Double-agonist polypeptide compound and medical application thereof

Abstract

The invention discloses a double-agonist polypeptide compound and medical application thereof, and belongs to the field of polypeptide medicine, the amino acid sequence of the GIP-R and GLP-1R double-agonist polypeptide compound is Y-Z-EGTFTSDSI-X2-LDKI-A-Q-Bn-X4-X5-VQWLI-X6-GGPSSG-A-PPPS, and the amino acid at the C terminal is amidated. The GIP-R and GLP-1R dual-excitation polypeptide compound disclosed by the invention has a more remarkable dual-excitation effect on a human glucose-dependent insulinotropic polypeptide (GIP) and a human glucagon-like peptide-1 (GLP-1) receptor, not only has the effects of reducing blood glucose and reducing weight, but also has a longer half-life period and higher bioavailability; adverse reactions such as nausea and vomiting caused by long-term use of existing medicines can be avoided, and the traditional Chinese medicine composition can be used as an effective raw material for preparing medicines for treating or preventing diabetes or weight-reducing medicines.

Description

Technical Field

[0001] The present invention belongs to the field of polypeptide medicine, and specifically relates to a dual agonist polypeptide compound and its medical use. The present invention is a divisional application with application number 2024109284017 and the invention name is a dual agonist polypeptide compound and its medical use. Background Art

[0002] The World Health Organization divides diabetes into type 1 diabetes, type 2 diabetes, gestational diabetes and special types of diabetes, among which type 2 diabetes accounts for the vast majority of diabetic patients. The formation of type 2 diabetes is mainly related to insulin resistance and pancreatic β-cell defects. Insulin resistance is mainly manifested as the inability of insulin to play a normal role on the target tissue, leading to metabolic disorders, while pancreatic β-cell defects usually manifest as insufficient insulin secretion. Since type 2 diabetes may usually cause a variety of vascular and non-vascular complications including obesity, cardiovascular disease, renal failure, coronary artery disease, microvascular disease, retinopathy, etc., type 2 diabetes has posed a great threat to human health so far. Therefore, the development of safe and efficient hypoglycemic drugs is of great significance and value for controlling blood sugar in patients with type 2 diabetes.

[0003] At present, the main treatment drugs for diabetes include biguanides, sulfonylureas, α-glucosidase inhibitors, glinides, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and insulin. Semaglutide is a GLP-1 receptor agonist developed by Novo Nordisk and is currently one of the most successful drugs for the treatment of diabetes. Compared with other types of hypoglycemic drugs, Semaglutide can not only lower blood sugar, but also provide weight loss effects. In addition, as a GLP-1 receptor agonist, Semaglutide also has the effect of regulating blood lipids, blood pressure and other hypoglycemic effects. It can reduce the risk of possible cardiovascular events while controlling blood sugar to provide better safety. Its target GLP-1 is a neuroendocrine hormone secreted by the small intestine. The hormone receptors are not only present in the regulatory area of ​​the brain, but also in the pancreas. At the same time, both regulatory areas can show control of blood sugar. Activating the GLP-1 receptor can promote insulin secretion and inhibit glucagon secretion in a glucose concentration-dependent manner, thereby increasing satiety, inhibiting food intake, delaying gastric emptying, etc., thereby achieving the ultimate goal of regulating blood sugar and losing weight.

[0004] Although Semaglutide is favored by patients with type 2 diabetes due to its good therapeutic effect, its dosage is still limited by adverse reactions such as nausea and vomiting, and single-target administration usually cannot achieve the effect of complete blood sugar control and weight loss. Gastric inhibitory polypeptide (GIP) is a peptide substance secreted by K cells in the intestine, which can stimulate insulin secretion in a glucose-dependent manner. In addition, GIP can reduce body weight by reducing food intake and increasing energy expenditure. GIP single-target therapy has shown a certain hypoglycemic effect on type 2 diabetes, but GIP in the human body under pathological conditions cannot fully function as it does under healthy physiological conditions. Summary of the invention

[0005] Purpose of the invention: In view of the problems existing in the prior art, the purpose of the present invention is to provide a class of GIP-R and GLP-1R dual agonist polypeptide compounds with a new structure or a pharmaceutically acceptable salt thereof. The polypeptide compound of the present invention is a dual incretin peptide compound that can stimulate human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. It not only has the effects of lowering blood sugar and reducing weight, but also has a longer half-life and higher bioavailability, and can be used to prepare drugs for treating or preventing diabetes or weight loss drugs.

