CN111825758A - GLP-1 and GIP co-agonist compounds - Google Patents
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Abstract
The invention provides a GLP-1 and GIP co-agonist compound, and provides a series of pharmaceutical compositions based on a dual agonist compound of human blood Glucose-dependent insulinotropic polypeptide (GIP) and an available medicinal salt thereof, wherein the pharmaceutical compositions have dual agonist effects on a human Glucagon-like peptide-1 (GLP-1) receptor and a human GIP receptor, and can be used for treating related diseases such as non-insulin-dependent diabetes, insulin-dependent diabetes and obesity.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a compound which has double agonist effects on a human glucagon-like peptide-1 (GLP-1) receptor and a human blood sugar-dependent insulinotropic polypeptide (GIP) receptor and can be used for treating metabolic diseases such as non-insulin-dependent diabetes, obesity and other related diseases.
Background
Diabetes mellitus is a metabolic disease in which the metabolism of glucose, protein and lipid in a human body is disordered due to insufficient insulin secretion in the body. According to the difference in their pathological mechanisms, diabetes is largely classified into insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes). Wherein 90-95% of diabetics worldwide are non-insulin-dependent diabetics. Non-insulin dependent diabetes mellitus is a long-term, chronic metabolic disease caused by impaired pancreatic beta-cell function and long-term insulin resistance, which is most characterized by a deficiency in insulin levels in the body and high blood glucose concentrations in the plasma. Studies have shown that non-insulin dependent diabetes mellitus is associated with a variety of high risk complications in patients and it often leads to patients suffering from cardiovascular disease, kidney failure, blindness, amputation and other various complications.
One of the major causes of noninsulin-dependent diabetes is obesity. Obesity is defined as: excessive or abnormal fat accumulation in the body that impairs human health. Obesity can also be defined as, according to the Body Mass Index (BMI) of a person: human BMI greater than or equal to 30kg/m2. The presence of obesity significantly increases the risk of cardiovascular disease, diabetes, musculoskeletal diseases and certain cancers in humans. In addition, an increase in the human body mass index also increases the risk of certain non-infectious diseases.
Because of the enormous number of patients and the significant economic burden on people for diabetes and its complications, the development of safe and effective drugs for treating diabetes has been the focus of attention of many research institutes and pharmaceutical enterprises. At present, the approved diabetes drugs on the market mainly comprise chemical synthesis small molecule oral hypoglycemic drugs, such as biguanides, sulfonyl compounds, insulin sensitizers, alpha-glycosides, recombinant insulin produced by biosynthesis, derivatives thereof and other injection hypoglycemic drugs. Although the medicine can effectively control the blood sugar level in the blood plasma of a diabetic patient clinically, the long-term use of the medicine is often accompanied by adverse reactions such as the weight increase of the patient and the like, and then the risk of potential cardiovascular diseases is increased and the use compliance of the patient is reduced. In consideration of the potential pathological relationship between diabetes and obesity and the potential risk of complications caused by obesity, the development of a drug which can effectively control blood sugar and properly reduce the weight of a diabetic patient has multiple meanings for the effective treatment of diabetes and the reduction of the potential risk of complications, so the development of a novel drug for treating diabetes is urgently needed clinically.
Glucagon-like peptide-1 (GLP-1) is a gastrointestinal tract regulating polypeptide containing 30 or 31 amino acid residues. GLP-1 secretion is regulated primarily by L-cells on the small intestine, depending on nutrient absorption and fluctuating blood glucose levels in the body. After food intake, the L-cells of the small intestine secrete large amounts of GLP-1 to enhance the endocrine function of the pancreas. GLP-1 polypeptides fulfill their physiological functions of controlling blood glucose and reducing appetite in vivo, primarily by activating GLP-1 receptors distributed on the cell membrane surface. The mechanism of GLP-1 for controlling blood sugar level in vivo is mainly to activate GLP-1 receptor distributed in islet beta cells so as to promote biosynthesis and secretion of insulin, and GLP-1 polypeptide can inhibit secretion of glucagon under the condition of high blood sugar level in vivo, gastric emptying and food intake and enhance degradation of glucose in vivo through specific nervous system action. Notably, the physiological function of GLP-1 polypeptides to promote insulin secretion is highly controlled by plasma glucose concentrations, so GLP-1 polypeptides do not induce severe and persistent hypoglycemia compared to other diabetes treatment drugs. In addition, the literature reports that GLP-1 polypeptide and analogs thereof have direct promotion effects on the growth, differentiation and proliferation of beta cells of experimental animals, and the GLP-1 polypeptide and analogs thereof can protect pancreatic islets, delay the physiological function of diabetes development and inhibit the apoptosis of the beta cells. GLP-1 polypeptides also have potential gastrin-inhibiting and feeding-stimulating gastric acid secretion properties, which means that GLP-1 polypeptides also have physiological effects in preventing digestive tract ulcers. GLP-1 polypeptides can also activate GLP-1 receptors distributed in the central nervous system of the brain to enhance satiety, reduce food intake, and achieve the physiological effects of maintaining or reducing body weight. Therefore, the extensive action mechanism and physiological function of the GLP-1 polypeptide and the analogues thereof mean that the GLP-1 polypeptide is an ideal medicament for treating non-insulin-dependent diabetes and obese diabetes.
The physiological functions of the GLP-1 polypeptide in aspects of controlling blood sugar, reducing weight and the like bring hopes for treating non-insulin-dependent diabetes/obese diabetes, but the natural GLP-1 of a human body has poor drug property, is easily degraded by dipeptidyl peptidase-IV (DPP-IV) in the body, so that the half life of the GLP-1 polypeptide in the human body is only 1-2 minutes. In the face of this difficulty, the pharmaceutical industry has constructed long-acting GLP-1 analogs and their derivatives by site-directed mutagenesis of the amino acids at the cleavage site, modification of the fatty acids in the polypeptide backbone, and conjugation of GLP-1 polypeptides to various proteins/polymer polymers. Long-acting GLP-1 analogs that are currently marketed and widely used clinically include canagliptin administered subcutaneously twice a day, liraglutide administered subcutaneously once a day, and dolacitide and somaglutide administered subcutaneously once a week, and the like.
