CN117320740A - GIP/GLP1 dual agonist treatment methods - Google Patents

GIP/GLP1 dual agonist treatment methods Download PDF

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Publication number
CN117320740A
CN117320740A CN202280015672.2A CN202280015672A CN117320740A CN 117320740 A CN117320740 A CN 117320740A CN 202280015672 A CN202280015672 A CN 202280015672A CN 117320740 A CN117320740 A CN 117320740A
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ethoxy
glu
amino
seq
acetyl group
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M·C·M·邦克
L·费尔南德斯兰多
J·S·里斯梅尔
A·罗德里格斯贝尔纳迪诺
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Eli Lilly and Co
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Eli Lilly and Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

One embodiment of the invention relates to a method of increasing HDL-C in a patient in need thereof. One embodiment of the invention relates to a method of reducing hypertension. One embodiment relates to a method of treatment of a refractory type 2 diabetic patient to provide normal HbA1c blood glucose.

Description

GIP/GLP1 dual agonist treatment methods
The present invention relates to the field of medicine. Methods of treating refractory type 2 diabetes (T2D) in patients who fail to achieve recommended glycemic targets with metformin and SGLT-2 are provided. Methods are provided relating to increasing HDL-C levels in a patient in need thereof. Methods of reducing blood pressure in a patient in need thereof are provided.
Glycosylated hemoglobin (HbAlc) is considered as a key marker for glycemic control in diabetes. The american diabetes association (American Diabetes Association) (ADA) guidelines indicate that less than or equal to 5.7% of patients with HbAlc are considered normoglycemic. The patient treatment goals of HbAlc may vary from patient to patient; however, continuously poorly controlled HbAlc disproportionately promotes the development of diabetes-related complications. Despite treatment using the ADA treatment paradigm, type 2 diabetics often fail to achieve euglycemia. Although not within normal ranges, the ADA guidelines recommend a reasonable HbAlc treatment goal of less than or equal to 7% following current treatment options for diet, exercise, metformin, oral diabetes treatment, and thus basal insulin. However, despite clinical treatment, many patients still fail to reach their HbAlc targets and are considered to have refractory type 2 diabetes.
Type 2 diabetes mellitus, which is refractory, is often explained by insulin secretion defects or beta cell damage, becomes more and more severe over time in the context of (relatively stable) insulin resistance. Patients with type 2 diabetes are more likely to have refractory type 2 diabetes for at least 8 years. Thus, there is a need to provide a treatment for refractory type 2 diabetes patients that is normal or near normal blood glucose. There is a need to provide a method of treatment for normoglycemia in refractory type 2 diabetes patients who have been treated for type 2 diabetes for at least 8 years.
Approximately half of the U.S. adults suffer from hypertension or low HDL-C. Hypertension is a risk factor for stroke, coronary Heart Disease (CHD) and other major health threats. Many type 2 diabetic and obese patients suffer from hypertension; however, approved diabetes treatments generally have little or no effect on controlling hypertension. There is a need to manage treatment options for hypertension. There is a need for a method of treating hypertension in diabetics.
Low serum levels of high density lipoprotein cholesterol (HDL-C) are another known risk factor for Coronary Heart Disease (CHD). Type 2 diabetics typically have low serum HDL-C levels; however, approved treatments for diabetes generally fail to increase HDL-C. Longitudinal demographic studies have demonstrated that HDL-C is inversely proportional and independently related to the risk of developing CHD. There is a need for pharmacotherapies that increase HDL-C levels. There is a need for a therapeutic method that increases HDL-C in type 2 diabetics.
The present invention provides methods of treating, preventing, or delaying hypertension comprising administering a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof. The invention further provides a method of treating, preventing or delaying the diagnosis of hypertension in a patient suffering from type 2 diabetes comprising administering a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
The present invention provides methods of treating, preventing or delaying low HDL-C comprising administering a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof. The invention further provides a method of treating, preventing or delaying the diagnosis of low HDL-C in a patient suffering from type 2 diabetes comprising administering a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
The present invention provides methods of treating, preventing or delaying treatment-refractory type 2 diabetes in a patient suffering from type 2 diabetes for at least 8 years comprising administering a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating refractory type 2 diabetes in a patient suffering from type 2 diabetes for at least 8 years comprising administering a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
In one embodiment, a patient in need of treatment for refractory type 2 diabetes has greater than 10% HbA1c.
In one embodiment, a patient in need of treatment for refractory type 2 diabetes has greater than 11% HbA1c.
In one embodiment, a patient in need of treatment for refractory type 2 diabetes has a HbA1c treatment target of 5.7%. In one embodiment, a patient in need of treatment for refractory type 2 diabetes has less than or equal to 5.7% HbA1c treatment targets.
In one embodiment, a patient in need of treatment for refractory type 2 diabetes has a HbA1c treatment target of 6%.
In one embodiment, a patient in need of treatment for refractory type 2 diabetes has a HbA1c treatment target of 7%.
The present invention provides methods of treating refractory type 2 diabetes in a patient that is unresponsive to metformin, SGLT-2, or a metformin+sglt-2 inhibitor, comprising administering a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
Thus, one embodiment provides a method of treating, preventing, or delaying hypertension in a patient in need thereof comprising administering to the patient an effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof once a week. A further embodiment provides a method of treating hypertension in a patient diagnosed with type 2 diabetes comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once a week.
In another aspect, the invention provides a method of preventing or delaying hypertension in a patient comprising administering to the patient a therapeutically effective amount of a GIP/GLP1 agonist once a week.
In another aspect, the invention provides a method of preventing or delaying the diagnosis of hypertension in a patient suffering from type 2 diabetes comprising administering to the patient a therapeutically effective amount of a GIP/GLP1 agonist once a week.
In another aspect, the invention provides the use of a GIP/GLP1 agonist for the manufacture of a medicament for treating, preventing or delaying the progression of hypertension in a patient, wherein the medicament is administered once a week.
The present invention provides methods of treating, preventing or delaying hypertension comprising administering to a patient in need of such treatment an effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
In one embodiment, a patient in need of treatment for hypertension has type 2 diabetes and is non-obese.
In one embodiment, a patient in need of treatment for hypertension has type 2 diabetes and obesity.
In one embodiment, a patient in need of treatment for hypertension has refractory type 2 diabetes.
In one embodiment, a patient in need of treatment for hypertension has type 2 diabetes for at least 8 years.
Thus, one embodiment provides a method of treating, preventing, or delaying the progression of hypertensive crisis in a refractory type 2 diabetic patient comprising administering to the patient an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, once a week.
In one embodiment, a patient in need of treatment for hypertensive crisis has type 2 diabetes and is non-obese.
In one embodiment, a patient in need of treatment for hypertensive crisis has type 2 diabetes and obesity.
In one embodiment, a patient in need of treatment for hypertensive crisis has refractory type 2 diabetes.
In one embodiment, a patient in need of treatment for hypertensive crisis has type 2 diabetes for at least 8 years.
Thus, one embodiment provides a method of treating, preventing, or delaying the progression of low HDL-C in a patient comprising administering to the patient once a week an effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a method of preventing or delaying hypertensive crisis in a patient comprising administering to the patient an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, once a week.
In another aspect, the invention provides a method of preventing or delaying low HDL-C in a patient comprising administering to the patient an effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof once a week.
In another aspect, the invention provides a method of treating hypertension in a patient receiving clinical treatment of type 2 diabetes with an oral antidiabetic agent for at least 1, 2, 3, 4 or 5 years, wherein the patient has an HbA1c of > 7%, comprising administering to the patient an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, once a week.
