Triple agonists of glp-1, gip, and gcg receptors and uses thereof

Abstract

The application relates to the field of biological medicines and provides a GLP-1, GIP and GCG receptor triple agonist and application thereof, and relates to a peptide compound with formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X1X2X3 is H-Aib-H, Y-Aib-Q or Y-Ac3c-Q; X17 is Q or K; X18X19 is YA, YQ or AQ; X20 is Aib or Ac3c; X21 is A, D, E or R; X23 is V or I; X24X25 is NW, QR, EY, RY, RH or RW; X28 is E, R or A; X40 is K or is not present; and the C-terminal amino acid is optionally amidated into a C-terminal primary amide. The peptide compound has the effects of reducing weight and controlling blood sugar.

Description

GLP-1, GIP and GCG receptor triple agonists and their uses Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a triple agonist of GLP-1, GIP and GCG receptors and its uses. Background Technology

[0002] Obesity and overweight, as relapsing chronic diseases, can further induce or aggravate other metabolic diseases, including type 2 diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), hyperlipidemia, cardiovascular disease, and other non-communicable diseases such as Alzheimer's disease and depression. Developing safe and effective drugs that reduce weight while controlling blood sugar, improving blood lipids, reducing liver fat accumulation, and decreasing the incidence of adverse cardiovascular events will not only benefit obese individuals but also significantly improve the condition of people with other metabolic diseases and even those with non-metabolic diseases. Therefore, this is currently a hot area of ​​global pharmaceutical research and development.

[0003] Glucagon-like peptide-1 (GLP-1) is a promising treatment for type 2 diabetes. It not only maintains blood glucose balance and avoids the risk of hypoglycemia caused by excessive glucose lowering, but also promotes weight loss and reduces the incidence of cardiovascular events. Glucose-dependent insulinotropic polypeptide (GIP) can promote glucagon secretion and inhibit gastric acid secretion. It has been shown to be an effective stimulant for insulin secretion from pancreatic β-cells after oral glucose ingestion, thus maintaining blood glucose balance and promoting weight loss. While GLP-1 receptor agonists or dual GIP and GLP-1 receptor agonists, such as semaglutide and tirzepatide, are approved for the treatment of type 2 diabetes, they also have significant drawbacks. These include dose-dependent side effects such as nausea and vomiting, and a certain deficiency in increasing lipid metabolism, as GIP also inhibits lipolysis.

[0004] Glucagon (GCG) analogues achieve weight loss by increasing metabolic expenditure and accelerating fat breakdown, compensating for the shortcomings of GLP-1R / GIPR (GLP-1 receptor / GIP receptor) agonists and making them one of the ideal targets for weight loss drugs. However, because glucagon receptor (GCGR) agonists promote glycogenolysis and release glucose into the bloodstream, leading to elevated blood glucose levels, single-target GCGR agonists have not been successfully developed. While dual-target GLP-1R / GCGR agonists may be superior to semaglutide in weight loss, they lack a blood glucose-lowering effect, thus limiting the application of this class of dual-target agonist drugs.

[0005] Theoretically, synergistic effects targeting three targets could yield superior weight loss, potentially improving blood sugar control, weight loss, and metabolic disorders while compensating for or reducing the side effects of single-target drugs. However, the primary and secondary selection of targets and the agonist ratio have become key challenges in drug design and development. Due to the different mechanisms of action of GLP-1, GIP, and GCG in vivo, the probability of off-target effects increases significantly with the number of targets, making the development of GLP-1R / GIPR / GCGR drugs extremely complex and difficult. For example, Retatrutide, a GLP-1R / GIPR / GCGR tri-target co-agonist currently in Phase 3 clinical trials, demonstrated in Phase 2 data on weight loss and MAFLD that while tri-target drugs are more efficient at weight loss than dual-target drugs, they also exhibit more pronounced side effects compared to Smegglutide and Telboride. Its safety and efficacy still require further validation. To date, no tri-target agonist has received clinical approval, and the number of GLP-1R / GIPR / GCGR drugs in clinical trials remains limited.

[0006] Therefore, there is an urgent need to develop new design methods to optimize target selection, increase targeting efficiency, and reduce off-target risks, in order to achieve optimized design of GLP-1R / GIPR / GCGR drugs, enabling the three targets to complement each other's mechanisms, exert synergistic effects, and reduce side effects. The application of AI technology in peptide drug development provides new ideas and methods for the research and development of such drugs, offering an efficient and rapid solution for the development of weight-loss and blood sugar-lowering drugs, and possesses significant social and economic value. Summary of the Invention

[0007] This disclosure is based on Carbon Cloud Group’s proprietary AI and chip design methods to develop and design a novel GLP-1 / GIP / GCG receptor co-agonist.

[0008] On the one hand, this disclosure provides a peptide compound having formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0009] X1X2X3-GTFTSDYSI-αMeL-LD-X 16 X 17 X 18 X 19 X 20 X 21 -FX 23 X 24 X 25 -LL-X 28 -GGPSSGAPPPSX 40 -NH2 (I)

[0010] Where X1X2X3 is H-Aib-H, Y-Aib-Q, or Y-Ac3c-Q; X 17 For Q or K; X 18 X 19 YA, YQ, or AQ; X 20 For Aib or Ac3c; X 21 The answer is A, D, E, or R; X 23 For V or I; X 24 X 25 For NW, QR, EY, RY, RH, or RW; X 28 For E, R, or A; X 40 It is K or absent; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0011] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is H-Aib-H, X 24 X 25 It is NW.

[0012] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA.

[0013] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 It is AQ.

[0014] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Ac3c-Q, X 18 X 19 for YA.

[0015] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is H-Aib-H, X 17 Let K, X 18 X 19 For AQ, X 24 X 25 It is NW.

[0016] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Ac3c-Q, X 17 For Q, X 18 X 19 for YA,X 20 For Aib, X 24 X 25 It is NW.

[0017] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist.

[0018] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is H-Aib-H, X 18 X 19 For AQ, X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For E; X 40 It does not exist.

[0019] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For RW, X 28 For E; X 40 It does not exist.

[0020] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For QR, X 28 For E; X 40 It does not exist.

[0021] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 Let K be the value.

[0022] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Ac3c, X 21 Let A and X be the two numbers. 23 For I, X 24 X 25 For EY, X 28 For E; X 40 It does not exist.

[0023] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 Let K be the value.

[0024] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X20 For Aib, X 21 For D, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist.

[0025] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For D, X 23 For I, X 24 X 25 For RY, X 28 R; X 40 It does not exist.

[0026] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For RH, X 28 For E; X 40 It does not exist.

[0027] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For YQ, X 20 For Aib, X 21 For D, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist.

[0028] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Ac3c-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X28 For A; X 40 It does not exist.

[0029] In some embodiments, X is a peptide compound or a pharmaceutically acceptable salt or solvate thereof. 16 X 17 K can optionally be modified by conjugation with a half-life extension group.

[0030] In some preferred embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, the modification by half-life extension group refers to the modification of the ε-amino group of the K side chain by a half-life extension group.

[0031] In some preferred embodiments, the half-life extension group has the structure of formula (II):

[0032] -([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H(II)

[0033] Where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is an integer from 16 to 18.

[0034] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q or K; X 18 X 19 For YA or AQ; X 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW; X 28 For E or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0035] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q or K; X 18 X 19 is YA; 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW, QR, or RW; X 28 For E or A; X 40 It is K or absent; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0036] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 18 X 19 is YA; 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW, QR, EY, RY, RH, or RW; X 28 For E, R, or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0037] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, wherein a is selected from integers 0-2, b is selected from integers 0-2, c is selected from integers 0-2, and d is 16 or 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0038] In some preferred embodiments, X1X2X3 is Y-Ac3c-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0039] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Ac3c; X 21 For A; X 23 For I; X 24 X25 For EY; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0040] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q or K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW; X 28 For E or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0041] In some more preferred embodiments, d is 18 in the aforementioned half-life extension group.

[0042] In some embodiments, in the aforementioned half-life extension groups, a is 1, b is 0, c is 1, and d is 18.