[0006] The present invention also provides a pharmaceutical composition of the GIP-R and GLP-1R dual agonist polypeptide compound and its medical use.

[0007] Technical solution: A class of GIP-R and GLP-1R dual agonist polypeptide compounds or pharmaceutically acceptable salts thereof of the present invention, wherein the amino acid sequence of the GIP-R and GLP-1R dual agonist polypeptide compound is: 1 -X 1 -EGTFTSDYSI-X 2 -LDKI-X 3 -QB n -X 4 -X 5 -VQWLI-X 6 -GGPSSG-X 7 -PPPS, and the C-terminal amino acid of the GIP-R and GLP-1R dual agonist polypeptide compound is amidated;

[0008] in,

[0009] Y 1 is selected from a tyrosine residue or a histidine residue;

[0010] X 1 Selected from α-aminoisobutyric acid residues;

[0011] X 2is selected from the group consisting of an α-aminoisobutyric acid residue, a 2-amino-3,3,3-trifluoro-2-methylpropionic acid residue, a 1-aminocyclobutanecarboxylic acid residue or an isovaline residue;

[0012] X 3 is selected from an α-aminoisobutyric acid residue or an alanine residue;

[0013] B n The side chain ε-amino group is ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) n -CO 2 H-modified lysine residue, wherein n is a natural number from 16 to 22, and its structural chemical formula is as follows:

[0014]

[0015] X 4 is selected from an α-aminoisobutyric acid residue, an alanine residue, a 2-aminobutyric acid residue or a norvaline residue;

[0016] X 5 is selected from the group consisting of a phenylalanine residue, a 3-(1-naphthyl)-alanine residue, a 3-chlorophenylalanine residue, a 3-trifluoromethylphenylalanine residue, a 3-fluorophenylalanine residue, a 2-fluorophenylalanine residue, a 2-chlorophenylalanine residue, a 2-trifluoromethylphenylalanine residue or a 3-(2-naphthyl)-alanine residue;

[0017] X 6 is selected from an α-aminoisobutyric acid residue, a serine residue or an alanine residue;

[0018] X 7 is selected from an α-aminoisobutyric acid residue, a 2-aminobutyric acid residue, a serine residue or a threonine residue.

[0019] The C-terminal amino acid of the above-mentioned polypeptide compound is amidated to form a C-terminal primary amide; specifically, the C-terminal is -CO-NH 2 .

[0020] Preferably, n=16, 17, 18, 19, 20, 21, 22. More preferably, n is a natural number from 17 to 22, n is a natural number from 18 to 22, n is a natural number from 19 to 22, n is a natural number from 20 to 22, and n is a natural number from 21 to 22.

[0021] Preferably, the amino acid sequence of the GIP-R and GLP-1R dual agonist polypeptide compound is selected from any one of the following:

[0022] (1) SEQ ID NO: 1

[0023] YZ-EGTFTSDYSI-Z-LDKI-ZQB 18 -ZF-VQWLI-Z-GGPSSGSPPPS-NH 2

[0024] (2)SEQ ID NO:2

[0025] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -ZF-VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0026] (3)SEQ ID NO:3

[0027] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AF-VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0028] (4)SEQ ID NO:4

[0029] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z 4 -F-VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0030] (5)SEQ ID NO:5

[0031] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z 5 -F-VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0032] (6)SEQ ID NO:6

[0033] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -ZZ 8 -VQWLI-A-GGPSSGAPPPS-NH 2

[0034] (7)SEQ ID NO:7

[0035] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z 4-Z 8 -VQWLI-A-GGPSSGAPPPS-NH 2

[0036] (8)SEQ-IDNO:8

[0037] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -ZZ 8 -VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0038] (9)SEQ-IDNO:9

[0039] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z 4 -Z 8 -VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0040] (10)SEQ-IDNO:10

[0041] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 8 -VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0042] (11)SEQ-IDNO:11

[0043] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -ZF-VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0044] (12)SEQ-IDNO:12

[0045] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z 4 -F-VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0046] (13)SEQ-IDNO:13

[0047] YZ-EGTFTSDYSI-Z-LDKI-ZQB 18 -AF-VQWLI-Z 14 -GGPPSG-Z-PPPS-NH 2

[0048] (14)SEQ ID NO:14

[0049] YZ-EGTFTSDYSI-Z-LDKI-ZQB 18 -AF-VQWLI-A-GGPSSGSPPPS-NH 2

[0050] (15)SEQ ID NO:15

[0051] YZ-EGTFTSDYSI-Z-LDKI-ZQB 18 -AF-VQWLI-Z-GGPSSGSPPPS-NH 2

[0052] (16)SEQ ID NO:16

[0053] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -ZZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0054] (17)SEQ ID NO:17