In another aspect, the invention provides a method of improving glycemic control in a patient suffering from type 2 diabetes mellitus and at risk of hypertension, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once a week, wherein the method reduces the risk of the patient developing hypertensive crisis.
In another aspect, the invention provides a method of improving glycemic control in a patient suffering from type 2 diabetes mellitus and at risk of hypertension, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once a week for at least 30 weeks, wherein the method reduces the risk of the patient developing hypertensive crisis.
In another aspect, the invention provides a method of improving weight management in a patient who is obese and at risk of hypertension, comprising administering to the patient an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, once a week, wherein the method reduces the risk of developing hypertensive crisis in the patient.
In another aspect, the invention provides a method of treating hypertension in a patient comprising administering an effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof to the patient once a week, wherein the patient's weight is within the normal weight range of the patient.
In another aspect, the invention provides a method of improving weight management in a patient who is obese and at risk of hypertension, comprising administering to the patient an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, once a week, wherein the method results in a reduced risk of developing hypertension in the patient.
In another aspect, there is provided a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying the progression of hypertensive crisis, wherein the GIP/GLP1 agonist is administered once a week.
In another aspect, a method provides a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying the progression of hypertension, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered once a week.
In another aspect, one embodiment is the use of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating, preventing or delaying the progression of hypertension, wherein the medicament is administered once a week.
In another aspect, there is provided the use of a GIP/GLP1 agonist for the manufacture of a medicament for the treatment, prevention or delay of progression of hypertension, wherein the medicament is administered once a week.
In another aspect, one embodiment is the use of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating, preventing or delaying the progression of hypertensive crisis, wherein the medicament is administered once a week.
In another aspect, there is provided the use of a GIP/GLP1 agonist for the manufacture of a medicament for treating, preventing or delaying the progression of hypertensive crisis, wherein the medicament is administered once a week.
In one embodiment, GIP/GLP1 agonists are described and claimed in WO 2020/024386 (Eli Lilly).
As used herein, "hypertensive crisis" refers to a dangerously high blood pressure and can be life threatening to the patient's organs or lives. The hypertensive crisis is typically a blood pressure of at least 180/120. Hypertension is typically 130/80 systolic/diastolic.
As used herein, "refractory type 2 diabetes" refers to patients who cannot achieve their HbA1c goals using oral standard of care drugs such as metformin.
As used herein, a "HbA1c target" refers to a desired average HbA1c level to be achieved by a patient as determined by the patient's clinical treatment plan and as measured using clinically approved methods. Current ADA guidelines suggest a reasonable HbAlc treatment goal of less than or equal to 7% following current treatment options for diet, exercise, metformin, oral diabetes treatment, and thus basal insulin. However, despite clinical treatment, many patients still fail to reach their HbAlc targets and are considered to have refractory type 2 diabetes. In one embodiment, hbA1c is targeted at 7% or less. In one embodiment, hbA1c is targeted at 5.7% or less.
In men and women aged 49 to 82 years, with no CHD at baseline (during the 12 year follow-up period) in the Framingham study, there was a highParticipants with HDL-C levels (80%) had 50 percent lower risk of cardiovascular events than participants with low HDL-C levels (20%) 2 . In a Prospective Cardiovascular M Bunster (PROCAM) study (4,500 volunteers, aged 16-65 years, follow-up 6 years), individuals with HDL-C < 35mg/dl were found to have four times the risk of coronary heart disease than individuals with HDL-C > 35 mg/dl. See Astmann G et al, high-density lipoprotein cholesterol as a predictor ofcoronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Athererclosclerosis. 1996;124 (Suppl): S11-S20.Gordon et al suggested that each increase in HDL-C by 1mg/dL resulted in a 2% to 3% reduction in the composite cardiovascular risk in an individual. Gordon DJ et al, high-density lipoprotein cholesterol and cardiovascular disease: four prospective American publications. Circulation.1989;79:8-15. Results from Veterans Administration HDL Intervention Trial (VA-HIT) indicate that only a modest increase in 6% HDL-C significantly reduces coronary heart disease morbidity and mortality by as much as 24% in patients initially with low HDL-C. Rubins HB et al Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of High-density lipoprotein cholestol. Veterans Affair High-Density Lipoprotein Cholesterol Intervention Trial Study group.N Engl J Med.1999;341:410-8.
Current treatments for increasing HDL-C may include lifestyle changes such as increased exercise and decreased dietary fat. Lifestyle changes are often insufficient to achieve the desired rise in HDL-C. Patients in need of HDL-C elevation require treatment options. There is a need for therapies that treat, prevent or delay low HDL-C.
The term "treating" or the like as used herein is intended to include slowing or attenuating the progression of a disease, condition, or disorder. These terms also include alleviating, ameliorating, reducing, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if the progression of the disorder or condition itself is not slowed or reversed. The term "preventing" and the like as used herein is intended to include avoiding the onset of a disease, condition, disorder or symptom. The term "delay" and the like as used herein is intended to include increasing the duration until the onset of a disease, condition, disorder or symptom. The term "compound" when used herein in connection with multiple outcomes refers to the first occurrence of any outcome. The term "increasing HDL-C" refers to an increase in the level of HDL-C measured from baseline. In one embodiment, the increased HDL-C change is a statistically significant increase. In one embodiment, increasing HDL-C is by greater than 2% from baseline. In one embodiment, increasing HDL-C is greater than 5% from baseline. In one embodiment, increasing HDL-C is greater than 7% from baseline. In one embodiment, increasing HDL-C is by greater than 10% from baseline.
By "therapeutically effective amount" is meant the amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use in the methods and uses of the invention or a pharmaceutical composition comprising a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use in the methods and uses of the invention that will result in the biological or medical response of the patient or the desired therapeutic effect on the patient that is sought by a researcher, doctor or other clinician. The effective amount of the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof may vary depending on the factors: the disease state, age, sex and weight of the individual, and the ability of the GIP/GLP1 agonist to elicit a desired response in the individual. An effective amount is also one in which the therapeutic benefit exceeds any toxic or detrimental effect. In certain embodiments, a therapeutically effective amount of a GIP/GLP1 agonist for use in the methods described herein is administered as an oral dosage form. In certain embodiments, a therapeutically effective amount of the GIP/GLP1 agonist is administered once daily. In certain embodiments, a therapeutically effective amount of a GIP/GLP1 agonist is administered twice daily. In certain embodiments, a therapeutically effective amount of the GIP/GLP1 agonist is administered daily as an oral formulation.
Additional embodiments are described below:
in one embodiment, a method of improving glycemic control and raising HDL-C in a type 2 diabetic patient comprises administering to the patient a therapeutically effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof once a week for at least 30 weeks.
In one embodiment, the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered for at least 40 weeks. In one embodiment, the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered for at least 52 weeks.
Hypertension and normal HbA1c blood glucose
A method of treating, preventing, or delaying the progression of hypertension in a patient comprising administering a therapeutically effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once a week. In one embodiment, the hypertension is selected from hypertension and hypertensive crisis.
A method of preventing or delaying hypertension in a patient comprising administering a therapeutically effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof to the patient once a week.
A method of preventing or delaying hypertension in a patient comprising administering to the patient a therapeutically effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof in an oral dosage form.
A method of improving glycemic control and treating, preventing, or delaying hypertension in a patient diagnosed with type 2 diabetes, comprising administering to the patient a therapeutically effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, once a week.
A method of improving glycemic control and treating, preventing, or delaying hypertension in a patient diagnosed with type 2 diabetes, comprising administering to the patient a therapeutically effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in an oral dosage form.