[0043] In some embodiments, in the aforementioned half-life extension groups, a is 2, b is 0, c is 1, and d is 18.

[0044] In some embodiments, in the aforementioned half-life extension groups, a is 0, b is 2, c is 1, and d is 18.

[0045] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 17 For Q; X 18 X 19is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0046] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0047] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0048] In some preferred embodiments, X1X2X3 is H-Aib-H; X16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0049] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0050] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 17 K; X 18 X 19For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0051] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0052] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0053] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0054] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0055] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d-CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RW; X 28 The amino acid is E; and the C-terminal amino acid is optionally amidated to form a C-terminal primary amide.

[0056] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 The amino acid is E; and the C-terminal amino acid is optionally amidated to form a C-terminal primary amide.

[0057] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0058] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0059] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0060] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0061] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Ac3c; X 21 For A; X 23 For I; X 24 X 25 For EY; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0062] In some preferred embodiments, X1X2X3 is Y-Ac3c-Q; X 16 K; X 17 For Q, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0063] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0064] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0065] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X18 X 19 is YA; 20 For Aib; X 21 For D; X 23 For I; X 24 X 25 For RY; X 28 R; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0066] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RH; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0067] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 YQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0068] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0069] In some embodiments, the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate is selected from:

[0070] The C-terminal amino acid of the peptide compound is optionally amidated to a C-terminal primary amide.

[0071] On the other hand, this disclosure provides a pharmaceutical composition or combination of pharmaceuticals comprising the aforementioned peptide compound or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0072] In some preferred embodiments, the aforementioned composition or pharmaceutical combination further includes a second therapeutic agent.

[0073] In some preferred embodiments, the aforementioned second therapeutic agent is selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors.

[0074] On the other hand, the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate or pharmaceutical composition or combination is used in the preparation of a medicament for treating or preventing metabolic disorder-related diseases or alleviating metabolic disorder-related conditions.

[0075] In some implementations, the aforementioned metabolic disorder-related diseases are selected from obesity, diabetes, dyslipidemia-related diseases, diabetes-induced chronic kidney disease (CKD), metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), metabolic syndrome, and neurodegenerative diseases.

[0076] In some preferred embodiments, the aforementioned neurodegenerative diseases are selected from Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).

[0077] In some implementations, the aforementioned metabolic disorder-related conditions are selected from adult cardiovascular death caused by obesity or overweight, heart attack, stroke, heart failure, diseases or conditions associated with overweight or obesity, binge eating, depression, dyslipidemia, atherosclerosis, hypertension, coronary heart disease, myocardial infarction, stroke, and impaired glucose tolerance (IGT).

[0078] In some implementations, the aforementioned use is in the preparation of drugs for weight loss, appetite regulation, prevention of weight rebound after successful weight loss, lowering blood lipids, or lowering blood sugar.

[0079] On the other hand, this disclosure provides a method for preparing the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, wherein the preparation method is a chemical synthesis method.

[0080] The beneficial effects achieved by this disclosure include at least the following:

[0081] The peptide compound disclosed herein has a non-protein-derived amino acid residue at position 2, which reduces its sensitivity to DPP-IV and increases its stability against proteolytic hydrolysis.

[0082] The peptide compound disclosed herein has a fatty acid chain linked by a linker at a lysine residue at position 16 or 17, which further prolongs the half-life of the peptide in the blood through its binding to albumin, improves the pharmacokinetics of the peptide, and supports the pharmacokinetic (PK) characteristics of once-weekly dosing in patients.

[0083] The peptide compounds disclosed herein effectively reduced the weight of obese mice without producing side effects such as vomiting and diarrhea commonly seen with GLP-1 analogs in animals.

[0084] Based on the activity observed in animal models, the peptide compounds disclosed herein exhibit significantly better weight loss effects than the control compounds Tirzepatide and Retatrutide, and have the potential to generate weight loss in patients by increasing animal energy expenditure data.

[0085] The disclosed peptide compounds have good blood glucose control effects, supporting the possibility of weekly administration in humans. Attached Figure Description

[0086] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this specification and, together with the description, serve to explain the principles of this specification.

[0087] Figure 1 shows a high-performance liquid chromatogram of the polypeptide D4-001 synthesized in Example 1.

[0088] Figure 2 shows the mass spectrum of the polypeptide D4-001 synthesized in Example 1.

[0089] Figure 3 shows the high performance liquid chromatogram of peptide D4-002 synthesized in Example 1.

[0090] Figure 4 shows the mass spectrum of the polypeptide D4-002 synthesized in Example 1.

[0091] Figure 5 shows the high performance liquid chromatogram of peptide D4-003 synthesized in Example 1.

[0092] Figure 6 shows the mass spectrum of the polypeptide D4-003 synthesized in Example 1.

[0093] Figure 7 shows a high-performance liquid chromatogram of the polypeptide D4-004 synthesized in Example 1.

[0094] Figure 8 shows the mass spectrum of the polypeptide D4-004 synthesized in Example 1.

[0095] Figure 9 shows the high performance liquid chromatogram of the polypeptide D4-005 synthesized in Example 1.

[0096] Figure 10 shows the mass spectrum of the polypeptide D4-005 synthesized in Example 1.

[0097] Figure 11 shows the high performance liquid chromatogram of the polypeptide D4-006 synthesized in Example 1.

[0098] Figure 12 shows the mass spectrum of the polypeptide D4-006 synthesized in Example 1.

[0099] Figure 13 shows the high performance liquid chromatogram of the polypeptide D4-007 synthesized in Example 1.

[0100] Figure 14 shows the mass spectrum of the polypeptide D4-007 synthesized in Example 1.

[0101] Figure 15 shows the high performance liquid chromatogram of the polypeptide D4-008 synthesized in Example 1.

[0102] Figure 16 shows the mass spectrum of the polypeptide D4-008 synthesized in Example 1.

[0103] Figure 17 shows the high performance liquid chromatogram of the polypeptide D4-009 synthesized in Example 1.

[0104] Figure 18 shows the mass spectrum of the polypeptide D4-009 synthesized in Example 1.

[0105] Figure 19 shows a high-performance liquid chromatogram of the polypeptide D4-012 synthesized in Example 1.

[0106] Figure 20 shows the mass spectrum of the polypeptide D4-012 synthesized in Example 1.

[0107] Figure 21 shows a high-performance liquid chromatogram of the polypeptide D4-013 synthesized in Example 1.

[0108] Figure 22 shows the mass spectrum of the polypeptide D4-013 synthesized in Example 1.

[0109] Figure 23 shows a high-performance liquid chromatogram of the polypeptide D4-014 synthesized in Example 1.

[0110] Figure 24 shows the mass spectrum of the polypeptide D4-014 synthesized in Example 1.

[0111] Figure 25 shows a high-performance liquid chromatogram of the polypeptide D4-015 synthesized in Example 1.

[0112] Figure 26 shows the mass spectrum of the polypeptide D4-015 synthesized in Example 1.

[0113] Figure 27 shows a high-performance liquid chromatogram of the polypeptide D4-016 synthesized in Example 1.

[0114] Figure 28 shows the mass spectrum of the polypeptide D4-016 synthesized in Example 1.

[0115] Figure 29 shows a high-performance liquid chromatogram of the polypeptide D4-018 synthesized in Example 1.

[0116] Figure 30 shows the mass spectrum of the polypeptide D4-018 synthesized in Example 1.

[0117] Figure 31 shows a high-performance liquid chromatogram of the polypeptide D4-019 synthesized in Example 1.

[0118] Figure 32 shows the mass spectrum of the polypeptide D4-019 synthesized in Example 1.

[0119] Figure 33 shows the high performance liquid chromatogram of the polypeptide D4-020 synthesized in Example 1.

[0120] Figure 34 shows the mass spectrum of the polypeptide D4-020 synthesized in Example 1.

[0121] Figure 35 shows a high-performance liquid chromatogram of the polypeptide D4-021 synthesized in Example 1.

[0122] Figure 36 shows the mass spectrum of the polypeptide D4-021 synthesized in Example 1.