Clinically, the side effects of the GLP-1 polypeptide and the derivatives thereof are mainly manifested by nausea, vomiting and diarrhea caused by gastrointestinal tracts; in addition, it has been found that GLP-1 polypeptides and derivatives thereof also induce an acceleration of the heartbeat in a subject and in certain cases increase the risk of pancreatitis in a patient. Thus, the administration dose of GLP-1 polypeptide and its derivatives is limited by the side effects it causes, and clinical use thereof is not effective in achieving glycemic control and weight loss in patients.
Glucose-dependent insulin release peptide (GIP) and GLP-1 polypeptides are among the incretins, which play a key physiological role in the metabolism of blood Glucose in the body. GIP is composed mainly of 42 amino acid residues in vivo and is secreted by the duodenum and proximal jejunal K cells according to the glucose level in plasma. GIP polypeptides exert their physiological effects by binding to GIP receptors distributed in pancreatic islet beta cells, adipose tissue, and the central nervous system. Like the GLP-1 polypeptide, the GIP polypeptide can stimulate insulin secretion from pancreatic islet β cells to lower blood glucose concentration in plasma and can protect pancreatic islet β cells to control glucose metabolism in vivo. In addition, the physiological functions of the GIP polypeptide include activation of its GIP receptor in adipose tissue to promote fat metabolism. Interestingly, intracerebroventricular injection of the GIP polypeptide into mice reduced food intake and body weight in the test animals, which seems to indicate that the GIP polypeptide also has some specific physiological functions in reducing body weight. It was found that the incretin function of the GIP polypeptide was greatly decreased in a non-insulin-dependent diabetic patient, resulting in the patient lacking or losing the incretin effect. Studies have shown that the inhibitory activity of GIP polypeptides produced by these diabetic patients is greatly diminished while blood glucose levels return to normal. Therefore, a clinical method for treating the non-insulin-dependent diabetes mellitus by using the GIP polypeptide can be used for restoring the tolerance of the non-insulin-dependent diabetes mellitus patient to the GIP polypeptide by matching with some clinically effective hypoglycemic drugs and further utilizing the incretin effect of the GIP polypeptide so as to obtain stronger hypoglycemic effect.
Some GLP-1/GIP receptor dual agonist compounds based on native GIP polypeptide sequences have been described in WO2011/119657, WO2013/164483 and WO 2014/192284.
One major disadvantage of polypeptide compounds as drugs is that: its stability in plasma in vivo is very poor. Renal clearance is due primarily to enzymatic reactions that hydrolyze the amide linkages between amino acids in the polypeptide sequence and to the smaller molecular weight of the polypeptide compound. It has been found that the introduction of unnatural amino acids or lipophilic substituents, such as fatty acid modifications, at specific sites in a polypeptide sequence can improve the enzymatic hydrolytic stability of a given peptide and inhibit renal clearance of the polypeptide compound. Wherein the fatty acid improves the pharmacokinetic properties of the polypeptide drug by binding to albumin in the plasma thereby reducing the rate of renal clearance. Meanwhile, the invention also notes that the length, the structure and the binding site of the fatty acid and the polypeptide have certain influence on the biological activity of the polypeptide compound.
Thus, in contrast to many GIP receptor selective agonist polypeptides in the art, the present invention is directed to: a GIP analogue having an agonist activity to a human GLP-1 receptor and a derivative thereof are provided, which have a dual agonist action to the human GLP-1 receptor and the human GIP receptor. In addition, certain compounds of the present invention have greater therapeutic effects in lowering blood glucose and reducing body weight than GLP-1 receptor agonists in the art. Finally, certain compounds of the present invention have extremely high plasma stability and have pharmacokinetic profiles that support once-a-week subcutaneous administration in humans.
Disclosure of Invention
The invention aims to provide a plurality of double agonist compounds based on human GIP polypeptide, which have double agonist action on human GLP-1 receptor and GIP receptor. In addition, certain polypeptide compounds and derivatives thereof provided by the present invention have higher plasma stability than the human native GLP-1 polypeptide and the human native GIP polypeptide, and can support the pharmacokinetic profile of once weekly subcutaneous administration in humans. The invention also aims to provide a pharmaceutical composition containing the derivative of the polypeptide dual agonist compound and the available medicinal salt thereof, and the pharmaceutical composition can be used for treating metabolic diseases such as non-insulin-dependent diabetes, obesity and the like.