In one embodiment, the method reduces the risk of developing hypertension in the patient. In one embodiment, the method reduces the risk of developing hypertensive crisis in the patient. In one embodiment, the method reduces the risk of a patient developing clinically low HDL-C.
A method of improving glycemic control in a type 2 diabetic patient, comprising administering a therapeutically effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once a week, wherein the method results in a reduced risk of the patient developing hypertension.
The method of any one of the above embodiments, wherein the patient has type 2 diabetes. The method of any one of the above embodiments, wherein the patient has refractory type 2 diabetes. The method of any one of the above embodiments, wherein the patient has type 2 diabetes for at least 8 years. The method of any one of the above embodiments, wherein the patient has type 2 diabetes for at least 10 years. The method of any one of the above embodiments, wherein the once weekly administration of the GIP/GLP1 agonist is for at least 40 weeks. The method of any one of the above embodiments, wherein the patient is non-obese.
The method of any one of the above embodiments, wherein the patient has one or more of: t2DM; hypertension; reduced HDL-C; and obesity.
In one embodiment, the patient has: there are no multiple cardiovascular risk factors for hypertension, or clinically significant hypertension.
In one embodiment, the patient has: a variety of cardiovascular risk factors, or HbA1c levels above 11%.
As used herein, "cardiovascular risk factor" refers to a risk factor for cardiovascular disease selected from the group consisting of: tobacco (any form of tobacco) is being used; treatment of hypercholesterolemia or well-documented untreated low density lipoprotein cholesterol (LDL-C) 3.4mmol/L (100 mg/dL) with at least 1 approved lipid-regulating therapy over the past 6 months; high density lipoprotein cholesterol (HDL-C) in men < 1.0mmol/L (40 mg/dL) and women < 1.3mmol/L (50 mg/dL) or triglycerides ≡2.3mmol/L (150 mg/dL) after treatment or untreated in the past 6 months; treating hypertension or untreated systolic pressure (SBP) of 130mm Hg or diastolic pressure (DBP) of 80mmHg or more with at least 1 blood pressure medication; measuring 102cm of waistline male; female 88cm.
As used herein, "non-obese" refers to a patient that is not obese according to applicable standards. In one embodiment, a non-obese patient has a body mass index of less than 30 BMI.
As used herein, "co-morbid" refers to a patient diagnosed with more than 2 medical conditions.
In one embodiment, the patient's risk of hypertensive crisis is reduced by at least about 14%.
In one embodiment, the patient's risk of hypertensive crisis is reduced by at least about 10%.
In one embodiment, HDL-C levels are increased. In one embodiment, HDL-C levels are increased to clinically desirable levels. In one embodiment, a method of improving glycemic control and raising HDL-C in a type 2 diabetic patient comprises administering to the patient a therapeutically effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof once a week for at least 30 weeks.
In one embodiment, the risk of occurrence of compounding (composition) of the following outcomes is reduced: hospitalization or death due to hypertension.
In one embodiment, the risk of mortality or hospitalization for hypertension is reduced in a patient treated with an effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
In one embodiment, the risk of occurrence of compounding (composition) of the following outcomes is reduced: hypertension and HbA1c above 5.7%. In one embodiment, the risk of occurrence of compounding (composition) of the following outcomes is reduced: low HDL-C, high blood pressure and HbA1C above 7%.
In one embodiment, the risk of occurrence of compounding (composition) of the following outcomes is reduced: low HDL-C, high blood pressure and HbA1C above 5.7%.
In one embodiment, the risk of occurrence of compounding (composition) of the following outcomes is reduced: low HDL-C, high blood pressure and HbA1C above 6%.
A method of achieving normal HbA1c blood glucose in a refractory type 2 diabetic patient comprising administering a therapeutically effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof to the patient once a week.
In one embodiment, the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered using a dose escalation regimen.
In one embodiment, the patient fails to achieve HbA1c < 7% for at least one year with one or two oral diabetic agents prior to treatment with a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
In one embodiment, the patient fails to achieve HbA1c < 8% for at least one year using one or both oral agents prior to treatment with the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
In one embodiment, the patient fails to achieve HbA1c < 10% for at least one year using one or both oral agents prior to treatment with the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof.
In one embodiment, the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered weekly for at least 30 weeks. In one embodiment, the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered weekly for at least 40 weeks. In one embodiment, the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered weekly for at least 50 weeks. In one embodiment, the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered weekly for at least 2 years. In one embodiment, the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered weekly for at least 3 years. In one embodiment, the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered weekly for at least 5 years.
In one embodiment, the patient is diagnosed with type 2 diabetes at least 8 years prior to administration of the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof.
In one embodiment, the patient is diagnosed with type 2 diabetes at least 10 years prior to administration of the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof.
In one embodiment, the patient is diagnosed with type 2 diabetes at least 13 years prior to administration of the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is at least 46 years old.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is at least 55 years old.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is at least 60 years old.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered metformin and an SGLT2 oral agent.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered an oral SGLT2 agent.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered metformin.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered basal insulin.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered metformin and basal insulin.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered SGLT2 and basal insulin.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered metformin, SGLT2 and basal insulin.
In one embodiment, the basal insulin is insulin glargine.
In one embodiment, the basal insulin is insulin deltoid.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered an SGLT2 oral drug.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered metformin, an oral SGLT2 drug, and insulin diglucoside.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered metformin, an oral SGLT2 drug, and insulin diglucoside.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered metformin, an SGLT2 oral drug, and insulin glargine.
In one embodiment, the patient to whom the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered is also administered metformin and insulin glargine.
In another aspect, the present invention provides a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use in any one of the above embodiments.
In another aspect, the invention provides the use of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for any one of the above embodiments.
In one embodiment, the GIP/GLP1 agonist is a compound of formula I:
R 1 X 1 X 2 X 3 GTX 6 TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 (SEQ ID NO：3)
wherein:
R 1 no Ac modification or N-terminal amino group;
X 1 selected from Y, H, D-Tyr, F, desH and desY;
X 2 selected from Aib, αmep, a, P and D-Ala;
or X 1 And X 2 Combine to form desH- ψ [ NHCO ]]-Aib；
X 3 Selected from E, N, aad and cTA;
X 6 selected from F, αmef and αmef (2F);
X 10 selected from A, L, H, 3Pal, 4Pal, V, Y, E, αMeF (2F), I, αMeY, Q, D-His, D-Tyr, cTA and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 11 Selected from S, αMeS and D-Ser;
X 12 selected from I,S, D-Ile and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 13 Selected from Nle, aib, L, αmel and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 14 Selected from L and K, wherein K is conjugated to C 16 -C 22 A fatty acid, wherein the fatty acid is conjugated to the K, optionally via a linker;
X 16 selected from K, E, orn, dab, dap, S, T, H, aib, αMeK, R and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 17 Selected from K, Q, I and conjugation to C 16 -C 22 An amino acid of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker;
X 19 selected from Q, A and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 20 Selected from Aib, Q, H, R, K, αMeK and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 21 Selected from H, aad, D, aib, T, A, E, I and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 22 Selected from F and αmef;
X 23 selected from I, L, A, G, F, H, E, V and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 24 Selected from S, aad, D-Glu, E, aib, H, V, A, Q, D, P and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 25 Selected from Y and αmey;
X 26 selected from L, alpha MeL and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 27 Selected from L, I and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 28 Selected from E, A, S, D-Glu and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 29 Selected from Aib, G, A and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 30 Selected from C, G, G-R 2 And K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H；
X 31 Absence or selection of PX 32 X 33 X 34 -R 2 (SEQ ID NO：4)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO：5)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 6), K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 -R 2 (SEQ ID NO: 7), K [ (2- [2- (2-amino-ethoxy) -ethoxy ] ]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 8) and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO：9)；
Wherein:
X 32 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 33 Is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 34 Selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 35 Is A or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 36 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 37 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 38 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 39 Selected from C, S and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 40 Selected from C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
q is selected from 14, 15, 16, 17, 18, 19 and 20; and
R 2 absence or NH of C-terminal groups 2 Modifying;
wherein if X 30 Is G-R 2 X is then 31 Absence of;
wherein X is 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 19 、X 20 、X 21 、X 23 、X 24 、X 26 、X 27 、X 28 、X 29 、X 30 、X 31 、X 32 、X 33 、X 34 、X 35 、X 36 、X 37 、X 38 、X 39 And X 40 May be a fatty acid-containing substituent; and
wherein X is 30 、X 34 、X 39 And X 40 May be C; and
wherein if X 30 、X 34 、X 39 And X 40 One is C, then X 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 19 、X 20 、X 21 、X 23 、X 24 、X 26 、X 27 、X 28 、X 29 、X 30 、X 31 、X 32 、X 33 、X 34 、X 35 、X 36 、X 37 、X 38 、X 39 And X 40 None of which contains a substituent of a fatty acid.