[0123] Figure 37 shows a high-performance liquid chromatogram of the polypeptide D4-022 synthesized in Example 1.

[0124] Figure 38 shows the mass spectrum of the polypeptide D4-022 synthesized in Example 1.

[0125] Figure 39 shows a high-performance liquid chromatogram of the polypeptide D4-023 synthesized in Example 1.

[0126] Figure 40 shows the mass spectrum of the polypeptide D4-023 synthesized in Example 1.

[0127] Figure 41 shows a high-performance liquid chromatogram of the polypeptide L13-D4-002 synthesized in Example 1.

[0128] Figure 42 shows the mass spectrum of the polypeptide L13-D4-002 synthesized in Example 1.

[0129] Figure 43 shows the results of the glucose tolerance test in C57 mice.

[0130] Figure 44 shows the AUC results of glucose tolerance in C57 mice.

[0131] Figure 45 shows the glucose tolerance test results of C57 mice after overnight fasting.

[0132] Figure 46 shows the glucose tolerance AUC results of C57 mice after overnight fasting.

[0133] Figure 47 shows the changes in blood glucose in DIO mice during continuous administration.

[0134] Figure 48 shows the changes in body weight of DIO mice during continuous administration.

[0135] Figure 49 shows the changes in body weight of DIO mice during three consecutive weeks of administration.

[0136] Figure 50 shows the changes in morning blood glucose in DIO mice during three consecutive weeks of administration.

[0137] Figure 51 shows the changes in fasting blood glucose in DIO mice during three consecutive weeks of administration.

[0138] Figure 52 shows the glucose tolerance test results of DIO mice after three consecutive weeks of administration. Detailed Implementation

[0139] I. Definition

[0140] In this disclosure, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the terms and laboratory procedures related to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology used herein are all widely used terms and routine procedures in their respective fields. To better understand this disclosure, definitions and explanations of relevant terms are provided below.

[0141] As used herein, the terms “a” and “an” as well as “the” and similar pronouns indicate singular and plural, unless otherwise specified herein or the context clearly contradicts them.

[0142] As used herein and unless otherwise stated, the terms “about” or “approximately” mean within 10% of a given value or range. Where an integer is required, the term means within 10% of a given value or range, rounded up or down to the nearest integer.

[0143] As used herein, "amino acid" refers to a molecule that contains both amino and carboxyl functional groups. In α-amino acids, the amino and carboxyl groups are attached to the same carbon atom (α-carbon). The α-carbon may have one or two additional organic substituents. Amino acids include L- and D-isomers and racemic mixtures. Unless otherwise specified, the amino acid residues in the polypeptide sequence of this invention are all L-isomers, i.e., L-amino acids. D-amino acids are indicated by adding a lowercase "d" before the amino acid name or abbreviation, such as dK.

[0144] The amino acid sequences of this invention contain conventional single-letter or three-letter codes for naturally occurring amino acids, as well as universally accepted three-letter codes for other amino acids. Commonly used abbreviation codes for molecular structures include:

[0145] Aib is α-aminoisobutyric acid;

[0146] αMeL is α-methyl-L-leucine;

[0147] Ac3c is 1-aminocyclopropane carboxylic acid;

[0148] AEEA is 2-(2-amino-ethoxy)-ethoxy]-acetyl;

[0149] εLys is the L-isomer of -NH(CH2)4CH(NH2)CO-

[0150] γGlu is an L isomer of -HNCH(COOH)CH2CH2CO-.

[0151] In this invention, the amino acid composition of the polypeptide can be altered without significantly affecting its biological activity. For example, a polypeptide sequence may contain one or more conserved amino acid substitutions. A conserved amino acid substitution is the replacement of one amino acid residue with another amino acid residue having a similar side chain. The literature classifies amino acid residues based on the nature of their side chains. Amino acid residues containing basic side chains include lysine, arginine, and histidine; amino acid residues containing acidic side chains and amide side chains include aspartic acid, glutamic acid, asparagine, and glutamine; amino acid residues with small aliphatic, nonpolar, or weakly polar side chains include glycine, alanine, threonine, serine, and proline; amino acid residues with large aliphatic, nonpolar side chains include leucine, isoleucine, and valine; aromatic amino acid residues include phenylalanine, tryptophan, and tyrosine; and amino acid residues with sulfur-containing side chains include cysteine ​​and methionine.

[0152] As used herein, the term "pharmaceutically acceptable salt or solvate" is intended to include pharmaceutically acceptable acid addition salts formed by the reactions of the compounds of the present invention with any of a variety of inorganic or organic acids. Pharmaceutically acceptable salts and common methods for their preparation are well known in the art. Commonly used pharmaceutically acceptable salts include trifluoroacetates, acetates, citrates, hydrochlorides, etc.

[0153] As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delayers compatible with drug administration. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, glucose solution, and 5% human serum albumin. Liposomes and non-aqueous carriers, such as immobilized oils, may also be used. The use of such media and reagents for pharmaceutically active substances is well known in the art.

[0154] As used herein, the term "treatment" includes suppressing, slowing, stopping, or reversing existing symptoms or the progression or severity of a patient's condition. Therefore, treatment encompasses prevention, treatment, and / or cure. Prevention refers to preventing underlying disease and / or preventing the worsening of symptoms or the development of disease.

[0155] II. Detailed Implementation Plan

[0156] The embodiments of this disclosure will be described in detail below with reference to examples. Those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this disclosure. The scope of this disclosure may include some embodiments having a combination of all or some of the described features. Where specific techniques or conditions are not specified in the examples, they are performed in accordance with the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0157] On the one hand, this disclosure provides a peptide compound having formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0158] X1X2X3-GTFTSDYSI-αMeL-LD-X 16 X 17 X 18 X 19 X 20 X 21 -FX 23 X 24 X 25 -LL-X 28 -GGPSSGAPPPSX 40 -NH2 (I)(SEQ ID No:25)

[0159] Where X1X2X3 is H-Aib-H, Y-Aib-Q, or Y-Ac3c-Q; X 17 For Q or K; X 18 X 19 YA, YQ, or AQ; X 20 For Aib or Ac3c; X 21 The answer is A, D, E, or R; X 23 For V or I; X 24 X 25 For NW, QR, EY, RY, RH, or RW; X 28 For E, R, or A; X 40 It is K or absent; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0160] In the polypeptides of the above compounds, the "-" between amino acids represents an amide bond.

[0161] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is H-Aib-H, X 24 X 25 It is NW.

[0162] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA.

[0163] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 It is AQ.

[0164] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is H-Aib-H, X 17 Let K, X 18 X 19 For AQ, X 24 X 25 It is NW.

[0165] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Ac3c-Q, X 17 For Q, X 18 X 19 for YA,X 20 For Aib, X 24 X 25 It is NW.

[0166] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist.

[0167] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is H-Aib-H, X 18 X 19 For AQ, X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For E; X 40 It does not exist.

[0168] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For RW, X 28 For E; X 40 It does not exist.

[0169] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For QR, X 28 For E; X 40 It does not exist.

[0170] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 Let K be the value.

[0171] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Ac3c, X 21 Let A and X be the two numbers. 23 For I, X 24 X 25 For EY, X 28 For E; X 40 It does not exist.

[0172] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X19 For AQ, X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 Let K be the value.

[0173] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Aib, X 21 For D, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist.

[0174] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For D, X 23 For I, X 24 X 25 For RY, X 28 R; X 40 It does not exist.

[0175] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For RH, X 28 For E; X 40 It does not exist.

[0176] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Aib-Q, X 18 X 19 For YQ, X 20 For Aib, X 21 For D, X 23 Let V, X 24 X25 For NW, X 28 For A; X 40 It does not exist.

[0177] In some embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, X1X2X3 is Y-Ac3c-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist.

[0178] In some embodiments, X is a peptide compound or a pharmaceutically acceptable salt or solvate thereof. 16 X 17 K can optionally be modified by conjugation with a half-life extension group.

[0179] In some preferred embodiments, in the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate, the modification by half-life extension group refers to the modification of the ε-amino group of the K side chain by a half-life extension group.