Accordingly, one embodiment of the present invention is to provide a polypeptide compound based on a human GIP sequence represented by the following formula:
R1-Tyr-X1-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X2-Ser-Ile-X3-Nle-X4-Y1-X5-X6-X7-X8-X9-Phe-X10-X11-Trp-Leu-X12-X13-X14-X15-X16-R2
(I)
wherein:
X1-X16 or Y1 are independently selected from any natural or unnatural amino acid or peptide fragment consisting thereof or are not present;
r1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
r2 is selected from-NH2or-OH;
the preferable scheme is as follows:
r1 is H;
r2 is-NH2。
In a preferred embodiment of the present invention, the substrate is,
x1 is an amino acid residue selected from Ala, Aib or D-Ala;
x2 is selected from the amino acid residues of Leu or Try;
x3 represents an amino acid residue selected from Ala, Gln or Tyr;
x4 is an amino acid residue selected from Glu or Asp;
x5 is an amino acid residue selected from Glu, Ile, or Gln;
x6 is selected from His, Ala, or Aib amino acid residues;
x7 is selected from Gln or Val amino acid residue;
x8 is selected from the group consisting of amino acid residues of Arg, Gln, Lys, or Y1;
x9 is selected from Leu, Glu, or Asp amino acid residue;
x10 is an amino acid residue selected from Ile or Val;
x11 is an amino acid residue selected from Asn, Ala, Glu, or Gln;
x12 is selected from Leu or Val amino acid residue;
x13 is selected from Ala or Arg amino acid residue;
x14 is selected from Gln or Gly amino acid residue;
x15 is selected from Lys, Gly or Y1 amino acid residues;
x16 represents a sequence selected from the following amino acids: -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-, -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1-or is absent;
y1 is selected from the group consisting of amino acid residues of Lys or wherein the side chain is substituted with a residue of formula ([2- (2-amino-ethoxy)]-acetyl group)a-(y-Glu)b-CO-(CH2)c-a Lys, Orn, Dap, Dab or Cys amino acid residue coupled to a substituent of COOH;
wherein: a is an integer between 1 and 3, b is an integer between 1 and 2, and C is an integer between 10 and 20.
A further preferred embodiment of the present invention is to provide a polypeptide compound based on a human GIP sequence represented by the following formula, and a derivative or pharmaceutically acceptable salt thereof, which has the following structure:
H-Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X2-Ser-Ile-X3-Nle-X4-Lys-X5-X6-X7-X8-X9-Phe-X10-X11-Trp-Leu-X12-Ala-X14-X15-NH2，
wherein:
X2-X12, X14 and X15 are as described in claim 3.
A further preferred embodiment of the present invention is to provide a polypeptide compound based on a human GIP sequence represented by the following formula:
H-Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-X3-Nle-Glu-Lys-X5-X6-Gln-X8-X9-Phe-X10-X11-Trp-Leu-Leu-Ala-Gln-Lys-NH2
wherein:
x3, X5, X6, X8-X11 are as defined in formula (I).
A further preferred embodiment of the present invention is to provide a polypeptide compound based on a human GIP sequence represented by the following formula:
H-Tyr-X1-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X2-Ser-Ile-X3-Nle-X4-Lys-X5-X6-X7-X8-X9-Phe-X10-X11-Trp-Leu-X12-X13-X14-X15-X16-NH2
wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15 and X16 are respectively and independently selected from any natural amino acid or unnatural amino acid or peptide fragment consisting of the natural amino acid or the unnatural amino acid;
the derivative of the polypeptide compound refers to the chemical modification of the polypeptide compound by utilizing lipophilic substituent groups, the typical modification mode is an amido bond, an ester bond or a thioether bond, and the preferable modification mode is an amido bond.
A preferred embodiment of the present invention is that X1 in the polypeptide compound is selected from the group consisting of Ala, Aib, D-Ala; x2 is selected from Leu, Tyr; x3 is selected from Ala, Gln, Tyr; x4 is selected from Asp, Glu; x5 is selected from Ile, Gln, Glu; x6 is selected from Ala, Aib, His; x7 is selected from Gln, Val; x8 is selected from Gln, Lys, Arg, Y1; x9 is selected from Asp, Glu, Leu; x10 is selected from Ile, Val; x11 is selected from Ala, Asn, Glu, Gln; x12 is selected from Leu, Val; x13 is selected from Ala, Arg; x14 is selected from Gly, Gln; x15 is selected from Lys, Gly, Y1; x16 represents an amino acid sequence selected from Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent;
wherein Y1 represents a side chain and a cyclic alcohol having the formula ([2- (2-amino-ethoxy)]-acetyl group)a-(y-Glu)b-CO-(CH2)c-a Lys, Orn, Dap, Dab or Cys amino acid residue coupled to a substituent of COOH; wherein: a is between 1 and 3B is an integer from 1 to 2, and C is an integer between 10 and 20.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Ala, X7 is Gln, X8 is Lys, X9 is Glu, X10 is Ile, X11 is Ala, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Ala, X7 is Gln, X8 is Y1, X9 is Glu, X10 is Ile, X11 is Ala, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Ala, X7 is Gln, X8 is Lys, X9 is Glu, X10 is Ile, X11 is Ala, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Ala, X7 is Gln, X8 is Lys, X9 is Glu, X10 is Ile, X11 is Ala, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Ala, X7 is Gln, X8 is Arg, X9 is Leu, X10 is Val, X11 is Glu, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Ala, X7 is Gln, X8 is Y1, X9 is Leu, X10 is Val, X11 is Glu, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Ala, X7 is Gln, X8 is Arg, X9 is Leu, X10 is Val, X11 is Glu, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Ala, X7 is Gln, X8 is Arg, X9 is Leu, X10 is Val, X11 is Glu, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Leu, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Ala, X7 is Val, X8 is Arg, X9 is Leu, X10 is Ile, X11 is Asn, X12 is Leu, X13 is Ala, X14 is Gly, X15 is Gly, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Leu, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Ala, X7 is Val, X8 is Y1, X9 is Leu, X10 is Ile, X11 is Asn, X12 is Leu, X13 is Ala, X14 is Gly, X15 is Gly, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or deleted;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Leu, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Ala, X7 is Val, X8 is Arg, X9 is Leu, X10 is Ile, X11 is Asn, X12 is Leu, X13 is Ala, X14 is Gly, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or deleted;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Leu, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Ala, X7 is Val, X8 is Arg, X9 is Leu, X10 is Ile, X11 is Asn, X12 is Leu, X13 is Ala, X14 is Gly, X15 is Gly, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Ala, X7 is Gln, X8 is Y1, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Aib, X7 is Gln, X8 is Lys, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Aib, X7 is Gln, X8 is Y1, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Aib, X7 is Gln, X8 is Lys, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Gln, X6 is Aib, X7 is Gln, X8 is Lys, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Y1, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Val, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Y1, X9 is Glu, X10 is Val, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Val, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Val, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Ala, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Y1, X9 is Glu, X10 is Ile, X11 is Ala, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or null; y1 wherein a is 2, b is 1 and c is 16 or 18. In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Ala, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Tyr, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Ile, X11 is Ala, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Aib, X7 is Gln, X8 is Arg, X9 is Leu, X10 is Val, X11 is Glu, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or deleted.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Aib, X7 is Gln, X8 is Y1, X9 is Leu, X10 is Val, X11 is Glu, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Aib, X7 is Gln, X8 is Arg, X9 is Leu, X10 is Val, X11 is Glu, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or null;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment of the invention, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Glu, X6 is Aib, X7 is Gln, X8 is Arg, X9 is Leu, X10 is Val, X11 is Glu, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Val, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, or deleted.