In one embodiment, the GIP/GLP1 agonist is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein:
X 17 Is conjugated to C 16 -C 22 An amino acid of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker; and
X 30 selected from G-R 2 And G;
wherein if X 30 G is, then X 31 Selected from PX 32 X 33 X 34 -R 2 (SEQ ID NO: 4), wherein X 32 Is S, X 33 Is S and X 34 Is G (SEQ ID NO: 15), and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 5), wherein X 32 Is S, X 33 Is S, X 34 Is G, X 35 Is A, X 36 Is P, X 37 Is P, X 38 Is P and X 39 Is S (SEQ ID NO: 16) (hereinafter referred to as "compound of formula III").
In one embodiment is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein X 17 The amino acid is conjugated to a fatty acid via a linker (hereinafter referred to as "compound of formula IIIa").
In one embodiment, the GIP/GLP1 agonist is a compound of formulas III and IIIa or a pharmaceutically acceptable salt thereof wherein:
X 10 selected from A, L, H, 3Pal, 4Pal, V, Y, E, αmef (2F), I, αmey, Q, D-His, D-Tyr, and cTA;
X 12 selected from I, S and D-Ile;
X 13 selected from Nle, aib, L and αmel;
X 14 selected from L and K;
X 16 selected from K, E, orn, dab, dap, S, T, H, aib, αmek and R;
X 19 selected from Q and a;
X 20 selected from Aib, Q, H, R, K and αmek;
X 21 selected from H, aad, D, aib, T, A, E and I;
X 23 selected from I, L, A, G, F, H, E and V;
X 24 Selected from S, aad, D-Glu, E, aib, H, V, A, Q, D and P;
X 26 selected from L and αmel;
X 27 selected from L and I;
X 28 selected from E, A, S and D-Glu;
X 29 selected from Aib, G and a;
X 30 selected from G and G-R 2 ；
Wherein if X 30 Is G; then X is 31 Selected from PX 32 X 33 X 34 -R 2 (SEQ ID NO: 4), wherein X 32 Is S, X 33 Is S and X 34 Is G (SEQ ID NO: 15), and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 5), wherein X 32 Is S, X 33 Is S, X 34 Is G, X 35 Is A, X 36 Is P, X 37 Is P, X 38 Is P and X 39 Is S (SEQ ID NO: 16) (hereinafter referred to as "compound of formula IIIb").
In one embodiment, the GIP/GLP1 agonist is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein:
R 1 absence of;
X 1 and X 2 Does not combine to form desH- ψ [ NHCO ]]-Aib；
X 17 Is conjugated to C 16 -C 22 And K of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker.
In one embodiment, the GIP/GLP1 agonist is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein:
X 1 y is;
X 2 is Aib;
X 3 is E;
X 10 selected from A, L, H, 3Pal, 4Pal, V and Y;
X 11 s is;
X 12 is I;
X 14 is L;
X 16 selected from K, E, orn, dab and Dap;
X 17 is conjugated to C 16 -C 22 K of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker;
X 19 is Q;
X 20 is Aib;
X 21 selected from H, aad, D, aib, T, A and E;
X 22 Is F;
X 23 is I;
X 24 selected from S, aad, D-Glu and E;
X 26 is L; and
X 28 selected from E and A.
In one embodiment, the GIP/GLP1 agonist is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein:
X 1 y is;
X 2 is Aib;
X 3 is E;
X 6 is αmef (2F);
X 10 selected from Y, 4-PaI and V;
X 11 s is;
X 12 is I;
X 13 selected from L, aib and αmel;
X 14 is L;
X 16 selected from E, K and Orn;
X 17 is conjugated to C 16 -C 22 K of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker;
X 19 is Q;
X 20 is Aib
X 21 Selected from E, A and T;
X 22 is F;
X 23 is I;
X 24 is D-Glu;
X 25 selected from Y and αmey;
X 26 is L;
X 27 is I;
X 28 is E;
X 29 is G;
X 30 is G; and
X 31 is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 5), wherein X 32 Is S, X 33 Is S, X 34 Is G, X 35 Is A, X 36 Is P, X 37 Is P, X 38 Is P, X 39 Is S (SEQ ID NO: 16).
In one embodiment, the GIP/GLP1 agonist is a compound of formulas III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X 16 Is Orn, X 13 Is alpha MeL, and X 25 Is Y. In one embodiment, the GIP/GLP1 agonist is a compound of formulas III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X 16 Is E, X 13 Is alpha MeL, and X 25 Is Y. In one embodiment, the GIP/GLP1 agonist is a compound of formulas III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X 16 Is E, X 13 Is alpha MeL, X 10 Y is X 25 Is αmey. In one embodiment, the GIP/GLP1 agonist is a compound of formulas III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X 16 Is Orn, X 13 Is alpha MeL, X 10 Is 4Pal, and X 25 Is Y.
In one embodiment, the GIP/GLP1 agonist is a peptide selected from the group consisting of SEQ ID NO: 10. SEQ ID NO: 11. SEQ ID NO: 12. SEQ ID NO:13 and SEQ ID NO:14 or a pharmaceutically acceptable salt thereof.
In one embodiment, the GIP/GLP1 agonist is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 1 Selected from Y, F and D-Tyr; x is X 6 Is F; and X is 13 Selected from Aib, L and αmel.
In one embodiment, the GIP/GLP1 agonist is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 Absence of; x is X 1 Selected from Y, F and D-Tyr; x is X 6 Is F; x is X 13 Selected from Aib, L and αmel; x is X 2 Is Aib; x is X 3 Is E; x is X 10 Y is; x is X 11 S is; x is X 12 Is I; x is X 14 Is L; x is X 16 Selected from K, E, orn, dab, dap, S, T, H, aib, αmek and R; x is X 17 Is conjugated to C 16 -C 22 An amino acid of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker; x is X 19 Is Q; x is X 20 Selected from Aib, Q, H and K; x is X 21 Selected from H, D, T, A and E; x is X 22 Is F; x is X 23 Is I; x is X 24 Selected from D-Glu and E; x is X 26 Is L; x is X 27 Is I; x is X 28 Selected from E, A, S and D-Glu; x is X 29 Selected from Aib, G and a; x is X 30 Selected from C, G and G-R 2 ；X 31 Absence or selection of PX 32 X 33 X 34 -R 2 (SEQ ID NO：4)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 5) and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 6); wherein: x is X 32 S is; x is X 33 S is; x is X 34 Selected from G and C; x is X 35 Is A; x is X 36 Is P; x is X 37 Is P; x is X 38 Is P; x is X 39 Selected from C and S; and X is 40 Is C.