[0055] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -Z 4 -Z 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0056] (18)SEQ ID NO:18

[0057] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -ZZ 8 -VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0058] (19)SEQ ID NO:19

[0059] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -Z 4 -Z 8 -VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0060] (20)SEQ ID NO:20

[0061] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 8 -VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0062] (21)SEQ ID NO:21

[0063] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -ZF-VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0064] (22)SEQ ID NO:22

[0065] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -Z 4 -F-VQWLI-Z 14 -GGPSSGAPPPS-NH 2

[0066] (23)SEQ ID NO:23

[0067] YZ-EGFTSTDES-Z 1 -LDKI-ZQB 18 -AF-VQWLI-A-GGPSSGSPPPS-NH 2

[0068] (24)SEQ ID NO:24

[0069] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AF-VQWLI-Z-GGPSSGSPPPS-NH2

[0070] (25)SEQ ID NO:25

[0071] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AF-VQWLI-Z 14 -GGPSSGSPPPS-NH 2

[0072] (26)SEQ ID NO:26

[0073] YZ-EGFTSTDES-Z 2 -LDKI-AQB 18 -AF-VQWLI-A-GGPPSSG-Z 4 -PPPS-NH 2

[0074] (27)SEQ ID NO:27

[0075] YZ-EGFTSTDES-Z 2 -LDKI-AQB 18 -AF-VQWLI-Z 14 -GGPPSG-Z 4 -PPPS-NH 2

[0076] (28)SEQ ID NO:28

[0077] YZ-EGFTSTDES-Z 2 -LDKI-AQB 18 -AZ 8 -VQWLI-A-GGPSSG-Z 4 -PPPS-NH 2

[0078] (29)SEQ ID NO:29

[0079] YZ-EGFTSTDES-Z 3 -LDKI-AQB 18 -AF-VQWLI-A-GGPSSGSPPPS-NH 2

[0080] (30)SEQ ID NO:30

[0081] YZ-EGFTSTDES-Z 3-LDKI-AQB 18 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0082] (31)SEQ ID NO:31

[0083] YZ-EGFTSTDES-Z 3 -LDKI-AQB 18 -AF-VQWLI-Z 14 -GGPSSGSPPPS-NH 2

[0084] (32)SEQ ID NO:32

[0085] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AF-VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0086] (33)SEQ ID NO:33

[0087] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 6 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0088] (34)SEQ ID NO:34

[0089] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 7 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0090] (35)SEQ ID NO:35

[0091] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0092] (36)SEQ ID NO:36

[0093] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 9 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0094] (37)SEQ ID NO:37

[0095] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 10 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0096] (38)SEQ ID NO:38

[0097] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 11 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0098] (39)SEQ ID NO:39

[0099] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 12 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0100] (40)SEQ ID NO:40

[0101] YZ-EGFTSTDES-Z 1 -LDKI-AQB 18 -AZ 13 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0102] (41)SEQ ID NO:41

[0103] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 6 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0104] (42)SEQ ID NO:42

[0105] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 7 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0106] (43)SEQ ID NO:43

[0107] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0108] (44)SEQ ID NO:44

[0109] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 9 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0110] (45)SEQ ID NO:45

[0111] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 10 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0112] (46)SEQ ID NO:46

[0113] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 11 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0114] (47)SEQ ID NO:47

[0115] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 12 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0116] (48)SEQ ID NO:48

[0117] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 13 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0118] (49)SEQ ID NO:49

[0119] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AF-VQWLI-Z-GGPSSGSPPPS-NH 2

[0120] (50)SEQ ID NO:50

[0121] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 6 -VQWLI-Z-GGPSSGSPPPS-NH 2

[0122] (51)SEQ ID NO:51

[0123] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 7 -VQWLI-Z-GGPSSGSPPPS-NH 2

[0124] (52)SEQ ID NO:52

[0125] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 8 -VQWLI-Z-GGPSSGSPPPS-NH 2

[0126] (53)SEQ ID NO:53

[0127] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 9 -VQWLI-Z-GGPSSGSPPPS-NH 2

[0128] (54)SEQ ID NO:54

[0129] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 10 -VQWLI-Z-GGPSSG-Z-PPPS-NH 2

[0130] (55)SEQ ID NO:55

[0131] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 11 -VQWLI-Z-GGPSSG-Z-PPPS-NH 2