[0180] In some embodiments, the aforementioned half-life extension group is related to X 16 X 17 or X 40 At least one of the K side chains has an ε-amino group linked by an amide bond.

[0181] In some preferred embodiments, the half-life extension group has the structure of formula (II):

[0182] -([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H(II)

[0183] Where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is an integer from 16 to 18.

[0184] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b-(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q or K; X 18 X 19 For YA or AQ; X 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW; X 28 For E or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0185] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q or K; X 18 X 19 is YA; 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW, QR, or RW; X 28 For E or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0186] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 18 X19 is YA; 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW, QR, EY, RY, RH, or RW; X 28 For E, R, or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0187] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, wherein a is selected from integers 0-2, b is selected from integers 0-2, c is selected from integers 0-2, and d is 16 or 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0188] In some preferred embodiments, X1X2X3 is Y-Ac3c-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0189] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Ac3c; X 21 For A; X 23 For I; X 24 X 25 For EY; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0190] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW; X 28 For E or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0191] In some more preferred embodiments, d is 18 in the aforementioned half-life extension group.

[0192] In some embodiments, in the aforementioned half-life extension groups, a is 1, b is 0, c is 1, and d is 18.

[0193] In some embodiments, in the aforementioned half-life extension groups, a is 2, b is 0, c is 1, and d is 18.

[0194] In some embodiments, in the aforementioned half-life extension groups, a is 0, b is 2, c is 1, and d is 18.

[0195] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0196] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0197] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0198] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0199] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 17 K; X 18 X 19 For AQ; X20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0200] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0201] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0202] In some preferred embodiments, X1X2X3 is H-Aib-H; X16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0203] In some preferred embodiments, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0204] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19For AQ; X 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0205] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0206] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0207] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0208] In some preferred embodiments, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0209] In some embodiments, if formula (II) contains lysine, the other groups are linked by an amide bond formed on the ε-amino group of the lysine residue side chain.

[0210] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0211] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0212] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Ac3c; X 21 For A; X 23 For I; X 24 X 25 For EY; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0213] Preferably, X1X2X3 is Y-Ac3c-Q; X 16 K; X 17 For Q, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0214] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0215] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d-CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0216] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 For D; X 23 For I; X 24 X 25 For RY; X 28 R; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0217] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RH; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0218] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 YQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0219] Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

[0220] In some embodiments, the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate is selected from:

[0221] The C-terminal amino acid of the peptide compound is optionally amidated to a C-terminal primary amide.

[0222] On the other hand, this disclosure provides a pharmaceutical composition or combination of pharmaceuticals comprising the aforementioned peptide compound or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0223] In some preferred embodiments, the aforementioned composition or pharmaceutical combination further includes a second therapeutic agent.

[0224] In some preferred embodiments, the aforementioned second therapeutic agent is selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors.

[0225] On the other hand, the aforementioned peptide compound or its pharmaceutically acceptable salt or solvate or pharmaceutical composition or combination is used in the preparation of a medicament for treating or preventing metabolic disorder-related diseases or alleviating metabolic disorder-related conditions.

[0226] In some implementation schemes, the aforementioned metabolic disorder-related diseases are selected from obesity, diabetes, dyslipidemia-related diseases, chronic kidney disease induced by diabetes (CKD), metabolic dysfunction-related fatty liver disease (MASLD), metabolic dysfunction-related steatohepatitis (MASH), metabolic syndrome, and neurodegenerative diseases.

[0227] In some preferred embodiments, the aforementioned neurodegenerative diseases are selected from Alzheimer's disease, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).

[0228] In some implementations, the aforementioned metabolic disorder-related conditions are selected from adult cardiovascular death caused by obesity or overweight, heart attack, stroke, heart failure, diseases or conditions associated with overweight or obesity, overeating, depression, dyslipidemia, atherosclerosis, hypertension, coronary heart disease, myocardial infarction, stroke, and impaired glucose tolerance (IGT).

[0229] In some implementations, the aforementioned use is in the preparation of drugs for weight loss, appetite regulation, prevention of weight rebound after successful weight loss, lowering blood lipids, or lowering blood sugar.

[0230] In some implementations, the administration route includes parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal, transmucosal, and rectal administration.

[0231] For the purpose of clarity and concise description, the features are described herein as part of some identical or separate embodiments; however, it will be understood that the scope of this disclosure may include some embodiments having a combination of all or some of the features described.

[0232] The abbreviations used in the following embodiments are as follows:

[0233] Alloc: allyloxycarbonyl;

[0234] Fmoc: 9-fluorenylmethoxycarbonyl;

[0235] DIPEA: N,N-diisopropylethylenediamine;

[0236] DCM: Dichloromethane;

[0237] HOAt: 1-Hydroxy-7-azobenzotriazole;

[0238] DMF: N,N-dimethylformamide;

[0239] PBS: Potassium dihydrogen phosphate (KH2PO4): 0.27 g / L, disodium hydrogen phosphate dodecahydrate (Na2HPO4·12H2O): 2.85 g / L, sodium chloride (NaCl): 8.5 g / L, potassium chloride (KCl): 0.2 g / L, pH 7.4.

[0240] Example

[0241] Example 1: Synthesis of Polypeptides

[0242] The laboratory synthetic route for the polypeptide disclosed in this application is as follows: using a common solid-phase coupling synthesis method, the C-terminus of the carboxyl group is coupled with Wang resin or chlorotriphenylmethyl resin, all amino acids are protected with Fmoc, and the lysine at position 20 (Lys) is protected with Alloc. When coupling the side chain, the Lys at position 20 is deprotected and couples with different fatty acid side chains. The basic synthetic process is as follows:

[0243] 1.1. Resin swelling

[0244] Weigh the appropriate amount of MBHA resin and pour it into a peptide solid-phase synthesis tube. Swell the resin with dichloromethane at a ratio of 1g to 10mL (the solvent should just cover the resin). The swelling time is approximately 30 minutes to 2 hours. After the resin has completely swelled, remove the solvent. Add DMF at a ratio of 1g to 10mL and wash the resin for 1 minute. Then, remove the solvent under vacuum. Repeat this operation twice. After swelling is complete, add a 20% piperidine DMF solution to remove the Fmoc protecting group. The removal time is 5 minutes + 7 minutes. After removal, wash the resin six times with DMF, 1 minute each time. The resin should turn purple when tested with ninhydrin.

[0245] 1.2. Peptide sequence elongation

[0246] Add the reaction raw materials according to the appropriate ratio (moles of active groups in the resin: moles of the materials): AA (amino acid, 3 equivalents), HOAt (3 equivalents), condensing agent (3 equivalents), and DIPEA (9 equivalents). The solvent is DMF. Under nitrogen protection, react at room temperature by blowing or shaking for 1-2 hours. Remove the solvent under vacuum, add DMF and wash three times, 1 minute each time. Then take a small amount of resin for ninhydrin testing (using a hot plate). If the resin is colorless, it indicates that this step of the condensation reaction is complete.

[0247] During peptide chain elongation, the Fmoc protecting group on the previous amino acid needs to be removed. Add 20% piperidine DMF solution to the reaction tube (enough to cover the resin), and remove the group over 5 min + 7 min. After removal, remove the piperidine solution and wash the tube six times with DMF solution for 1 min each time. After Fmoc removal, the ninhydrin detection resin should turn purple (the color may vary slightly depending on the amino acid).

[0248] Continue adding amino acids as described above until the peptide sequence is complete.

[0249] 1.3. Remove Alloc and connect sidechain fragments

[0250] If K at position 16, 17, or 40 is composed of ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2) 18 -CO2H (purchased from Jier Biochemical, Cas No: 1188328-37-1) side chain modification is performed after the main chain peptide resin coupling is completed. Then, 0.5 equivalents of tetra-triphenylphosphine palladium and 20 equivalents of morpholine are added, and the reaction is carried out in DCM as solvent for two hours. Samples are taken for MS detection. If the result is correct, the side chain can be coupled.