In one embodiment, the GIP/GLP1 agonist is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 1 Selected from Y, F and D-Tyr; x is X 6 Is F; and X is 13 Selected from Aib, L and α MeL；X 28 is A; x is X 29 Is G; x is X 30 Is G; x is X 31 Is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO：5)；X 34 Is G; and X is 39 Is S.
In one embodiment, the GIP/GLP1 agonist is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 1 Selected from Y and D-Tyr; and X is 13 Is αmel.
In one embodiment, the GIP/GLP1 agonist is a peptide selected from the group consisting of SEQ ID NO: 21. SEQ ID NO: 22. SEQ ID NO: 23. SEQ ID NO: 24. SEQ ID NO:25 and SEQ ID NO:26 or a pharmaceutically acceptable salt thereof.
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI:
X 1 X 2 EGTX 6 TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30
(SEQ ID NO：27)
wherein the method comprises the steps of
X 1 Selected from Y and R 1 Y；
R 1 Ac modification of the N-terminal amino group;
X 2 is Aib;
X 6 selected from αmef and αmef (2F);
X 10 Selected from 4Pal, Y, αMeF (2F), αMeL, αMeV, ac4c, ac5c, ac6c, bip, 1Nal, 2Nal, OMeY, hTyr, nle, V, 4CPhe, chG, chA, bzt, 2FA, 4TAA, 2TA, 3TA and KZ 1 ；
X 11 Selected from S, α MeS, aib, G, dap, ac5c and tlie;
X 12 selected from I and KZ 1 ；
X 13 Selected from αmel and αmef;
X 16 is Orn;
X 17 selected from Q, I and KZ 1 ；
X 20 Selected from Aib, orn, 4Pal, αmef, ac5c, and Ac6c;
X 21 selected from E, KZ 1 G, orn and 4Pal;
X 22 selected from F, 2ClPhe, 3ClPhe, 2FPhe, 3,5FPhe, 1Nal, 2Nal, αMeF (2F), chA, bzt and αMeF;
X 24 selected from D-Glu, E, G and KZ 1 ；
X 25 Selected from Y, αMeY, αMeF and KZ 1 ；
X 28 Selected from E, orn and KZ 1 ；
X 30 Selected from G, orn, KZ 1 、K(Z 1 )R 6 、OrnR 2 And GR (glass fiber reinforced plastics) 2 ；
R 2 Selected from X 31 、X 31 SSG(SEQ ID NO：28)、X 31 SSG-R 3 (SEQ ID NO：29)、X 31 SSGX 35 PPPX 39 (SEQ ID NO：30)、X 31 SSGX 35 PPPX 39 R 3 (SEQ ID NO：31)、X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO：32)、X 31 SSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 33) and modification of the c-terminal group, wherein the modification is NH 2 ；
R 6 Selected from PSSG (SEQ ID NO: 34), PSSG-R 3 (SEQ ID NO：35)、PSSGX 35 PPPX 39 (SEQ ID NO：36)、PSSGX 35 PPPX 39 R 3 (SEQ ID NO：37)、PSSGX 35 PPPX 39 X 40 (SEQ ID NO：38)、PSSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 39) and modification of the c-terminal group, wherein the modification is NH 2 ；
X 31 Selected from P and KZ 1 ；
X 35 Selected from A and Orn;
X 39 selected from S and Orn;
X 40 is KZ 1 ；
R 3 Is a modification of the C-terminal group, wherein the modification is NH 2 ；
Wherein X is 10 、X 12 、X 17 、X 21 、X 24 、X 25 、X 28 、X 30 、X 31 And X 40 Is KZ 1 Or K (Z) 1 )R 6 ；
Z 1 Selected from R 5 and-R 4 R 5 ；
R 4 Is a joint; and
R 5 is a fatty acid.
Providing a compound of formula VII or a pharmaceutically acceptable salt thereof:
X 1 X 2 EGTX 6 TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30 (SEQ ID NO：40)
wherein the method comprises the steps of
X 1 Selected from Y and R 1 Y；
R 1 Ac modification of the N-terminal amino group;
X 2 Is Aib;
X 6 selected from αmef and αmef (2F);
X 10 selected from 4Pal, Y, αMeF (2F), αMeL, αMeV, ac4c, ac5c, ac6c, bip, 1Nal, 2Nal, OMeY, hTyr, nle, V, 4CPhe, chG, chA, bzt, 2FA, 4TAA, 2TA, 3TA and KZ 1 ；
X 11 Selected from Ac5c, S, α MeS, aib, G, dap and tlie;
X 12 selected from I and KZ 1 ；
X 13 Selected from αmel and αmef;
X 16 is Orn;
X 17 selected from Q, I and KZ 1 ；
X 20 Selected from Aib, orn, 4Pal, αmef, ac5c, and Ac6c;
X 21 selected from E, KZ 1 G, orn and 4Pal;
X 22 selected from F, 2ClPhe, 3ClPhe, 2FPhe, 3,5FPhe, 1Nal, 2Nal, αMeF (2F), chA, bzt and αMeF;
X 24 selected from D-Glu, E, G and KZ 1 ；
X 25 Selected from Y, αMeY, αMeF and KZ 1 ；
X 28 Selected from E, orn and KZ 1 ；
X 30 Selected from G, orn, KZ 1 And GR (glass fiber reinforced plastics) 2 ；
R 2 Selected from X 31 SSG(SEQ ID NO：28)、X 31 SSG-R 3 (SEQ ID NO：29)、X 31 SSGX 35 PPPX 39 (SEQ ID NO：30)、X 31 SSGX 35 PPPX 39 R 3 (SEQ ID NO：31)、X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO：32)、X 31 SSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 33) and modification of the c-terminal group, wherein the modification is NH 2 ；
X 31 Selected from P and KZ 1 ；
X 35 Selected from A and Orn;
X 39 selected from S and Orn;
X 40 is KZ 1 ；
R 3 Is a modification of the C-terminal group, wherein the modification is NH 2 ；
Wherein X is 10 、X 12 、X 17 、X 21 、X 24 、X 25 、X 28 、X 30 、X 31 And X 40 Is KZ 1 ；
Z 1 Selected from R 5 and-R 4 R 5 The method comprises the steps of carrying out a first treatment on the surface of the And
R 4 is a joint;
R 5 is a fatty acid.
In one embodiment, the GIP/GLP1 agonist is a peptide of formula VI or a pharmaceutically acceptable salt thereof, wherein Z 1 Selected from the group consisting of
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)A base),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 10 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 -(γ-Glu)-CO-(CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ] ]Acetyl group 2 -(εK)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl-(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(γ-Glu)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (7- (4-carboxyphenoxy) heptanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (8- (4-carboxyphenoxy) octanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (11- (4-carboxyphenoxy) undecanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethyl ] Oxy group]-acetyl) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -CO-(CH 2 ) 12 -CO 2 H，
-PEG3-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
-PEG4-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (11- (4-carboxyphenoxy) undecanoyl,
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 14 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -Ahx- (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -Aoc- (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
-Ahx- (2- [2- (2-amino-ethoxy)]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
-Aoc- (2- [2- (2-amino-ethoxy) -ethoxy]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -Ahx- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -Aoc- (γ -Glu) - (10- (4-carboxyphenoxy) decanoyl),
ahx- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
-Aoc- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
PEG4- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
PEG3- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -Aoc-CO- (CH 2 ) 12 -CO 2 H，
-PEG6-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
-PEG5-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
PEG6- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
PEG5- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -Trx-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -Trx- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -Trx- (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -Trx- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu) 2 -CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu) 2 - (10- (4-carboxyphenoxy) decanoyl),
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetylGroup) - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H, and
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl).