[0132] (56)SEQ ID NO:56

[0133] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 12 -VQWLI-Z-GGPSSG-Z-PPPS-NH 2

[0134] (57)SEQ ID NO:57

[0135] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 13 -VQWLI-Z-GGPSSG-Z-PPPS-NH 2

[0136] (58)SEQ ID NO:58

[0137] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AF-VQWLI-Z 14 -GGPSSGSPPPS-NH 2

[0138] (59)SEQ ID NO:59

[0139] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 6 -VQWLI-Z 14 -GGPSSGSPPPS-NH 2

[0140] (60)SEQ ID NO:60

[0141] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 7 -VQWLI-Z 14 -GGPSSGSPPPS-NH 2

[0142] (61)SEQ ID NO:61

[0143] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 8 -VQWLI-Z 14 -GGPSSGSPPPS-NH 2

[0144] (62)SEQ ID NO:62

[0145] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 9 -VQWLI-Z 14 -GGPSSGSPPPS-NH 2

[0146] (63)SEQ ID NO:63

[0147] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 10 -VQWLI-Z 14 -GGPPSG-Z-PPPS-NH 2

[0148] (64)SEQ ID NO:64

[0149] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 11 -VQWLI-Z 14 -GGPPSG-Z-PPPS-NH 2

[0150] (65)SEQ ID NO:65

[0151] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 12 -VQWLI-Z 14 -GGPPSG-Z-PPPS-NH 2

[0152] (66)SEQ ID NO:66

[0153] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 13 -VQWLI-Z 14 -GGPPSG-Z-PPPS-NH 2

[0154] (67)SEQ ID NO:67

[0155] HZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0156] (68)SEQ ID NO:68

[0157] YZ-EGTFTSDYSI-Z-LDKI-AQB 16 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0158] (69)SEQ ID NO:69

[0159] YZ-EGTFTSDYSI-Z-LDKI-AQB 17 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0160] (70)SEQ ID NO:70

[0161] YZ-EGTFTSDYSI-Z-LDKI-AQB 19 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0162] (71)SEQ ID NO:71

[0163] YZ-EGTFTSDYSI-Z-LDKI-AQB 20 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0164] (72)SEQ ID NO:72

[0165] YZ-EGTFTSDYSI-Z-LDKI-AQB 21 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0166] (73)SEQ ID NO:73

[0167] YZ-EGTFTSDYSI-Z-LDKI-AQB 22 -AZ 8 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0168] (74)SEQ ID NO:74

[0169] HZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AF-VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0170] (75)SEQ ID NO:75

[0171] YZ-EGTFTSDYSI-Z-LDKI-AQB 16 -AZ 7 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0172] (76)SEQ ID NO:76

[0173] YZ-EGTFTSDYSI-Z-LDKI-AQB 17 -AZ 7 -VQWLI-A-GGPSSGSPPPS-NH 2

[0174] (77)SEQ ID NO:77

[0175] YZ-EGTFTSDYSI-Z-LDKI-AQB 19 -AZ 7 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0176] (78)SEQ ID NO:78

[0177] YZ-EGTFTSDYSI-Z-LDKI-AQB 20 -AZ 7 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0178] (79)SEQ ID NO:79

[0179] YZ-EGTFTSDYSI-Z-LDKI-AQB 16 -AZ 9 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0180] (80)SEQ ID NO:80

[0181] YZ-EGTFTSDYSI-Z-LDKI-AQB 17 -AZ 9 -VQWLI-A-GGPSSGSPPPS-NH 2

[0182] (81)SEQ ID NO:81

[0183] YZ-EGTFTSDYSI-Z-LDKI-AQB 19 -AZ 9 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0184] (82)SEQ ID NO:82

[0185] YZ-EGTFTSDYSI-Z-LDKI-AQB 20 -AZ 9 -VQWLI-A-GGPSSG-Z 4 -PPPS-NH 2

[0186] (83)SEQ ID NO:83

[0187] YZ-EGTFTSDYSI-Z-LDKI-AQB 16 -AZ 6 -VQWLI-A-GGPPSSG-Z-PPPS-NH 2

[0188] (84)SEQ ID NO:84

[0189] YZ-EGTFTSDYSI-Z-LDKI-AQB 17 -AZ 6 -VQWLI-A-GGPSSG-Z-PPPS-NH 2

[0190] (85) SEQ ID NO:85

[0191] YZ-EGTFTSDYSI-Z-LDKI-AQB 19 -AZ 6 -VQWLI-A-GGPSSG-Z-PPPS-NH 2

[0192] (86) SEQ ID NO:86

[0193] YZ-EGTFTSDYSI-Z-LDKI-AQB 20 -AZ 6 -VQWLI-A-GGPSSG-Z-PPPS-NH 2

[0194] (87) SEQ ID NO:87

[0195] YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -AZ 8 -VQWLI-A-GGPSSG-Z 4 -PPPS-NH 2