[0251] If K at position 16, 17, or 40 is composed of ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-γGlu-CO-(CH2) 18 For -CO2H side chain modification, after the main chain peptide resin coupling is completed, add the reaction raw materials according to the appropriate ratio (moles of active groups in the resin: moles of the material): AA (amino acid, 3 equivalents), HOAt (3 equivalents), condensing agent (3 equivalents), and DIPEA (9 equivalents). The solvent is DMF. Under nitrogen protection, react at room temperature by blowing or shaking for 1-2 hours. Remove the solvent under vacuum, add DMF and wash three times, 1 minute each time. Then take a small amount of resin for ninhydrin testing (using a hot plate). If the resin is colorless, it indicates that this condensation reaction is complete.

[0252] If K at position 16 or 17 is (εLys)2-γGlu-CO-(CH2) 18For -CO2H side chain modification, after the main chain peptide resin coupling is completed, add the reaction raw materials according to the appropriate ratio (moles of active groups in the resin: moles of the materials): AA (lysine and glutamic acid, 3 equivalents), HOAt (3 equivalents), condensing agent (3 equivalents), DIPEA (9 equivalents), and DMF as solvent. Under nitrogen protection, react at room temperature by blowing or shaking for 1-2 hours. Remove the solvent under vacuum, add DMF and wash three times, 1 minute each time. Then, take a small amount of resin for ninhydrin testing (using a hot plate). A colorless resin indicates that this condensation reaction is complete.

[0253] During peptide side chain elongation, the Fmoc protecting group on the previous amino acid needs to be removed. Add 20% piperidine DMF solution to the reaction tube (enough to cover the resin), and the removal time is 5 min + 7 min. After the removal is complete, remove the piperidine solution and wash six times with DMF solution, 1 min each time. After Fmoc removal, the ninhydrin detection resin should turn purple (the color may vary slightly depending on the amino acid).

[0254] Continue adding amino acids to the side chain peptide sequence using the method described above.

[0255] 1.4. Pyrolysis

[0256] Methanol is added to shrink the resin. After shrinkage, the methanol is filtered off under reduced pressure, and the resin is dried (the dried resin is in powder form and can slide freely). It is then cleaved using a classic lysis buffer to obtain crude GLP-1 peptides.

[0257] 1.5. Purification

[0258] The crude peptide was purified to >97% purity (15-20% purification yield) by reversed-phase HPLC on a C18 column using a water / acetonitrile (containing 0.05% v / v TFA) gradient. The appropriate fractions were combined and freeze-dried.

[0259] The names, sequences, and salt forms of the synthesized peptides are as follows, and the high-performance liquid chromatograms and mass spectra of each peptide are shown in Figures 1-40:

[0260] To investigate the effect of α-methylleucine (αMeL) at position 13 on the three-target agonist efficacy, this patent synthesized a D4-002 derivative with Leu substitution at position 13, named L13-D4-002, whose sequence is shown below:

[0261] Its structure is as follows:

[0262] In subsequent tests, the performance of D4-002 and L13-D4-002 in various tests was compared head-to-head.

[0263] Example 2: Detection of GLP-1R / GIPR / GCGR agonist activity at the cellular level

[0264] By applying the peptides synthesized in Example 1 to H_GLP1R Reporter HEK-293 (Jiman Biotechnology, catalog number GM-C25537), H_GIPR Reporter HEK-293 (Jiman Biotechnology, catalog number GM-C24030), and H_GCGR Reporter HEK-293 cell lines (Jiman Biotechnology, catalog number GM-C31698), which express human GLP-1R / GIPR / GCGR genes and pCRE-Luc genes respectively (these are Luciferase reporter gene cell lines constructed based on the cAMP-PKA signaling pathway), and using a luciferase reporter assay kit (One-Gl luciferase assay kit, Promega) to detect the cAMP produced by the recipient cells, dose-response curves were established, and EC50 was calculated. 50 The specific steps are as follows:

[0265] Cells were cultured in DMEM medium containing 10% FBS, 4 μg / mL blastidin, and 0.75 μg / mL puromycin in cell culture flasks. When the confluence reached about 90%, the culture supernatant was discarded, 2 ml of trypsin was added for digestion, and digestion was terminated with DMEM medium containing 10% FBS. The cells were centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in 2 ml of DMEM medium containing 10% FBS. Cell counts were then performed.

[0266] Cells were diluted in DMEM medium containing 10% FBS, 4 μg / mL blastomycin, and 0.75 μg / mL puromycin, and 100 μl was seeded into each well of a 96-well plate to achieve a cell density of 1.5 × 10⁻⁶ cells / well. 4After discarding the supernatant from cells seeded in 96-well plates, peptide compounds were added to cell culture wells at 100 μl / well, along with natural GLP-1 (MCE, 1013659), GIP (GIL, 55416), glucagon (Bide Pharmaceuticals, BD132093), or retaglutide (GIL Synthetic) as controls. These compounds were diluted to specified concentrations using DMEM medium containing 1% FBS. The mixture was incubated at 37°C (in the presence of 0.05% human serum albumin) for 4 hours before detection. Detection was performed according to the luciferase reporter assay kit instructions. The results are shown in Table 1. D4-001–D4-014 showed agonistic activity against all three receptors: GLP-1R, GIPR, and GCGR. Compared to retaglutide, D4-001–D4-003 showed stronger agonistic activity against GCGR, while D4-004–D4-009 showed stronger agonistic activity against GLP-1R.

[0267] For the excitatory capacity of GLP-1R, D4-002 is significantly superior to L13-D4-002.

[0268] Table 1: Functional efficacy of peptides and cAMP efficiency (ECG) 50 )

[0269] Example 3: Human and mouse plasma stability experiment

[0270] Take 199 μL of blank plasma of various species into a 1.5 mL centrifuge tube and pre-incubate at 37°C and 300 rpm for 10 min in an Eppendorf Thermomixer. Repeat this process for 3 samples. Add 1 μL of the test sample working solution or positive control working solution to the pre-incubated plasma and vortex to mix (final concentration 1.00 μM). Immediately take 20 μL of plasma sample, add 80 μL of ice precipitant (50% methanol-50% acetonitrile internal standard solution), vortex to mix, and centrifuge (4°C, 12000 rpm, 10 min). Take the supernatant as the 0 h sample. Continue incubating the remaining sample at 37°C. At the time points shown below, take 20 μL of plasma sample, add 80 μL of ice precipitant (50% methanol-50% acetonitrile internal standard solution), vortex to mix, and centrifuge (4°C, 12000 rpm, 10 min). Take the supernatant as the sample for each time point.

[0271] Incubation times for the test group and positive control group were 0, 4 h, 1 d, 2 d, 4 d, and 7 d. Collected samples were stored at -20℃ for later analysis. Drug plasma concentrations were determined using a Sciex Triple Quad 5500 (SCIEX) LC-MS / MS system. MRM parameters for each compound are shown in Table 2 below.

[0272] Table 2: MRM parameters for each compound

[0273] All measured and calculated data should retain three significant figures, including the numerical values ​​generated during drug concentration analysis and the numbers calculated for pharmacokinetic parameters.

[0274] (1) Calculation of the residual rate

[0275] (2) Calculation of elimination rate constant and half-life

[0276] According to first-order reaction kinetics, t 1 / 2 Critical value = ln2 / ((1 / T) max )ln(1 / residual rate)); When the residual rate is >80%, it is considered that no metabolic elimination has occurred. The residual rate is calculated as 80% when calculating the critical value, and Tmax is calculated according to the final incubation time of the experiment.

[0277] The average substrate residue and elimination half-life in human plasma after incubation for different times using the substrate elimination method are shown in Table 3 below:

[0278] Table 3: Mean residual rate (%) and half-life (d) of different test substances after incubation in human plasma (n=3)

[0279] The results showed that after 7 days of incubation in human plasma, the mean substrate residue rates of D4-002, D4-003, D4-004, D4-005, D4-007, D4-008, D4-012, and retaglutide were 92%, 106%, 90%, 100%, 95%, 99%, 99%, and 73%, respectively. This suggests that retaglutide has lower stability in human plasma than peptides D4-002–005, 007, and 008.