In one embodiment, the GIP/GLP1 agonist is a peptide of formula I or a pharmaceutically acceptable salt thereof, wherein Z 1 Selected from the group consisting of
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ] ]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 10 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 -(γ-Glu)-CO-(CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (epsilon K) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(γ-Glu)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -CO- (CH 2 ) 12 -CO 2 H
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (7- (4-carboxyphenoxy) heptanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (8- (4-carboxyphenoxy) octanoyl), and
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl).
In one embodiment, the GIP/GLP1 agonist is a peptide of formula VI or a pharmaceutically acceptable salt thereof, wherein Z 1 Selected from the group consisting of
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 10 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ] ]Acetyl group 3 -(γ-Glu)-CO-(CH 2 ) 14 -CH 3 ，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (epsilon K) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) -CO- (CH 2 ) 12 -CO 2 H，
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(γ-Glu)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -CO-(CH 2 ) 12 -CO 2 H，
-(εK)-(εK)-(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) -CO- (CH 2 ) 12 -CO 2 H，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (7- (4-carboxyphenoxy) heptanoyl),
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (8- (4-carboxyphenoxy) octanoyl), and
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl).
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from-CO- (CH) 2 ) 12 -CO 2 H、-CO-(CH 2 ) 10 -CO 2 H. - (10- (4-carboxyphenoxy) decanoyl), - (4- (4-iodophenyl) butanoyl), - (4- (4-tert-butylphenyl) butanoyl), -CO- (CH) 2 ) 14 -CH 3 、-CO-(CH 2 ) 12 -CH 3 、-CO-(CH 2 ) 10 -CH 3 - (7- (4-carboxyphenoxy) heptanoyl), - (8- (4-carboxyphenoxy) octanoyl), (11- (4-carboxyphenoxy) undecanoyl), - (12- (4-carboxyphenoxy) dodecanoyl) and-CO- (CH) 2 ) 14 -CO 2 H。
In one embodiment, the GIP/GLP1 agonist is a chemical of formula VIA compound or pharmaceutically acceptable salt thereof, wherein R 5 Selected from-CO- (CH) 2 ) 12 -CO 2 H、-CO-(CH 2 ) 10 -CO 2 H. - (10- (4-carboxyphenoxy) decanoyl), - (4- (4-iodophenyl) butanoyl), - (4- (4-tert-butylphenyl) butanoyl), -CO- (CH) 2 ) 14 -CH 3 、-CO-(CH 2 ) 12 -CH 3 、-CO-(CH 2 ) 10 -CH 3 - (7- (4-carboxyphenoxy) heptanoyl) and- (8- (4-carboxyphenoxy) octanoyl).
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from the group consisting of
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) -,
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu) 2 )-，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 -(γ-Glu)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-(γ-Glu)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (epsilon K) - (gamma-Glu) -,
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -Trx- (gamma-Glu) -,
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -Trx-(γ-Glu)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -Aoc-,
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -Aoc- (gamma-Glu) -,
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -Ahx- (gamma-Glu) -,
-PEG3-(γ-Glu)-，
-PEG4-(γ-Glu)-，
-PEG5-(γ-Glu)-，
-PEG6-(γ-Glu)-，
ahx- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) -,
-Aoc- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) -,
- (εK) - (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) -,
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-，
-(εK)-(γ-Glu)-，
-(εK)-(γ-Glu)-(γ-Glu)-，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -，
-(εK)-(εK)-(γ-Glu)-，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -,
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -,
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl) -,
- (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl) - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -sum of
(2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) -.
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from the group consisting of
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-.
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) -,
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 -(γ-Glu)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(εK)-(γ-Glu)-，
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (epsilon K) - (gamma-Glu) -,
- (εK) - (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) -,
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-，
-(εK)-(γ-Glu)-，
-(εK)-(γ-Glu)-(γ-Glu)-，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -，
-(εK)-(εK)-(γ-Glu)-，
- (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -, and
- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) - (gamma-Glu) - (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) -.
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 17 And X 31 Each is KZ 1 . In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 17 And X 24 Each is KZ 1 . In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 17 And X 21 Each is KZ 1 . In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 17 And X 28 Each is KZ 1 . At the position ofIn one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 17 And X 40 Each is KZ 1 . In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 21 And X 40 Each is KZ 1 . In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 21 And X 28 Each is KZ 1 . In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 24 And X 28 Each is KZ 1 。
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein X 1 Y is; x is X 6 Is αmef (2F); x is X 10 Selected from 4Pal, Y and KZ 1 ；X 11 Selected from S, αMeS and Aib; x is X 12 Is I; x is X 13 Is that α MeL；X 16 Is Orn; x is X 17 Selected from I and KZ 1 ；X 20 Is Aib; x is X 21 Selected from KZ 1 And E; x is X 22 Selected from F and αmef; x is X 24 Selected from D-Glu and KZ 1 ；X 25 Is αmey; x is X 28 Selected from E and KZ 1 ；X 30 Selected from G and GR 2 ；R 2 Selected from X 31 SSGX 35 PPPX 39 (SEQ ID NO：30)、X 31 SSGX 35 PPPX 39 R 3 (SEQ ID NO: 31) and X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO: 32) and modification of the c-terminal group, wherein the modification is NH 2 ；X 31 Selected from P and KZ 1 ；X 35 Selected from A and Orn; x is X 39 Selected from S and Orn; x is X 40 Selected from KZ 1 ；R 3 Is a modification of the C-terminal group, wherein the modification is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein is selected from X 10 、X 17 、X 21 、X 24 、X 28 And X 31 One and only one of (2) is KZ 1 ；Z 1 is-R 4 R 5 ；R 4 Is a joint; and R is 5 Is a fatty acid; or a pharmaceutically acceptable salt thereof.
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H)SSGAPPPS-NH 2 (SEQ ID NO：41)，
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：17)，
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy) ]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：18)，
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butyryl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO: 19), and
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 ) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 )SSGAPPPS-NH 2 (SEQ ID NO：19)。
In one embodiment, the GIP/GLP1 agonist is wherein R 4 The linker is a compound of 1 to 2 amino acids selected from epsilon K and gamma Glu. In one embodiment, R 4 The linker comprises 1 to 3 (2- [2- (2-amino-ethoxy) -ethoxy groups]-acetyl) moiety. In one embodiment, the GIP/GLP1 agonist is wherein R 5 Fatty acid moiety via lysine and R 5 R between fatty acids 4 A compound having a linker conjugated to lysine.
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein R 4 The linker comprises 0 to 4 amino acids; and 0 to 3 (2- [2- (2-amino-ethoxy) -ethoxy]-acetyl) moiety. In one embodiment, the GIP/GLP1 agonist is wherein R 4 The linker comprises a compound of 1 to 3 amino acids each independently selected from epsilon K and gamma-Glu. In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein R 4 The linker comprises 1 to 2 amino acids each independently selected from epsilon K and gamma-Glu. In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two Z 1 Fatty acid moiety, wherein Z 1 Each R of the moieties 5 Fatty acids via R 4 Conjugation of linkers to different lysines of the peptide, wherein R 4 The linker comprises 0 to 2 gamma-Glu amino acid residues. In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two Z1 fatty acid moieties, wherein each R of Z1 5 Fatty acids via R 4 Conjugation of linkers to different lysines of the peptide, wherein R 4 Comprising 1 to 3 amino acids and 1 to 3 (2- [2- (2-amino-ethoxy) -ethoxy groups ]-acetyl) moiety. In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two identical Z 1 Fatty acid moiety, wherein Z 1 R of (2) 5 Fatty acids each via R 4 Conjugation of linkers to different lysines of the peptide, wherein R 4 Comprising 1 to 3 individual choicesAmino acids from εK and γ -Glu; and 1 to 3 (2- [2- (2-amino-ethoxy) -ethoxy groups attached to the amino acid]-acetyl) moiety. In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two identical Z 1 Fatty acid moiety, wherein Z 1 R of (2) 5 Fatty acids each via R 4 Conjugation of linkers to different lysines of the peptide, wherein R 4 Comprising 1 or 2 (2- [2- (2-amino-ethoxy) -ethoxy groups attached]Up to 3 amino acids each independently selected from gamma-Glu and epsilon K.