[0196] In the above polypeptide sequence: Z is an α-aminoisobutyric acid residue; 1 is the residue of 2-amino-3,3,3-trifluoro-2-methylpropionic acid; Z 2 is a 1-aminocyclobutanecarboxylic acid residue; Z 3 is an isovaline residue; Z 4 is a 2-aminobutyric acid residue; Z 5 is a norvaline residue; Z 6 is a 3-(1-naphthyl)-alanine residue; Z 7 is a 3-chlorophenylalanine residue; Z 8 is a 3-trifluoromethylphenylalanine residue; Z 9 is a 3-fluorophenylalanine residue; Z 10 is a 2-fluorophenylalanine residue; Z 11 is a 2-chlorophenylalanine residue; Z 12 is a 2-trifluoromethylphenylalanine residue; Z 13 is a 3-(2-naphthyl)-alanine residue; Z14 is a D-serine residue; B 16 It is the side chain ε-amino group ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 16 -CO 2 H modified lysine residues; B 17 It is the side chain ε-amino group ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 17 -CO 2 H modified lysine residues; B 18 It is the side chain ε-amino group ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 18 -CO 2 H modified lysine residues; B 19 It is the side chain ε-amino group ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 19 -CO 2 H modified lysine residues; B 20 It is the side chain ε-amino group ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 20 -CO 2 H modified lysine residues; B 21 It is the side chain ε-amino group ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 21 -CO 2 H modified lysine residues; B 22 It is the side chain ε-amino group ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 22 -CO 2 H-modified lysine residues.

[0197] Preferably, the salt is a salt formed by a GIP-R and GLP-1R dual agonist polypeptide compound and one of the following compounds: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3- Hydroxy-2-naphthoic acid, nicotinic acid, pamonic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

[0198] On the other hand, the present invention provides a pharmaceutical composition comprising the above-mentioned GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0199] Preferably, the pharmaceutically acceptable carrier is a pharmaceutically acceptable excipient, diluent, buffer, adjuvant, auxiliary agent or vehicle.

[0200] Preferably, the preparation is in the form of tablets, capsules, elixirs, syrups, lozenges, inhalants, sprays, injections, films, patches, powders, granules, blocks, emulsions, suppositories or combination preparations.

[0201] On the other hand, the present invention provides a use of the above-mentioned GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease or condition caused by or characterized by excessive weight, or in the preparation of a weight loss medicament.

[0202] Preferably, the disease or condition is selected from obesity, diabetes, and hyperglycemia.

[0203] Preferably, the disease or condition is a human disease or condition.

[0204] Preferably, the GIP-R and GLP-1R dual agonist polypeptide compound or its pharmaceutically acceptable salt or the pharmaceutical composition is used in the preparation of a medicament for treating and / or preventing a disease or condition caused by or characterized by excessive weight by simultaneously, separately or sequentially administering an effective amount of one or more of metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors or sodium-glucose co-transporters, or in the preparation of a weight-loss drug.

[0205] Unless otherwise specified, the terms in this invention generally have the following meanings:

[0206]

[0207] The present invention combines the GLP-1 target with other targets to develop a new dual-target diabetes drug to improve the effect of treating diabetes and reduce the occurrence of adverse reactions. In view of the physiological synergy between GIP agonists and GLP-1 agonists, the present invention combines the two to develop new dual-target GIP / GLP-1 drugs GIP-R and GLP-1R dual agonist polypeptide compounds, which have stronger effects on controlling blood sugar and reducing body weight, and also provide new drug options and treatment plans for clinical applications of patients with type 2 diabetes.

[0208] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0209] The present invention provides a GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof with a completely new structure, which can be prepared by artificial synthesis, i.e., a polypeptide solid phase synthesis method, has a simple structure and low cost, and is convenient for popularization and application as well as industrial production.