[0280] The average substrate residue in mouse plasma after incubation for different times and the half-life were obtained by applying the substrate elimination method and linear fitting, as shown in Table 4 below.

[0281] The results showed that after 7 days of incubation in mouse plasma, the mean substrate residues of D4-001, D4-002, D4-003, D4-004, D4-005, D4-006, D4-007, D4-008, D4-012, and L13-D4-002 (retaglutide) were 23%, 25%, 24%, 28%, 22%, 16%, 17%, 30%, 13%, 15%, and 27%, respectively. The elimination half-life t0 in mouse plasma was also [not specified]. 1 / 2The time to metabolism was within the range of 2.35–3.99 days. This indicates that the test substances were metabolized slowly in mouse plasma. Among them, D4-006, 012, and L13-D4-002 showed slightly lower stability in mouse plasma, while the other peptides showed no significant difference and were all relatively stable.

[0282] Table 4: Mean residual rate (%) of different test substances after incubation in mouse plasma

[0283] Example 4: Rat Pharmacokinetic Experiment

[0284] Male SD rats weighing approximately 200g were acclimatized to their environment for 3 days. They were then subcutaneously administered the drug at a concentration of 100μmol / kg. Blood samples were collected from the external jugular vein at 5 min, 30 min, 1 h, 2 h, 6 h, 24 h, 30 h, 48 h, 54 h, 72 h, 96 h, 120 h, and 144 h, with approximately 200μL collected each time. The blood was gently mixed in an anticoagulant EP tube containing heparin sodium, centrifuged at 6800 rpm for 5 minutes at 4°C, and the supernatant was stored at -80°C.

[0285] Drug plasma concentrations were detected using a Sciex Triple Quad 5500 (SCIEX) LC-MS / MS system. The parameters are shown in Table 5. Each co-agonist exhibited a half-life of several hours in rats (T0). 1 / 2 ), of which D4-002, D4-008 and retaglutide half-life and MRT (0-t) It is close to the known good in vivo stability.

[0286] Table 5: Mean plasma pharmacokinetic parameters after a single subcutaneous administration of 100 nmol / kg to male DIO mice

[0287] Example 5: Intraperitoneal glucose tolerance test in C57 mice

[0288] Male C57 / bl6 mice (purchased from Beston) aged 8-10 weeks were housed under standard conditions with free access to water and food from arrival. They were used for experiments after 5 days of acclimatization. Mice were used in experiments once a week, after which they were euthanized.

[0289] Before the experiment, mice were weighed and administered the drug subcutaneously at a dose of 30 nmol / kg, 10 ml / kg. They were then fasted but allowed free access to water for 6 hours. Blood glucose was measured at the tail end using the Roche Smart Glucose Meter (China), and mice were randomly grouped according to their blood glucose levels (5 or 6 mice / group), with each group having a similar initial average blood glucose level. Glucose (2 g / kg, 10 ml / kg) was injected intraperitoneally, and blood glucose levels were measured at 15, 30, 60, and 120 minutes. The AUC (area under curve, mmol*min / L) was calculated to assess the effect of the compounds on blood glucose. The results are shown in Figures 43 and 44. In the glucose tolerance test, D4-002 and D4-001 effectively controlled blood glucose in mice, and their blood glucose control ability was comparable to that of retaglutide.

[0290] To evaluate the effect of α-methylation modification of leucine at position 13 on the ability of receptor co-agonists to control blood glucose in animals, a glucose tolerance test was conducted on D4-002 and L13-D4-002 mice after overnight fasting. Male C57 / bl6 mice (purchased from Guangdong Zhiyuan Biomedical Technology Co., Ltd.) aged 8-10 weeks were housed under standard conditions with free access to water and food from arrival, and were used for the experiment after 5 days of acclimatization. The mice were euthanized after the experiment.

[0291] Before the experiment, mice were weighed and randomly divided into three groups (n=5 / group): D4-002, L13-D4-002, and solvent group. The mice were administered the compound subcutaneously at doses of 30 nmol / kg and 5 ml / kg, respectively. They were then fasted overnight but allowed free access to water. Blood glucose was measured at the "0" time point the following morning via orbital sampling. Subsequently, glucose (2 g / kg, 10 ml / kg) was injected intraperitoneally, and blood glucose levels were measured at 15, 30, 60, and 120 minutes. The AUC (area under curve, mmol*min / L) was calculated to assess the effect of the compound on blood glucose. The results are shown in Figures 45 and 46. After a single subcutaneous administration and overnight fasting, the blood glucose levels ("0" time point) in the D4-002 and L13-D4-002 groups were significantly lower than those in the solvent control group. Following intraperitoneal injection of glucose, at all time points from 15 to 120 minutes, the blood glucose levels in mice in the D4-002 and L13-D4-002 groups were significantly lower than those in the solvent control group (p<0.01). At 15 minutes after glucose injection, the blood glucose level in the D4-002 group was significantly lower than that in the L13-D4-002 group. The blood glucose AUC in both the D4-002 and L13-D4-002 groups was significantly lower than that in the solvent control group (p<0.01), and the blood glucose AUC in the D4-002 group was significantly lower than that in the L13-D4-002 group (p<0.05). Therefore, in healthy mice, at a subcutaneous dose of 30 nmol / kg, the blood glucose-lowering ability of D4-002 is superior to that of L13-D4-002.

[0292] Example 6: In vivo study of the drug's effects on weight loss, metabolism, and biochemistry in an obese model (DIO) C57 / B16 mice.

[0293] The compound synthesized in Example 1 was administered to C57Bl6 DIO mice to investigate its effects on parameters such as weight loss, metabolism, and blood glucose.

[0294] Six-week-old C57 / BI6 mice were fed a high-calorie diet for 14 weeks to create C57Bl6 DIO mice, which exhibited characteristics of metabolic syndrome such as insulin resistance and dyslipidemia, despite not having diabetes. The mice were then transported to the experimental site and housed individually in a temperature-controlled environment (23℃-26℃) with a 12-hour light-dark cycle (lights were turned on at 21:00) and free access to food (XTHF60) and water. After 2-3 weeks of acclimatization, the mice were randomly assigned to experimental groups based on their weight, ensuring similar weights (approximately 40g-50g) across groups. Each group contained 5 mice.

[0295] D4-002, D4-008, Retaglutide, and Telboride (Jianxiang Biotechnology, CAS2023788-19-2) were dissolved in PBS and administered subcutaneously (5 mL / kg) to DIO mice on a free-feeding basis, along with a solvent control group (PBS), between 10:00 AM and 12:00 PM. Administration was repeated three times a week for 15 days (days 1-15). Body weight and food intake were measured daily throughout the study, including one day after the last administration (day 15). The absolute and relative changes in body weight were calculated by subtracting the body weight of the same animal before the first injection. The mean ± SEM data for each group of 5 animals were statistically analyzed, and the results are shown in Table 6. Blood glucose levels were measured 6 hours after fasting on days 1 and 12 (using an Accu-Chek blood glucose meter); morning blood glucose levels were measured on days 3 and 10, and the results are shown in Figure 47.

[0296] Table 6: Weight changes in each experimental group on day 15 after drug administration

[0297] Statistical analysis of mouse body weight changes was performed using repeated measures ANOVA and Dunnett's method for multiple comparisons. A p-value < 0.05 was considered statistically significant (*). As shown in Figure 48, after two weeks of experimentation, the body weight of DIO mice in each treatment group decreased to varying degrees. Compared with the solvent control group, the body weight of mice in the telpotetide, retaglutide, D4-002, and D4-008 groups was significantly reduced (p < 0.001). Furthermore, the proportion of body weight loss in the retaglutide (p < 0.05), D4-002 (p < 0.01), and D4-008 (p < 0.05) groups was significantly greater than that in the telpotetide group. Further, the weight loss rate in the D4-002 group was significantly better than that in the retaglutide group (p < 0.05), suggesting that D4-002 is a superior weight-loss compound compared to retaglutide.