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two identical Z 1 Fatty acid moiety, wherein Z 1 R of (2) 5 Fatty acids each via R 4 Conjugation of linker, wherein R 4 The linker has the formula:
- (epsilon K) a1- (gamma-Glu) a2- (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) a3- (epsilon K) b1- (gamma-Glu) b2-;
Wherein a1 is selected from 0, 1 and 2; a2 is selected from 0, 1 and 2; a3 is selected from 0, 1, 2 and 3; b1 is 0 or 1; and b2 is 0 or 1. In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two identical Z 1 Fatty acid moiety, wherein Z 1 R of (2) 5 Fatty acids each via R 4 Conjugation of linker, wherein Z 1 Has the following formula:
- (epsilon K) a1- (gamma-Glu) a2- (2- [2- (2-amino-ethoxy)]-acetyl) a3- (εK) b1- (γ -Glu) b2-CO- (CH) 2 )q-CO 2 H, wherein a1 is selected from 0, 1 and 2; a2 is selected from 0, 1 and 2; a3 is selected from 0, 1, 2 and 3; b1 is 0 or 1; b2 is 0 or 1; and q is selected from 10, 12, 14 and 16.
In one embodiment is a GIP/GLP1 agonist, wherein a1 is 1, a2 is 0, a3 is 2, b1 is 0, b2 is 1, and q is 12; and the structure is as follows:
- (epsilon K) - (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )12-CO 2 H。
In one embodimentThe GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, which comprises two identical Z 1 Fatty acid moiety, wherein Z 1 R of (2) 5 Fatty acids each via R 4 Conjugation of linker, wherein R 4 Linker and R 5 The fatty acid component has the formula:
wherein q2 is selected from 7, 8, 10, 11 and 12.
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two identical Z 1 Fatty acid moiety, wherein Z 1 R of (2) 5 Fatty acids each via R 4 Conjugation of linker, wherein R 5 The fatty acid is selected from the group consisting of- (7- (4-carboxyphenoxy) heptanoyl) and- (8- (4-carboxyphenoxy) octanoyl). In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two identical Z 1 Fatty acid moieties, each via R 4 Conjugation of linker, wherein R 5 The fatty acid is selected from the group consisting of- (10- (4-carboxyphenoxy) decanoyl), - (4- (4-iodophenyl) butanoyl) and- (4- (4-tert-butylphenyl) butanoyl).
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two identical Z 1 Fatty acid moieties, each via R 4 Conjugation of linker, wherein R 5 The fatty acid is selected from-CO- (CH) 2 ) 14 -CH 3 、-CO-(CH 2 ) 12 -CH 3 and-CO- (CH) 2 ) 10 -CH 3 。
In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable salt thereof, comprising two identical Z 1 Fatty acid moieties, each via R 4 Conjugation of linker, wherein R 5 The fatty acid is selected from-CO- (CH) 2 ) 12 -CO 2 H and-CO- (CH) 2 ) 10 -CO 2 H. In one embodiment, the GIP/GLP1 agonist is a compound of formula VI or a pharmaceutically acceptable thereofAn acceptable salt comprising two identical Z 1 Fatty acid moieties, each via R 4 Conjugation of linker, wherein R 5 The fatty acid is selected from-CO- (CH) 2 ) 10 -CH 3 and-CO- (CH) 2 ) 12 -CH 3 。
In one embodiment, the GIP/GLP1 agonist is wherein R 5 The fatty acid is selected from-CO- (CH) 2 ) 12 -CO 2 H、-CO-(CH 2 ) 10 -CO 2 H. - (10- (4-carboxyphenoxy) decanoyl), - (4- (4-iodophenyl) butanoyl), - (4- (4-tert-butylphenyl) butanoyl), -CO- (CH) 2 ) 14 -CH 3 、-CO-(CH 2 ) 12 -CH 3 、-CO-(CH 2 ) 10 -CH 3 Compounds of the type, - (7- (4-carboxyphenoxy) heptanoyl) and- (8- (4-carboxyphenoxy) octanoyl).
Certain GIP/GLP1 agonist compounds are generally effective over a wide dosage range. For example, the dose administered parenterally once a week may be in the range of 0.05mg to about 30mg per week per person.
GLP-1 is a 36 amino acid peptide whose major biologically active fragment is a C-terminal amidated peptide of 30-amino acid (GLP-1) 7-36 ) (SEQ ID NO: 2) And (3) generating.
GIP is a 42 amino acid peptide (SEQ ID NO: 1), which is also known as incretin, similar to GLP-1, and plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic beta cells in the presence of glucose.
In one embodiment, the GIP/GLP1 agonist compound has desirable GIP and GLP receptor activity, wherein the GIP agonist potency is 2.5 to 5 times the GLP1 receptor potency as measured by the casein cAMP assay described below, wherein the potency is normalized to native GIP and GLP on the day of the assay. In one embodiment, the GIP/GLP1 agonist compound has desirable GIP and GLP receptor activity, wherein the GIP agonist potency is 2.5 to 10 times the GLP1 receptor potency as measured by the casein cAMP assay, wherein the potency is normalized to native GIP and GLP on the day of the assay.
The term "amino acid" as used herein refers to naturally occurring amino acids and non-natural amino acids. Amino acids are typically depicted using standard single letter codes (e.g., l=leucine) as well as α -methyl substitution residues of natural amino acids (e.g., α -methyl leucine or αmel and α -methyl lysine or αmek) and certain other unnatural amino acids such as α -aminoisobutyric acid or "Aib", "4Pal", "Orn", and the like. The structure of these amino acids is as follows:
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as used herein, "Orn" refers to ornithine. As used herein, "4Pal" refers to 3-mono (4-pyridyl) -L-alanine. As used herein, "αmef (2F)" refers to α -methyl 2-F-phenylalanine. As used herein, "αmey", "αmek" and "αmel" refer to αmethyl tyrosine, αmethyl lysine and αmethyl leucine, respectively. As used herein, "e" and "D-Glu" each refer to D-glutamic acid. As used herein, "D-His" and "h" each refer to D-histidine. As used herein, "D-Tyr" and "y" each refer to D-tyrosine. As used herein, "D-Ser" and "s" each refer to D-serine. As used herein, "D-Ala" and "a" each refer to D-alanine. As used herein, "αmef (2F)" refers to α -methyl-F (2F) and α -methyl-Phe (2F). As used herein, "αmef" refers to α -methyl-F and α -methyl-Phe. As used herein, "αmey" refers to α -methyl-Tyr. As used herein, "αmek" refers to α -methyl-Lys. As used herein, "αmel" refers to α -methyl-Leu. As used herein, "αmes" refers to α -methyl-serine and α -methyl-Ser. As used herein, "αmep" refers to α -methyl-proline and α -methyl-Pro. As used herein, "DesH" refers to desHis. As used herein, "desY" refers to desTyr.