[0210] Compared with the existing polypeptide compound (Semaglutide), the GIP-R and GLP-1R dual agonist polypeptide compound of the present invention has a more significant dual agonist effect on the receptors of human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). It not only has the effects of lowering blood sugar and reducing weight, but also has a longer half-life and higher bioavailability. It can avoid the adverse reactions such as nausea and vomiting caused by long-term use of existing drugs, and can be used as an effective raw material for the preparation of drugs for treating or preventing diabetes or weight loss drugs. DETAILED DESCRIPTION

[0211] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0212] The present invention is further described below in conjunction with specific embodiments.

[0213] The present invention obtains a new structure of GIP-R and

[0214] GLP-1R dual agonist polypeptide compounds. The polypeptide compounds SEQ ID NO: 1-87 in the embodiments of the present invention can all be directly synthesized by the polypeptide solid phase method, and the polypeptides designed by the present invention are all directly synthesized by biological companies.

[0215] Among them, B n is a known residue, see literature for details: Discovery of the Once-Weekly Glucagon-Like Peptide-1(GLP-1)Analogue Semaglutide, J.Med.Chem.2015,58,7370-7380; CN110684082A; wherein the size of n can be designed and prepared differently according to existing methods.

[0216] Example 1

[0217] 1. Experiment on the agonist activity of peptide compounds on human GIP-R and GLP-1R receptors

[0218] HEK293 cells were co-transfected with cDNA encoding human GIP-R and GLP-1R receptors, and stably transfected cell lines were selected and cultured with DMEM medium (containing 10% fetal calf serum FCS, 100 IU / mL penicillin, and 100 μg / mL streptomycin). The hypoglycemic drug Semaglutide was selected as a positive control. In the test of determining the polypeptide compound, 3×10 4 Cells (200 μL / well) were inoculated in 96-well plates, and peptide compounds were diluted to different multiples using culture medium and added to co-transfected HEK293 cells. After 20 minutes of cell incubation, the fluorescence readings were measured using a CisBio cAMP detection kit and a multifunctional microplate reader. A standard curve was established to convert the fluorescence readings into corresponding cAMP values. The EC values ​​of the peptides were calculated using Graphpad Prism 7.0 software using nonlinear regression. 50 The experimental results are shown in Table 1. The agonist activity of the polypeptide compound on human GIP-R and GLP-1R receptors (EC 50 ,nM).

[0219] As shown in Table 1, compared with the positive drug Semaglutide, all 87 peptide compounds showed more than 2 times the agonist activity on the human GLP-1R receptor (EC50 ); at the same time, they showed more than 100 times the agonist activity for GIP receptors (EC 50 ), which were significantly stronger than the positive drug Semaglutide.

[0220] Table 1 The agonist activity (EC) of all 87 tested peptide compounds on human GIP-R and GLP-1R receptors 50 ,nM)

[0221]

[0222]

[0223] 2. Effects of polypeptide dual agonists on body weight, fat intake, blood glucose and triglyceride levels in obese C57BL / 6J DIO mice.

[0224] C57BL / 6J mice (DIO) are particularly suitable for the study or modeling of type II diabetes models. The effects of the compounds of the present invention on weight loss, body composition and hepatic steatosis in mice were evaluated in C57BL / 6J DIO mice. In this experiment, diet-induced obese C57BL / 6J DIO male mice (23-24 weeks old) were placed in an SPF-level environment with a standard diet and free access to water. All experimental operations were carried out in accordance with the guidelines for the ethics and use of experimental animals. After 2 weeks of adaptive feeding on a standard diet, the mice were randomly assigned to treatment groups (n=10 / group) according to their body weight, and each group had a similar starting average body weight. Negative control vehicle, positive control drug Semaglutide (10nmol / kg and 30nmol / kg) and polypeptide compound (dose range 10-100nmol / kg) were dissolved in vehicle (20mM citrate buffer, pH 7.0) and injected subcutaneously to free-feeding DIO mice 30-90 minutes before the start of the dark cycle, once every three days for 15 days. Daily weight changes of mice were measured throughout the study. The absolute change in body weight was calculated by subtracting the weight of the same animal before the first injection of the compound. On days 0 and 14, total fat mass was measured by nuclear magnetic resonance (NMR) using an EchoMRI-100TM (Echo Medical Systems, Houston, TX) instrument. Blood glucose was measured using a blood glucose meter (Accu-Chek) in the tail vein blood of mice on the 15th day, and then the mice were killed to collect liver homogenates and liver triglycerides were measured on a Hitachi Modular P analyzer.