In another preferred embodiment, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Y1, X9 is Glu, X10 is Val, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or deleted;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Val, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Y1, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, or deleted;
y1 wherein a is 2, b is 1 and c is 16 or 18.
In another preferred embodiment, X1 is Aib, X2 is Tyr, X3 is Ala, X4 is Glu, X5 is Ile, X6 is Ala, X7 is Gln, X8 is Gln, X9 is Glu, X10 is Val, X11 is Gln, X12 is Leu, X13 is Ala, X14 is Gln, X15 is Lys, X16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1;
y1 wherein a is 2, b is 1 and c is 16 or 18.
The invention also relates to a preferable technical scheme, which has the general formula (I) or the pharmaceutical salt thereof, wherein Y1 is K (-OEG-OEG-yGlu-C18-OH), and the group has the following chemical formula:
the invention further preferably adopts a technical scheme that the GIP analogue or the medicinal salt thereof has the general formula (I), wherein Y1 is Lys amino acid residue.
In another embodiment, the above-described polypeptide compounds of the present invention and pharmaceutically acceptable salts thereof.
The polypeptide dual agonist compound and its derivatives provided by the present invention belong to amphoteric compounds, and those skilled in the art can react with acidic or basic compounds to form salts by using the known techniques, and the acids commonly used for forming acid addition salts are: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid; salts include sulfate, pyrosulfate, trifluoroacetate, sulfite, bisulfite, phosphate, hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetate, propionate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, propionate, caprylate, Naphthalene-2-sulfonate, mandelate and the like, preferably trifluoroacetate. Alkaline substances, which may also form salts with GLP-1 analogues, include ammonium, alkali or alkaline earth metal hydroxides, and carbonates, bicarbonates, typically sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, and the like.
The pharmaceutical compositions according to the invention containing the polypeptide dual agonist compounds may be administered parenterally to treat patients in need of such treatment. The parenteral administration route can be selected from subcutaneous injection, intramuscular injection or intravenous injection. The polypeptide dual agonist compounds of the invention may also be administered by the transdermal route, such as via the scalp of a patch, or alternatively by iontophoretic patch; or by transmucosal route.
The polypeptide dual agonist compounds and pharmaceutical compositions thereof provided by the present invention can be prepared using techniques conventional in the pharmaceutical industry, including appropriate dissolution and mixing of the components to obtain the desired final composition. For example, the polypeptide dual agonist compound is dissolved in an amount of water that is slightly less than the final volume of the prepared composition. Isotonic agents, such as sodium chloride, mannitol, glycerol, propylene glycol, sugars or sugar alcohols, preservatives, surfactants and buffers are added as required. Preservatives such as phenol, o-cresol, p-cresol, m-cresol, methyl paraben, benzyl alcohol. Suitable buffering agents include sodium acetate, sodium carbonate, glycine, histidine, lysine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and surfactants such as poloxamer, poloxamer-188, poloxamer-407, tween-80, and tween-20. And adjusting the pH of the solution, if necessary, with an acid such as hydrochloric acid, or a base such as aqueous sodium hydroxide, and finally adjusting the volume of the solution with water to obtain the desired concentration of the component. In addition to the above ingredients, the present invention provides pharmaceutical compositions comprising a sufficient amount of a basic amino acid or a basic agent having the same effect to reduce the formation of aggregates such as lysine, histidine, arginine, imidazole in the composition during storage.
The polypeptide compound and the derivative thereof provided by the invention adopt a solid phase synthesis method, a synthesis carrier is Rink-amide ChemMatrix (Biotage) resin, alpha-amino of the amino acid derivative used in the synthesis process is protected by Fmoc group (fluorenylformyl carbonyl), and the side chain of the amino acid selects the following protection groups according to different functional groups: cysteine side chain mercapto, glutamine side chain amino and histidine side chain imidazolyl are protected by Trt (trityl), arginine side chain guanidino is protected by Pbf (2,2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl), tryptophan side chain indolyl and lysine side chain amino are protected by Boc (tert-butyloxycarbonyl), and threonine side chain hydroxyl, tyrosine side chain phenolic group and serine side chain hydroxyl are protected by tBu (tert-butyl). In the synthesis process, the carboxyl of the C-terminal amino acid residue of the polypeptide is condensed to polymer insoluble Rink-amide ChemMatrix resin in the form of amido bond, then Fmoc protective group on alpha-amino is removed by using nitrogen, nitrogen-Dimethylformamide (DMF) solution containing 20% piperidine, and then the solid phase carrier and the next amino acid derivative in the sequence are condensed in excess to form amido bond so as to connect the peptide chain. Repeating the operations of condensation → washing → deprotection → washing → the next round of amino acid condensation to reach the desired peptide chain length to be synthesized, finally reacting with trifluoroacetic acid: water: the mixed solution of triisopropylsilane (90: 5: 5, v: v: v) reacts with resin to crack the polypeptide from the solid phase carrier, and then the polypeptide and the solid crude product of the polypeptide derivative are obtained after the polypeptide is settled by freezing isopropyl ether. The polypeptide solid crude product is dissolved by acetonitrile/water mixed solution containing 0.1 percent of trifluoroacetic acid, and purified and separated by a C-18 reverse phase preparative chromatographic column to obtain pure products of the polypeptide and the derivatives thereof.
