-L is 2-methyl-leucine (or α-methyl-leucine), and it is connected to the preceding and following amino acids by an amide bond (peptide bond); Alternatively, in formula (II), n is 8 or 9; X2 is X1 is 2. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 1, characterized in that The polypeptide derivative is a polypeptide whose main peptide chain has only Xaa 17 The side chain ε-amino group of the Lys at the position is connected to the side chain containing a long fatty acid, a PEG linker and glutamic acid modification as shown in formula (II) in the form of an amide bond.

3. The polypeptide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: The amino acids in the polypeptide derivative are L-type.

4. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claims 1 and 2, wherein the polypeptide derivative comprises the following structure: Formula (1) Formula (2) Formula (3) Formula (4) Formula (5) Formula (6) Formula (7) Formula (8) 5. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claims 1 and 2, characterized in that: When Xaa 23 When it is Val, Xaa 24 is Gln; when Xaa 23 When it is Ile, Xaa 24 Glu.

6. The method for preparing the polypeptide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: It includes the steps of synthesis of branched chain fragments, synthesis of fully protected polypeptide main chains, coupling of branches to peptide resins, cleavage and removal of peptide chains and full protection of side chains, chromatographic purification and freeze-drying, or it includes the steps of synthesizing peptide chains by solid phase method, coupling each module of the branch chain with peptide resins in turn by solid phase method, cleavage and removal of protecting groups and resin mounting, chromatographic purification and freeze-drying.

7. A pharmaceutical composition comprising the polypeptide derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, and the pharmaceutically acceptable salt is a sodium-containing salt.

8. Use of the polypeptide derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating and / or preventing at least one of the following diseases: metabolic syndrome, obesity, diabetes, obesity-related diseases and diabetes-related diseases.

9. Use of the polypeptide derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating and / or preventing at least one of the following diseases: non-alcoholic simple fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH) and related diseases such as cirrhosis and hepatocellular carcinoma.

10. Use of the polypeptide derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating and / or preventing at least one of the following diseases: insulin resistance, impaired glucose tolerance, prediabetes, elevated fasting blood glucose, type 2 diabetes, hypertension, dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral arterial disease and / or stroke.

11. Use of the polypeptide derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating and / or preventing at least one of the following diseases: obesity-related inflammation, obesity-related gallbladder disease and / or obesity-induced sleep apnea.

12. Use of the polypeptide derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating or preventing at least one of the following diseases: cardiovascular and cerebrovascular diseases, including sudden cardiac death (SCD), heart failure with preserved ejection fraction (HFpEF), myocardial infarction (AMI), and stroke (CIS).

13. Use of the polypeptide derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating and / or preventing at least one of the following diseases: Alzheimer's disease (AD), Parkinson's disease (PD).

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