[0225] As shown in Table 2, compared with the negative control group mice, there are extremely significant differences in the changes in body weight and fat mass of the polypeptide group mice (****, p<0.0001), indicating that the polypeptide compound of the present invention (SEQ ID NO: 1-87) can effectively reduce body weight and fat mass. At the same time, compared with Semaglutide, the polypeptide group mice are more effective in reducing body weight and fat mass, and the therapeutic effect is increased by more than 2 times. Therefore, the polypeptide compound of the present invention is suitable for the development of weight loss indications. In addition, from all 87 polypeptide compounds with a common motif structure, 16 representative polypeptides (including SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 13, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 32, SEQ ID NO: 35, SEQ ID NO: 43, SEQ ID NO: 52, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 67, SEQ ID NO: 74 and SEQ ID NO: 86) were selected for animal treatment experiments in high, medium and low dose groups. As shown in Table 2, these 16 polypeptide compounds reduce body weight and fat mass in a dose-dependent manner. As further shown in Table 3, compared with Semaglutide, the polypeptide compounds (SEQ ID NO: 1-87) can effectively and significantly reduce blood sugar and triglycerides, especially in reducing triglycerides. The effect is significantly better. In summary, the polypeptide compound described in the present invention has more significant simultaneous blood sugar lowering and weight loss effects, and can be applied to the development of diabetes treatment drugs or weight loss drugs.

[0226] Table 2 Effects of drug administration on the body weight and fat mass of DIO mice in the experiment (n=10)

[0227]

[0228]

[0229]

[0230]

[0231] SPSS software was used to analyze the data in this experiment, and the experimental data of each group were expressed as mean ± standard deviation (mean ± SEM). When ****p<0.0001, the experimental group was statistically significant compared with the control group.

[0232] Table 3 Effects of all 87 tested peptide compounds on blood glucose and liver triglycerides in DIO mice

[0233]

[0234]

[0235]

[0236] SPSS software was used to analyze the data in this experiment, and the experimental data of each group were expressed as mean ± SEM. When ***p<0.001, ****p<0.0001, the experimental group was statistically significant compared with the control group.

[0237] Example 2

[0238] In vivo pharmacokinetic study of the polypeptide compound of the present invention.

[0239] The pharmacokinetic properties of the polypeptide compounds of the present invention in cynomolgus monkeys were evaluated. The compounds were administered intravenously or subcutaneously (0.2 mg / kg) in a single dose of 0.21 ml / kg in 20 mM citric acid buffer (pH 7.0). Blood was collected from each animal at 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 204, 240 and 312 hours after administration. After solid phase extraction, the plasma concentration of the polypeptide compounds was determined by LC / MS method. The in vivo half-life (T) was calculated using Phoenix software. 1 / 2 ) and bioavailability F (%).

[0240] As shown in the results of the above experimental Table 4, compared with Semaglutide, the half-life of the dual agonist polypeptides (SEQ ID NO: 1-87) provided by the present invention in animals is more than 40 hours. Compared with Semaglutide, the polypeptide compounds (SEQ ID NO: 1-87) provided by the present invention show a longer half-life and higher bioavailability than Semaglutide, so the polypeptide compounds provided by the present invention have a better long-term therapeutic effect than Semaglutide. Therefore, the long-acting dual agonist polypeptides of the present invention are suitable for the development of blood sugar and weight reduction indications.

[0241] Table 4 Half-life T after single subcutaneous administration of 0.2 mg / kg to male cynomolgus monkeys 1 / 2 (hr) and bioavailability F (%)

[0242]

[0243]

[0244] It can be seen from the above examples that the dual agonist polypeptide compound of the present invention is a class of highly effective dual agonist polypeptide compounds, which have dual agonist activity (EC 50 ) is significantly stronger than Semaglutide, and is also significantly superior to Semaglutide in terms of lowering blood sugar and reducing weight, and has a longer half-life and higher bioavailability. It can be used as an effective raw material for the preparation of drugs for the treatment or prevention of diabetes or weight loss drugs.

[0245] Finally, it should be noted that there are other ways to implement the present invention. Accordingly, the embodiments of the present invention are described as examples, but are not limited to the contents described in the present invention, and may also be modified within the scope of the present invention or added to the claims. All publications or patents cited in the present invention will be used as references of the present invention.