[0298] Example 7: Study on the effects of drugs on weight loss, metabolism, and biochemical parameters in obese model (DIO) C57 / B16 mice

[0299] To compare the effects of α-methylation of leucine at position 13 of peptide sequence D4-002 on body weight, metabolism, and biochemistry in obese mice, and to compare the differences in the effects of D4-002, D4-004, D4-005, and retaglutide on body weight, metabolism, and biochemistry in obese mice, D4-002, D4-005, D4-004, L13-D4-002, and retaglutide were administered to C57Bl6 DIO mice, and data on body weight, blood glucose, and biochemical parameters were collected and analyzed.

[0300] Six-week-old C57 / BI6 mice were fed a high-calorie diet for 14 weeks to create C57Bl6 DIO mice, which exhibited characteristics of metabolic syndrome such as insulin resistance and dyslipidemia, despite not having diabetes. The mice were then transported to the experimental site and housed individually in a temperature-controlled environment (23℃-26℃) with a 12-hour light-dark cycle (lights were turned on at 21:00) and free access to food (XTHF60) and water. After 2-3 weeks of acclimatization, the mice were randomly assigned to experimental groups based on their weight, resulting in similar weights (approximately 40g to 52g) across groups. Each group contained 5 mice.

[0301] D4-002, D4-004, D4-005, L13-D4-002, and retaliglutide, along with solutions dissolved in PBS and a solvent control (PBS), were administered subcutaneously (5 mL / kg) to freely feeding DIO mice between 10:00 AM and 12:00 PM, three times a week for 21 days (days 1-22). Body weight was measured daily throughout the study, and food intake was measured three times a week, including three days after the last administration (day 22). The absolute and relative changes in body weight were calculated by subtracting the body weight of the same animal before the first injection. The mean ± SEM data for each group of five animals were statistically analyzed, and the results are shown in Table 7. The weight loss rate of mice from day 1 to 22 is shown in Figure 49. Morning blood glucose levels were measured on days 3, 10, and 17, and the results are shown in Figure 50. Blood glucose levels were measured 6 hours after fasting on days 3, 13, and 24, and the results are shown in Figure 51.

[0302] Table 7: Body weight changes in each experimental group on day 22 of drug administration (mean ± SEM)

[0303] Statistical analysis of mouse body weight changes was performed using repeated measures ANOVA and the Tukey method for multiple comparisons. A p-value < 0.05 was considered statistically significant (*). As shown in Figure 49, after three weeks of experimentation, the body weight of DIO mice in each treatment group decreased to varying degrees. Compared with the solvent control group, the body weight of mice in the retaglutide group, D4-002, D4-004, D4-005, and L13-D4-002 groups was significantly lower (p < 0.0001). The weight loss rate in the D4-002 group was greater than that in the L13-D4-002 group (p < 0.001), while the proportion of body weight loss in the D4-002 (p < 0.001), D4-004 (p < 0.001), and D4-005 (p < 0.01) groups was also significantly greater than that in the retaglutide group. In summary, the weight loss results show that D4-002 has a significantly stronger weight loss effect than L13-D4-002, indicating that the modification at site 13 has a clear advantage in weight loss efficacy. Furthermore, D4-002, D4-004, and D4-005 all exhibit better weight loss effects than retaglutide, suggesting that D4-002, D4-004, and D4-005 are superior weight loss drugs compared to retaglutide.

[0304] On days 3 and 10 after drug administration, the morning blood glucose levels in mice in the D4-002, 004, and retaglutide groups were significantly lower than those in the solvent control group (p<0.05) and the L13-D4-002 group (p<0.05). The morning blood glucose levels in mice in the D4-005 group were significantly lower than those in the solvent control group (p<0.05).

[0305] On day 17 of drug administration, the morning blood glucose levels in mice in the D4-002 group were significantly lower than those in the retaglutide group (p<0.05) and the L13-D4-002 group (p<0.05). There were no significant differences in morning blood glucose levels in the other drug administration groups.

[0306] On day 3 before administration (D-3), there were no differences in fasting blood glucose levels among the administered groups and the solvent control group. On day 13 after administration (D13), the fasting blood glucose levels of mice in the D4-002, D4-005, L13-D4-002, and Retaglutide groups were significantly lower than those in the solvent control group (p<0.01). There were no significant differences in fasting blood glucose levels among the other groups. On day 17 after administration (D17), the fasting blood glucose levels of mice in the D4-002, D4-004, D4-005, and Retaglutide groups were significantly lower than those in the solvent control group (p<0.01). The fasting blood glucose levels of mice in the D4-002 group were significantly lower than those in the L13-D4-002 group (p<0.01). The fasting blood glucose levels of mice in the D4-004, D4-005, and Retaglutide groups were significantly lower than those in the L13-D4-002 group (p<0.05). There were no significant differences in fasting blood glucose levels among the other groups.

[0307] The results of the glucose tolerance test are shown in Figure 52. It can be seen that after the drug administration (D24), the fasting blood glucose, 15-minute peak blood glucose, and AUC of D4-002, D4-005, D4-004, and retaglutide were significantly lower than those of L13-D4-002 (p<0.01) and the solvent control group (p<0.01). There were no significant differences in the 15-minute peak blood glucose and AUC among the groups of D4-002, D4-005, D4-004, and retaglutide. The blood glucose AUC of L13-D4-002 (p<0.01) was significantly lower than that of the solvent control group (p<0.05).

[0308] Based on comprehensive blood glucose data, D4-002 has a better blood glucose lowering ability than L13-D4-002 and is no weaker than Retaglutide.

[0309] After administration of drug D22, blood samples were collected from all animals to detect the concentrations of blood cholesterol, triglycerides, and pancreatic amylase. The biochemical results of each group of animals are shown in Table 8.

[0310] Table 8: Biochemical parameters of D22 in DIO mice after continuous subcutaneous administration (n=5)

[0311] At the end of the dosing cycle (D22), the serum total cholesterol and triglyceride concentrations in the D4-002, D4-004, D4-005, Retaglutide, and L13-D4-002 groups were significantly lower than those in the solvent control group (p<0.01). Specifically, the serum total cholesterol level in the D4-002 group was significantly lower than that in the D4-004 group (p<0.05), and the serum total cholesterol level in the L13-D4-002 group was significantly lower than that in the solvent control group (p<0.01). There were no differences in serum total cholesterol and triglyceride levels among the other groups.

[0312] The serum pancreatic amylase concentrations in the D4-002, D4-004, D4-005, and Retaglutide groups (L13-D4-002) were significantly lower than those in the solvent control group (p<0.01). The pancreatic amylase level in D4-002 was significantly lower than that in D4-005 (p<0.05) and D4-004 (p<0.01). When comparing D4-002 and Retaglutide groups alone, the serum pancreatic amylase concentration in D4-002 was significantly lower than that in Retaglutide (T test, p<0.05). The average serum pancreatic amylase concentration in the D4-002 group was lower than that in other treatment groups. Considering the potential risks of GLP-1R agonists such as pancreatitis and pancreatic cancer, we believe that D4-002 has a greater advantage in terms of potential side effects compared to Retaglutide, D4-004, and D4-005.

[0313] Based on the data from this DIO study, we believe that the α-methylation modification of leucine at position 13 of D4-002 has significant effects on controlling blood sugar and reducing weight, and is essential for weight loss drugs. Compared to retaglutide, D4-002 has significant advantages in reducing weight and lowering the risk of pancreatic-related diseases.