The polypeptides synthesized in the present specification and their derivatives are shown in table 1.
Table 1:
detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The amino acid sequences of the present invention contain the standard single or three letter codes for twenty amino acids, all amino acid residues of the present invention preferably being in the L-form unless specifically indicated. In addition, Aib is alpha aminoisobutyric acid and D-Ala is D-alanine
The term agonist is defined as a substance that activates the type of receptor in question:
the term GLP-1/GIP dual agonist as used in the context of the present invention refers to a substance or ligand which can activate both the GLP-1 receptor and the GIP receptor. In the present invention, the term treatment includes inhibiting, slowing, stopping or reversing the progression or severity of the existing symptoms or condition.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The following specific embodiments are provided in order to explain the present invention in more detail, but the present invention is not limited thereto.
1. Experimental reagent
2. Laboratory apparatus
| Serial number | Instrument for measuring the position of a moving object | Origin of origin |
| 1 | H-CLASS analysis type ultra-high performance liquid chromatography | WATERS |
| 2 | Xevo liquid chromatography/mass spectrometry combination | WATERS |
| 3 | Labconco multifunctional freeze dryer | Thermo-Fisher Scientific |
| 4. | Prep150 preparative high performance liquid chromatography | WATERS |
| 5. | Multi-channel high-speed centrifugal machine | Sigma |
3. Detailed description of the preferred embodiments
3.1 chemical Synthesis of Compound No. 1:
coupling of Fmoc-L-Lys (Boc) -OH to Rink-amide ChemMatrix resin:
weighing Rink-amide ChemMatrix resin (Biotage,0.1mmol) and placing the resin in a disposable polypropylene polypeptide synthesis solid phase reaction tube, adding DMF (10ml) to swell the resin for 10 minutes under nitrogen bubbling, vacuumizing to remove the DMF, adding DMF (10ml) to wash the resin, and repeatedly washing for 2 times; Fmoc-L-Lys (Boc) -OH (1mmol),3- (diethoxyphosphoryloxy) -1,2, 3-benzotriazin-4-one (DEPBT) (1mmol) and diisopropylethylamine (DIEA, 2mmol) were weighed, dissolved by adding DMF (10ml), the solution was added to the swollen Rink-amide ChemMatrix resin, the reaction was shaken at room temperature for 2 hours, after the reaction was completed, the resin was washed with DMF, Dichloromethane (DCM) alternately 2 times, and finally 3 times with DMF.
Fmoc-L-Lys (Boc) -Rink-amide resin Fmoc-protecting group removal:
piperidine/DMF (20%, 10ml) was added to the solid phase reaction tube containing Fmoc-L-Lys (Boc) -Rink amide resin, followed by shaking at room temperature for 10 minutes and then removed, followed by addition of piperidine/DMF (20%, 10ml) and shaking at room temperature for 10 minutes and then removed. After the reaction was complete, the resin was washed 4 times with DMF (10 ml).
3.1.3. Coupling of peptide chain sequences:
the sequence from amino terminus to carboxy terminus was as in the peptide chain sequence of Compound No. 1 (H-Tyr-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Ala-Nle-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH2) The amounts of amino acid derivatives and condensing reagents and their condensing methods were the same as for coupling Fmoc-L-Lys (Boc) -OH to Rink-amide ChemMatrix resin, and the amino acid residues used in the synthesis were: Fmoc-L-Tyr (tBu) -OH, Fmoc-L-Ala-OH, Fmoc-L-Glu (OtBu) -OH, Fmoc-Gly-OH, Fmoc-L-Thr (tBu) -OH, Fmoc-L-Phe-OH, Fmoc-L-Ser (tBu) -OH, Fmoc-L-Asp (OtBu) -OH, Fmoc-L-Ile-OH, Fmoc-L-Nle-OH, Fmoc-L-Lys (OH), (Fmoc-L-His Boc) -OH, Fmoc-L-Gln Tr (Boc) -OH, Fmoc-L-Val-OH, Fmoc-L-Asn (Trt) -OH, Fmoc-L-Trp (Boc) -OH, Fmoc-L-Leu-OH. Repeated condensation of amino acid derivatives and Fmoc deprotection FinalTo obtain a resin peptide having the polypeptide sequence of Compound No. 1.
3.1.4. Cleavage of the resinoid:
the resin peptide obtained in the previous step was washed with DMF and DCM in sequence for 3 times, then dried under vacuum, and then 10ml of a freshly prepared lysate (trifluoroacetic acid: triisopropylsilane: water, 90: 5: 5, v: v: v) was added and reacted at room temperature for 2 hours with shaking. Filtering after the reaction is finished, washing the resin for 2 times by using trifluoroacetic acid, merging the filtrates, adding a large amount of frozen anhydrous isopropyl ether to precipitate a solid, centrifuging, and removing a supernatant to obtain a crude polypeptide product of which the compound number is 1.
3.1.5. Reverse phase liquid chromatography purification of crude peptide:
the crude peptide was dissolved in a mixed solvent containing 0.1% trifluoroacetic acid, 20% acetonitrile/water, filtered through a 0.22 μm membrane and separated by a WATERS Prep-150 LC reversed-phase high performance liquid chromatography system, with buffers A (0.1% trifluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). Wherein the chromatographic column is an X-SELECT OBDC-18 reversed phase chromatographic column, the detection wavelength of a chromatograph is set to be 220nm in the purification process, and the flow rate is 20 mL/min. And collecting related fractions of the product, and freeze-drying to obtain a pure polypeptide product of the compound number 1 with the yield of 20%. The purity and the compound identity of the pure polypeptide are determined by the combination of analytical high performance liquid chromatography and liquid chromatography/mass spectrometry, wherein the purity is 96.41%, and the calculated molecular weight value of the compound is as follows: 3501.8, the molecular weight of the compound was found to be: 3501.6.