[0246] The above description is only a preferred embodiment of the present invention, which is only illustrative for the present invention and is not intended to limit the protection scope of the present invention. For those skilled in the art, the present invention may have various changes and variations. Any changes, modifications, equivalent substitutions, replacements, combinations, simplifications, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof, characterized in that: The amino acid sequence of the GIP-R and GLP-1R dual agonist polypeptide compound is: YZ-EGTFTSDYSI-X2-LDKI-AQB n -X4-X5-VQWLI-X6-GGPSSG-A-PPPS, and the C-terminal amino acid of the GIP-R and GLP-1R dual agonist polypeptide compound is amidated; X2 is selected from an α-aminoisobutyric acid residue, a 2-amino-3,3,3-trifluoro-2-methylpropionic acid residue, a 1-aminocyclobutanecarboxylic acid residue or an isovaline residue; B n ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) on the side chain ε-amino n -CO2H modified lysine residue, wherein n is a natural number from 16 to 22, and its structural chemical formula is as follows: X4 is selected from an α-aminoisobutyric acid residue, an alanine residue, a 2-aminobutyric acid residue or a norvaline residue; X5 is selected from a phenylalanine residue, a 3-(1-naphthyl)-alanine residue, a 3-chlorophenylalanine residue, a 3-trifluoromethylphenylalanine residue, a 3-fluorophenylalanine residue, a 2-fluorophenylalanine residue, a 2-chlorophenylalanine residue, a 2-trifluoromethylphenylalanine residue or a 3-(2-naphthyl)-alanine residue; X6 is selected from an α-aminoisobutyric acid residue, a serine residue or an alanine residue.

2. The GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The amino acid sequence of the GIP-R and GLP-1R dual agonist polypeptide compound is selected from any one of the following: (1) SEQ ID NO: 6 YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z-Z8-VQWLI-A-GGPSSGAPPPS-NH2 (2) SEQ ID NO:7 YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z4-Z8-VQWLI-A-GGPSSGAPPPS-NH2 (3) SEQ ID NO: 8 YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z-Z8-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (4) SEQ ID NO: 9 YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z4-Z8-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (5) SEQ ID NO: 10 YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -A-Z8-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (6) SEQ ID NO: 11 YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -ZF-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (7) SEQ ID NO: 12 YZ-EGTFTSDYSI-Z-LDKI-AQB 18 -Z4-F-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (8) SEQ ID NO: 18 YZ-EGTFTSDYSI-Z1-LDKI-AQB 18 -Z-Z8-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (9) SEQ ID NO: 19 YZ-EGTFTSDYSI-Z1-LDKI-AQB 18 -Z4-Z8-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (10) SEQ ID NO: 20 YZ-EGTFTSDYSI-Z1-LDKI-AQB 18 -A-Z8-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (11) SEQ ID NO: 21 YZ-EGTFTSDYSI-Z1-LDKI-AQB 18 -ZF-VQWLI-Z 14 -GGPSSGAPPPS-NH2 (12) SEQ ID NO: 22 YZ-EGTFTSDYSI-Z1-LDKI-AQB 18 -Z4-F-VQWLI-Z 14 -GGPSSGAPPPS-NH2; In the above polypeptide sequence: Z is an α-aminoisobutyric acid residue; Z1 is a 2-amino-3,3,3-trifluoro-2-methylpropionic acid residue; Z4 is a 2-aminobutyric acid residue; Z8 is a 3-trifluoromethylphenylalanine residue; Z 14 is a D-serine residue; B 18 It is the side chain ε-amino group ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H modified lysine residues.

3. The GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The salt is a salt formed by the GIP-R and GLP-1R dual agonist polypeptide compound and one of the following compounds: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxybenzoyl)benzoic acid, -2-naphthoic acid, nicotinic acid, pamonic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

4. Use of the GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for reducing body weight or fat mass, or in the preparation of a weight loss drug.

5. A pharmaceutical composition comprising the GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutically acceptable carrier is a pharmaceutically acceptable excipient, diluent, buffer or adjuvant.

7. The pharmaceutical composition according to claim 5, characterized in that The preparation is in the form of tablets, capsules, elixirs, syrups, lozenges, inhalants, sprays, injections, films, patches, powders, granules, blocks, emulsions, suppositories or combination preparations.

8. Use of the pharmaceutical composition according to claim 5 in the preparation of a drug for reducing body weight or fat mass, or in the preparation of a drug for weight loss.

9. Use of the GIP-R and GLP-1R dual agonist polypeptide compound or a pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 5 in the preparation of a drug for treating obesity, diabetes or hyperglycemia.

10. Use of the GIP-R and GLP-1R dual agonist polypeptide compound or its pharmaceutically acceptable salt according to claim 1 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for reducing body weight or fat mass by simultaneously, separately or sequentially administering an effective amount of one or more of metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors or sodium-glucose co-transporters, or in the preparation of a weight-loss medicament.

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