[0314] Example 8: Maximum tolerated dose of drug after single administration in C57 / B16 mice

[0315] To compare the safety of D4-002 with retaglutide, a maximum tolerated dose for a single subcutaneous administration was tested. Male C57 / bl6 mice aged 6-8 weeks were housed under standard conditions with free access to water and food from arrival, and were used for the experiment after 5 days of acclimatization. A single subcutaneous injection was administered, and the mice were observed for 14 days after drug withdrawal. Animal grouping is shown in Table 9 below:

[0316] Table 9: Grouping of Experiments for Maximum Tolerable Single-Dose Dosage

[0317] During the experiment, no significant abnormalities were observed in any mice in the solvent group after drug administration. In the D4-002 0.3 μmol / kg group, 4 mice showed decreased activity on the third day of administration, recovering on the fourth day. In the D4-002 1 μmol / kg group, 4 mice showed decreased activity on the fourth day, with 2 male mice recovering on the fourth day; 2 female mice developed hematuria on the fourth day and died on the fifth and sixth days, respectively. In the Retaglutide 0.3 μmol / kg group, 4 mice showed decreased activity on the third day, with 1 female and 1 male recovering on the fourth day; 1 female mouse showed decreased activity and decreased body temperature on the fifth day and died on the sixth day after drug administration; 1 male mouse showed decreased activity on the sixth day of administration and recovered on the seventh day. In the Retaglutide 1 μmol / kg group, 4 mice showed decreased activity on the third day, with 1 female and 1 male mice dying on the fifth day; another 2 mice showed decreased activity and decreased body temperature on the fifth day, both dying on the sixth day. No significant abnormalities were observed in the mice at other times. Based on the above results, the maximum tolerated dose (MTD) of D4-002 administered via a single subcutaneous injection in C57 mice was 0.3 μmol / kg. Retaglutide, at low doses, caused fatal and intolerable toxicity in animals, with an MTD less than 0.3 μmol / kg. Therefore, D4-002 is considered to have better safety than retaglutide and possesses broad development prospects.

Claims

1. A peptide compound having formula (I) or a pharmaceutically acceptable salt or solvate thereof: X1X2X3-GTFTSDYSI-αMeL-LD-KX 17 X 18 X 19 X 20 X 21 -F-X 23 X 24 X 25 -LL-X 28 -GGPSSGAPPPSX 40 -NH2 (I) in, X1X2X3 can be H-Aib-H, Y-Aib-Q, or Y-Ac3c-Q; X 17 For Q or K; X 18 X 19 It can be YA, YQ, or AQ; X 20 It can be Aib or Ac3c; X 21 The answer is A, D, E, or R; X 23 For V or I; X 24 X 25 For NW, QR, EY, RY, RH, or RW; X 28 It can be E, R, or A; X 40 It is K or absent; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

2. The peptide compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein, X1X2X3 is H-Aib-H, X 24 X 25 For NW; or X1X2X3 is Y-Aib-Q, X 18 X 19 For YA; or X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ; or X1X2X3 is Y-Ac3c-Q, X 18 X 19 For YA; or X1X2X3 is H-Aib-H, X 17 Let K, X 18 X 19 For AQ, X 20 For Aib, X 24 X 25 For NW; or X1X2X3 is Y-Ac3c-Q, X 17 For Q, X 18 X 19 for YA,X 20 For Aib, X 24 X 25 For NW; or for X1X2X3 for Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist; or X1X2X3 is H-Aib-H, X 18 X 19 For AQ, X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For E; X 40 It does not exist; or X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For RW, X 28 For E; X 40 It does not exist; or X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For QR, X 28 For E; X 40 It does not exist; or X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 For K; or X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Ac3c, X 21 Let A and X be the two numbers. 23 For I, X 24 X 25 For EY, X 28 For E; X 40 It does not exist; or X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 For K; or X1X2X3 is Y-Aib-Q, X 18 X 19 For AQ, X 20 For Aib, X 21 For D, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist; or X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For D, X 23 For I, X 24 X 25 For RY, X 28 R; X 40 It does not exist; or X1X2X3 is Y-Aib-Q, X 18 X 19 for YA,X 20 For Aib, X 21 Let R, X 23 For I, X 24 X 25 For RH, X 28 For E; X 40 It does not exist; or X1X2X3 is Y-Aib-Q, X 18 X 19 For YQ, X 20 For Aib, X 21 For D, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist; or X1X2X3 is Y-Ac3c-Q, X 18 X 19 for YA,X 20 For Aib, X 21 For E, X 23 Let V, X 24 X 25 For NW, X 28 For A; X 40 It does not exist.

3. The peptide compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein, X 16 X 17 X 40 K can optionally be modified by conjugation with a half-life extension group; Preferably, the modification by the half-life extension group refers to the modification of the ε-amino group of the K side chain by the half-life extension group; Preferably, the half-life extension group has the structure of formula (II): -([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H (II) Where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is an integer from 16 to 18; Preferably, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q or K; X 18 X 19 For YA or AQ; X 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW; X 28 For E or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q or K; X 18 X 19 is YA; 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW, QR, or RW; X 28 For E or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 18 X 19 is YA; 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW, QR, EY, RY, RH, or RW; X 28 For E, R, or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, wherein a is selected from integers 0-2, b is selected from integers 0-2, c is selected from integers 0-2, and d is 16 or 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Ac3c-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Ac3c; X 21 For A; X 23 For I; X 24 X 25 For EY; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation, where a is an integer from 0 to 2, b is an integer from 0 to 2, c is an integer from 0 to 2, and d is 16 or 18; X 17 For Q or K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E or R; X 23 For V or I; X 24 X 25 For NW; X 28 For E or A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; More preferably, d is 18.

4. The peptide compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein, a = 1, b = 0, c = 1, d = 18; or a = 2, b = 0, c = 1, d = 18; or a = 0, b = 2, c = 1, d = 18. Preferably, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is H-Aib-H; X 16 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is H-Aib-H; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 16 or 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RW; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 0, b is 2, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For QR;X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 K; X 18 X 19 For AQ; X 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Ac3c; X 21 For A; X 23 For I; X 24 X 25 For EY; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Ac3c-Q; X 16 K; X 17 For Q, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 2, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 For AQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 For D; X 23 For I; X 24 X 25 For RY; X 28 R; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 is YA; 20 For Aib; X 21 R; X 23 For I; X 24 X 25 For RH; X 28 For E; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; X 18 X 19 YQ; X 20 For Aib; X 21 For D; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 It does not exist; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Preferably, X1X2X3 is Y-Aib-Q; X 16 K; X 17 For Q; X 18 X 19 is YA; 20 For Aib; X 21 For E; X 23 For V; X 24 X 25 For NW; X 28 For A; X 40 The value is K, and the ε-amino group of the K side chain is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl). a -(εLys) b -(γGlu) c -CO-(CH2) d -CO2H conjugation modification, where a is 1, b is 0, c is 1, and d is 18; and the C-terminal amino acid is optionally amidated to a C-terminal primary amide.

5. The peptide compound according to claim 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide compound is selected from: The C-terminal amino acid of the peptide compound is optionally amidated to a C-terminal primary amide.

6. A pharmaceutical composition or combination of pharmaceuticals comprising a peptide compound according to any one of claims 1-5 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient; Preferably, the composition or pharmaceutical combination further includes a second therapeutic agent; Preferably, the second therapeutic agent is selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors.

7. Use of the peptide compound according to any one of claims 1-5 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition or combination according to claim 6, in the preparation of a medicament for treating or preventing metabolic disorder-related diseases or alleviating metabolic disorder-related conditions.

8. The use according to claim 7, wherein the metabolic disorder-related disease is selected from obesity, diabetes, dyslipidemia-related diseases, chronic kidney disease induced by diabetes (CKD), fatty liver disease associated with metabolic dysfunction (MASLD), fatty liver disease associated with metabolic dysfunction (MASH), metabolic syndrome, and neurodegenerative diseases; preferably, the neurodegenerative disease is selected from Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS); The metabolic disorder-related conditions are selected from adult cardiovascular death caused by obesity or overweight, heart attack, stroke, heart failure, diseases or conditions associated with overweight or obesity, binge eating, depression, dyslipidemia, atherosclerosis, hypertension, coronary heart disease, myocardial infarction, stroke, and impaired glucose tolerance (IGT).

9. The use according to claim 7 or 8, wherein the use is in the preparation of a medicament for weight loss, appetite regulation, prevention of weight rebound after successful weight loss, lowering blood lipids or lowering blood sugar.

10. A method for preparing the peptide compound or its pharmaceutically acceptable salt or solvate according to any one of claims 1-5, wherein the preparation method is a chemical synthesis method.

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