3.2 chemical Synthesis of Compound Nos. 2 to 33
The polypeptide compound of compound number 2-33 of the present invention is synthesized using the experimental protocol of compound 1, and purity and compound molecular weight are determined using analytical ultra high performance liquid chromatography and liquid chromatography/mass spectrometry, as specifically shown in table 2 below:
3.3 chemical Synthesis of Compound No. 34:
3.3.1 coupling of Fmoc-L-Lys (Mtt) -OH to Rink-amide ChemMatrix resin:
weighing Rink-amide ChemMatrix resin (0.1mmol) and placing the Rink-amide ChemMatrix resin into a disposable polypropylene solid phase synthesis reaction tube, adding DMF (10ml) to swell the resin for 5 minutes, vacuumizing to remove the DMF, adding DMF (10ml) to wash the resin, and repeatedly washing for 2 times; Fmoc-L-Lys (Mtt) -OH (1mmol),3- (diethoxyphosphoryloxy) -1,2, 3-benzotriazin-4-one (DEPBT) (1mmol) and DIEA (2mmol) were weighed, dissolved by adding DMF (10ml), the solution was added to the swollen Rink-amidiChemMatrix resin, and the reaction was performed at room temperature for 2 hours with shaking, after which the resin was washed alternately with DMF, Dichloromethane (DCM) 2 times, and finally washed with DMF 3 times.
Fmoc deprotection and peptide chain extension
Fmoc deprotection of Fmoc-L-Lys (Mtt) -Rink amide ChemMatrix resin and subsequent extension of the peptide chain A resin peptide containing Compound No. 34 was obtained by the same synthesis method as in example one, wherein Boc-L-Tyr (t-Bu) -OH was used as the N-terminal amino acid residue.
3.3.3. Mtt deprotection and lysine side chain modification of resinopeptides
After completion of the extension of the above peptide-resin, a hexafluoroisopropanol/dichloromethane mixed solution (30%, 10ml) was added, and after 45 minutes of the reaction at room temperature, the solution was removed by shaking, and after the reaction was completed, the resin was washed 6 times with DMF. Additional coupling/deprotection cycles to extend lysine side chains using Fmoc/tBu solid phase Synthesis strategy involving Fmoc-NH-PEG2-COOH, Fmoc-L-Glu-OtBu and HOOC- (CH)2)16-COOt-Bu. In all couplings, the reaction was carried out at room temperature and was built using 1mmol of amino acid, 1mmol of DEPBT and 2mmol of DIEA in DMF for 4 hours.
3.3.4. Cleavage and product purification
The resin peptide obtained in the previous step was washed with DMF and DCM in this order 2 times, then dried under vacuum, and then added with a freshly prepared lysate (trifluoroacetic acid: triisopropylsilane: water: 90: 5: 5, v: v: v) and reacted at room temperature for 2 hours with shaking. Filtering after the reaction is finished, washing the resin for 2 times by using trifluoroacetic acid, merging the filtrates, adding a large amount of frozen anhydrous isopropyl ether to precipitate a solid, centrifuging, and removing a supernatant to obtain a crude polypeptide product of which the compound number is 34.
3.3.5 reverse phase liquid chromatography purification of Compound 34
The crude peptide of 34 was dissolved in a mixed solvent containing 0.1% trifluoroacetic acid, 20% acetonitrile/water, filtered through a 0.22um membrane and separated by a WATERS Prep150 LC reverse phase high performance liquid chromatography system with buffers a (0.1% trifluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). Wherein the chromatographic column is an X-SELECTOBD C-18 reversed phase chromatographic column, the detection wavelength of a chromatograph is set to be 220nm in the purification process, and the flow rate is 20 mL/min. And collecting related fractions of the product, and freeze-drying to obtain a pure polypeptide product of the compound number 34 with the yield of 18%. The purity of the pure polypeptide product is determined by the combination of analytical high performance liquid chromatography and liquid chromatography/mass spectrometry, the purity of the compound is 97.23 percent, and the molecular weight of the compound is 5046.6.
3.4 chemical Synthesis of Compound Nos. 35-47
The experimental protocol for compound 34 was used to synthesize the compound number 35-47 polypeptide compounds of the invention and the purity and molecular weight of the compounds were determined by analytical high performance liquid chromatography coupled with liquid chromatography/mass spectrometry as shown in table 3 below.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
1. Experimental reagent
2. Laboratory apparatus
3. Test example
3.1. Evaluation of agonist Activity of test Compounds at glucagon-like peptide-1 receptor (GLP-1R)
3.1.1 purposes of the experiment
The purpose of this test example was to measure the agonist activity of the numbered compounds at the glucagon-like peptide-1 receptor (GLP-1R)
3.1.2 Experimental methods:
frozen CHO-K1/GLP-1R/CRE-luc stably-transformed cell strains are taken out of a liquid nitrogen tank, placed in a water bath kettle at 37 ℃ for rapid thawing, resuspended in DMEM/F12 culture medium (Gibco Cat #11330032), washed once after centrifugation, resuspended in an experimental buffer, namely DMEM/F12 culture medium containing 0.1% casein (Sigma Cat # C3400), adjusted in cell density by the experimental buffer, spread in 384-well plates (Sigma Cat # CLS4514) at the density of 2500 cells/5 mu L/well, and then added with IBMX working solution (Sigma Cat # I7018) prepared by 2.5 mu L buffer at the final concentration of 0.5mM and 2.5 mu L of polypeptide samples diluted in gradient, centrifuged at 1000rpm for 1min, shaken for 30 seconds for uniform mixing, and placed at room temperature for 30 minutes for incubation. Detection was performed using the CisbiocAMP-Gs Dynamic kit (Cisbio Cat #62AM4PEC), and cAMP-d2 and Anti-cAMP-Eu3+ -Cryptote were diluted 20-fold with cAMP Lysis & protection Buffer, respectively, and mixed well. Add 5. mu.L diluted cAMP-d2 solution into each well, add 5. mu.L diluted Anti-cAMP-Eu3+ -Cryptate solution, shake for 30 seconds, mix well, incubate for 1 hour at room temperature in the dark.
3.1.3 Experimental data processing method:
HTRF signal reading was performed using a Biotek Synergy H1 microplate reader with an excitation wavelength of 320nm and emission wavelengths of 620nm and 665 nm. ComputingSignal ratio (665nm/620nm 10,000), and nonlinear fitting of signal ratio to sample concentration in GraphPad Prism 6 using a four parameter equation to yield EC50The values, specific data are shown in table 4 below.
3.2. Evaluation of agonist Activity of test Compounds at glucose-dependent insulin Release peptide receptor (GIPR)
3.2.1 purpose of the experiment
Test of agonist activity of the numbered compounds at glucose-dependent insulin releasing peptide receptor (GIPR) 3.2.2 experimental methods:
wild type CHO-K1 cells were harvested, the cell suspension was adjusted to appropriate density, plated in 6 well plates at 2 mL/well, placed in 5% CO at 37 deg.C2After overnight attachment in the incubator, the transfection mixture (hGIPR plasmid, Fugene HD (Promega Cat # E2311), OptiMEM (Gibco Cat #31985070) was mixed and left to stand at room temperature for 15 minutes, added to the corresponding cell well in a volume of 100. mu.L, transfected for 24h to overexpress hGIPR on the CHO-K1 cell surface, cells in 6-well plates were collected after the end of the transient, washed once with the assay buffer DMEM/F12 medium (Gibco Cat #11330032) containing 0.1% casein (Sigma Cat # C3400), cell density was adjusted using the assay buffer, plated in 384-well plates (Sigma Cat # CLS4514) at a density of 5000 cells/5. mu.L/well, then 2.5. mu.L of IBMX working fluid (Sigma Cat # I7018) prepared in buffer per well was added, final IBIBMX concentration was 0.5mM, and 2.5. mu.L of diluted polypeptide sample, mixed at 1000rpm, incubated at 30 minutes, incubated with Ci-BiocGmC 4 for detection using the assay method, cAMP-d2 and Anti-cAMP-Eu3+ -Cryptate were treated with cAMP lysine, respectively&The Detection Buffer is diluted by 20 times and mixed evenly. Add 5. mu.L diluted cAMP-d2 solution into each well, add 5. mu.L diluted Anti-cAMP-Eu3+ -Cryptate solution, shake for 30 seconds, mix well, incubate for 1 hour at room temperature in the dark.
3.2.3 Experimental data processing method:
HTRF signal reading was performed using a Biotek Synergy H1 microplate reader with an excitation wavelength of 320nm and emission wavelengths of 620nm and 665 nm. The signal ratio (665nm/620nm 10,000) was calculated and used to sample concentration in GraphPad Prism 6Carrying out nonlinear fitting on the four-parameter equation to obtain EC50The values, specific values are shown in table 4 below.
Table 4: testing agonist activity of compounds at human GLP-1R and human GIPR receptor
Conclusion of the experiment
Some of the tested compounds exhibited strong agonist activity at both the human GLP-1 receptor and the human GIP receptor, with compounds 7, 9, 11, 13, 16, 19 or 23 exhibiting agonist activity at both the human GLP-1 receptor and the human GIP receptor comparable to the native polypeptide. The fatty acid modified compounds all showed strong activity towards GIP receptor (<0.05 nM). These polypeptides exhibit greater agonist activity at both the human GLP-1 receptor and the human GIP receptor, particularly in terms of GIP receptor activity, as compared to many GLP-1 receptor agonist polypeptides in the art.
Claims (27)
1. A GIP analogue comprising an amino acid sequence of the general formula (I) or a pharmaceutically acceptable salt form thereof, having the structure:
R1-Tyr-X1-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X2-Ser-Ile-X3-Nle-X4-Y1-X5-X6-X7-X8-X9-Phe-X10-X11-Trp-Leu-X12-X13-X14-X15-X16-R2
(I)
wherein:
X1-X16 or Y1 are independently selected from any natural or unnatural amino acid or peptide fragment thereof, or are absent;
r1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
r2 is selected from-NH2or-OH.
2. The GIP analog of formula (I) or a pharmaceutically acceptable salt form thereof as claimed in claim 1,
r1 is H;
r2 is-NH2。
3. The GIP analog of formula (I) or a pharmaceutically acceptable salt form thereof as claimed in claim 1,
wherein:
x1 is an amino acid residue selected from Ala, Aib or D-Ala;
x2 is selected from the amino acid residues of Leu or Try;
x3 represents an amino acid residue selected from Ala, Gln or Tyr;
x4 is an amino acid residue selected from Glu or Asp;
x5 is an amino acid residue selected from Glu, Ile, or Gln;
x6 is selected from His, Ala, or Aib amino acid residues;
x7 is selected from Gln or Val amino acid residue;
x8 is selected from the group consisting of amino acid residues of Arg, Gln, Lys, or Y1;
x9 is selected from Leu, Glu, or Asp amino acid residue;
x10 is an amino acid residue selected from Ile or Val;
x11 is an amino acid residue selected from Asn, Ala, Glu, or Gln;
x12 is selected from Leu or Val amino acid residue;
x13 is selected from Ala or Arg amino acid residue;
x14 is selected from Gln or Gly amino acid residue;
x15 is selected from Lys, Gly or Y1 amino acid residues;
x16 represents a sequence selected from the following amino acids: -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-, -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1-or is absent;
y1 is selected from the group consisting of amino acid residues of Lys or wherein the side chain is substituted with a residue of formula ([2- (2-amino-ethoxy)]-acetyl group)a-(y-Glu)b-CO-(CH2)c-a Lys, Orn, Dap, Dab or Cys amino acid residue coupled to a substituent of COOH;
wherein a is an integer between 1 and 3, b is an integer between 1 and 2, and C is an integer between 10 and 30.
4. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Tyr;
x4 represents Glu;
x5 represents Gln;
x6 represents Ala;
x7 represents Gln;
x8 represents Lys or Y1;
x9 represents Glu;
x10 represents Ile;
x11 represents Ala;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
5. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Ala;
x4 represents Glu;
x5 represents Glu;
x6 represents Ala;
x7 represents Gln;
x8 represents Arg or Y1;
x9 represents Leu;
x10 represents Val;
x11 represents Glu;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
6. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Leu;
x3 represents Ala;
x4 represents Glu;
x5 represents Glu;
x6 represents Ala;
x7 represents Val;
x8 represents Arg or Y1;
x9 represents Leu;
x10 represents Ile;
x11 represents Asn;
x12 represents Leu;
x13 represents Ala;
x14 represents Gly;
x15 represents Gly or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
7. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Tyr;
x4 represents Glu;
x5 represents Gln;
x6 represents Ala;
x7 represents Gln;
x8 represents Gln or Y1;
x9 represents Glu;
x10 represents Ile;
x11 represents Gln;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
8. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Tyr;
x4 represents Glu;
x5 represents Gln;
x6 represents Aib;
x7 represents Gln;
x8 represents Lys or Y1;
x9 represents Glu;
x10 represents Ile;
x11 represents Gln;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
9. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Tyr;
x4 represents Glu;
x5 represents Ile;
x6 represents Ala;
x7 represents Gln;
x8 represents Gln or Y1;
x9 represents Glu;
x10 represents Ile;
x11 represents Gln;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
10. A GIP analogue of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Tyr;
x4 represents Glu;
x5 represents Ile;
x6 represents Ala;
x7 represents Gln;
x8 represents Gln or Y1;
x9 represents Glu;
x10 represents Val;
x11 represents Gln;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
11. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Tyr;
x4 represents Glu;
x5 represents Ile;
x6 represents Ala;
x7 represents Gln;
x8 represents Gln or Y1;
x9 represents Glu;
x10 represents Ile;
x11 represents Ala;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
12. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Ala;
x4 represents Glu;
x5 represents Glu;
x6 represents Aib;
x7 represents Gln;
x8 represents Arg or Y1;
x9 represents Leu;
x10 represents Val;
x11 represents Glu;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or not.
13. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
wherein:
x1 represents Aib;
x2 represents Tyr;
x3 represents Ala;
x4 represents Glu;
x5 represents Ile;
x6 represents Ala;
x7 represents Gln;
x8 represents Gln or Y1;
x9 represents Glu;
x10 represents Val;
x11 represents Gln;
x12 represents Leu;
x13 represents Ala;
x14 represents Gln;
x15 represents Lys or Y1;
x16 represents a sequence selected from amino acids: Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1 or is absent.
14. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 13,
wherein:
x8 is Y1.
15. The GIP analog of the general formula (II) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 13,
wherein:
x15 is Y1.
16. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 13,
wherein:
x16 is Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Y1.
17. The GIP analog of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 16,
wherein:
a is 2;
b is an integer between 1 and 2;
c is an integer between 16 and 18.
18. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 3 to 16,
wherein:
a is 2;
b is 1;
c is 16.
19. The GIP analog of the general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 3 to 16,
wherein:
a is 2;
b is 1;
c is 18.
20. The GIP analog of formula (I), or a pharmaceutically acceptable salt form thereof, according to claim 1, having the structure:
H-Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X2-Ser-Ile-X3-Nle-X4-Lys-X5-X6-X7-X8-X9-Phe-X10-X11-Trp-Leu-X12-Ala-X14-X15-NH2，
wherein:
X2-X12, X14 and X15 are as described in claim 3.
21. The GIP analog of formula (I), or a pharmaceutically acceptable salt form thereof, according to claim 1, having the structure:
H-Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-X3-Nle-Glu-Lys-X5-X6-Gln-X8-X9-Phe-X10-X11-Trp-Leu-Leu-Ala-Gln-Lys-NH2
wherein:
x3, X5, X6, X8-X11 are as described in claim 3.
22. The GIP analog of formula (I), or a pharmaceutically acceptable salt form thereof, as claimed in any one of claims 1 to 21,
the structure of Y1 is as follows:
23. the GIP analog of formula (I), or a pharmaceutically acceptable salt form thereof, as claimed in any one of claims 1 to 21,
wherein said Y1 is an amino acid residue of Lys.
24. A GIP analog or a pharmaceutically acceptable salt thereof, having the structure:
25. a pharmaceutical composition comprising a GIP analogue of general formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-24, and a pharmaceutically acceptable carrier or excipient therefor.
26. Use of a GIP analogue of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-24, or a pharmaceutical composition according to claim 25 for the manufacture of a medicament for the treatment of non-insulin dependent diabetes mellitus, insulin dependent diabetes mellitus or obesity.
27. A GIP analogue of general formula (I) or a pharmaceutically acceptable salt thereof for use in simultaneous, separate or sequential combination with a further agent according to any one of claims 1-24, wherein the agent is one or more selected from metformin, thiazolidinediones, sulphonylureas, dipeptidyl peptidase inhibitors and sodium glucose transporters.
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