As used herein, "AEEA" refers to (2- [2- (2-amino-ethoxy) -ethoxy ]]-acetyl group; "AEEA2" means (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the And "AEEA3" means (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 3 。
As used herein, "Ahx" is 6-aminocaproyl-; "Aoc" is 8-aminooctanoyl-; "PEG3" is [3- (2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy) -propionyl ] -; "PEG4" is (3- [2- (2- [2- (2-amino-ethoxy) -ethoxy ] -propionyl) -; "PEG5" is [3- (2- [2- (2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy) -propionyl ] -; and "PEG6" is (3- [2- (2- [2- (2- [2- (2-amino-ethoxy) -ethoxy ] -propionyl) -. "Tle" is tert-leucine.
As used herein with respect to one or more GIP or GLP-1 receptors, the terms "activity," "activation," and the like refer to the ability of a compound or pharmaceutically acceptable salt thereof to bind to and elicit a response at a receptor as measured using assays known in the art, such as in vitro assays described below.
The affinity of a GIP/GLP1 agonist compound or a pharmaceutically acceptable salt thereof for each GIP and GLP-1 receptor can be measured using techniques known in the art for measuring the level of receptor binding, including, for example, those measurements described in the examples below, and are generally expressed as Ki values. The activity of GIP/GLP1 agonist compounds at each receptor can also be measured using techniques known in the art, including in vitro activity assays as described below, and is generally expressed as EC 50 Values, which are the concentration of the compound that caused half maximum simulation (half-maximal simulation) in the dose response curve.
In one embodiment, the GIP/GLP1 agonist is a compound or pharmaceutically acceptable salt thereof, wherein the compound is a potent GIPR/GLP-1R dual agonist, i.e., as by cellMembrane guanosine 5' - (gamma-thio) triphosphate- [ 35 S]A partial agonist of GLP-1R as demonstrated by the (gtpγs) binding assay and a partial agonist of GLP-1R as demonstrated by the β -arrestin-2 recruitment assay. In one embodiment, the GIP/GLP1 agonist is a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound that is present in the GLP-1R HEK293 cell membrane guanosine 5' - (gamma-thio) triphosphate- [ 35 S]Stimulation of GLP-1R-induced G.alpha.in a (GTPγS) binding assay s Activating. In one embodiment, the GIP/GLP1 agonist is guanosine 5' - (gamma-thio) triphosphate at the GLP-1R HEK293 cell membrane [ 35 S]A compound exhibiting 75% or less partial agonism in a (gtpγs) binding assay and 35% or less partial agonism in a GLP-CHO cell β -inhibitor recruitment assay.
In one embodiment, the GIP/GLP1 agonist refers to a compound that exhibits 35% or less partial agonism in a GLP-CHO cell beta-arrestin recruitment assay, and administering an effective amount of the compound in GLP-1R HEK293 cell membrane guanosine 5' - (gamma-thio) triphosphate- [ 35 S](GTPγS) binding assays exhibit 75% or less partial agonism.
The term "effective amount" as used herein refers to the amount or dose of a compound of the invention, or a pharmaceutically acceptable salt thereof, that provides the desired effect in a patient being diagnosed or treated when administered to the patient in single or multiple doses. The effective amount can be determined by one skilled in the art using known techniques and by observing results obtained in similar circumstances. In determining an effective amount for a subject, a number of factors are considered, including, but not limited to: species of mammal; its body shape, age and general health; specific diseases or disorders of concern; the extent or involvement or severity of the disease or disorder; response of the individual patient; the particular compound being administered; mode of administration; bioavailability characteristics of the administered formulation; a selected dosing regimen; use with drug therapy; and other related situations.
As used herein, "EDTA" refers to ethylenediamine tetraacetic acid. As used herein, "DMSO" refers to dimethylsulfoxide. As used herein, "CPM" refers to counts per minute. As used herein, "IBMX" refers to 3-isobutyl-1-methylxanthine. As used herein, "LC/MS" refers to liquid chromatography/mass spectrometry. As used herein, "HTRF" refers to homogeneous time-resolved fluorescence. As used herein, "BSA" refers to bovine serum albumin.
The invention is further illustrated by the following examples, which should not be construed as limiting. As used herein, "measure (estimand)" refers to the efficacy and treatment regimen that is evaluated to determine the efficacy of the GIP/GLP1 agonist due to the requirements of certain regulatory authorities. Efficacy assessment (efficacy estimand) is used to evaluate the outcome of a person before stopping study of the drug or initiating rescue therapy for persistent severe hyperglycemia. Treatment regimen assessment (treatment-management estimand) required by certain regulatory authorities, including the U.S. food and drug administration, evaluates the therapeutic effects on humans under study, regardless of compliance with GIP/GLP1 agonists or whether rescue therapies for persistent severe hyperglycemia are introduced.
In other embodiments, the invention provides the following:
embodiment 1. A GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use in treating refractory type 2 diabetes in a patient, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered once a week.
Embodiment 2. A GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use in treating hypertension in a patient, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered once a week.
Embodiment 3. A GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for elevating HDL-C in a patient, wherein the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered once a week.
Embodiment 4. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 3, wherein the patient has type 2 diabetes for at least 8 years.
Embodiment 5. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 4, wherein the HbA1c target of the patient is less than 7%.
Embodiment 6. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 5, wherein the HbA1c target of the patient is equal to or less than 5.7%.
Embodiment 7. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 6, wherein the HbA1c of the patient is greater than 10%.
Embodiment 8. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 7, wherein the HbA1c of the patient is greater than 11%.
Embodiment 9. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 8, wherein the patient is at least 46 years old.
Embodiment 10. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 9, wherein the patient is at least 60 years old.
Embodiment 11. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 10, wherein the patient is taking an SGLT2 inhibitor.
Embodiment 12. The GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 11, wherein the patient is taking metformin.
Embodiment 13. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 12, wherein no basal insulin is administered to the patient.
Embodiment 14. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 13, wherein the patient fails to reach their HbA1c target upon administration of metformin and an SGLT2 inhibitor.
Embodiment 15. The GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 14, wherein the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered for at least 40 weeks.
Embodiment 16. The GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 15, wherein the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered for at least 50 weeks.
Embodiment 17. The GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 16, wherein the GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof is administered for at least 2 years.
Embodiment 18. The GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 17, wherein the patient is non-obese.
Embodiment 19. The GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 18, wherein the patient has co-morbid hypertension.
Embodiment 20. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 19, wherein the patient has co-morbid low HDL-C.
Embodiment 21. The GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 17 or 19 to 20, wherein the patient has co-morbid obesity.
Embodiment 22. The GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 21, wherein the patient has at least two cardiovascular risk factors.
Embodiment 23. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 21, wherein the patient is free of cardiovascular risk factors.
Embodiment 24. The GIP/GLP1 agonist or pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 23, wherein the patient has type 2 diabetes for at least 10 years.
Examples
Example 1 clinical trials Using GIP/GLP1 agonists
The inclusion criteria listed in table 1 below were designed to include participants similar to those found in typical diabetes practices, and include some orally refractory type 2 diabetics. Including elderly patients. The study lasted 52 weeks.
Table 1. Optional criteria example 1.
The study was designed to consist of a screening visit followed by a single blind 3 week placebo run-in period. Thereafter, patients were randomized to GIP/GLP1 agonist (administered using an ascending dose regimen) or insulin de-glu (standard titration regimen) and were followed at approximately monthly intervals. Patients receiving insulin deluge followed a standard insulin deluge titration protocol during the course of the study. The study protocol included blood pressure measurements at each visit and blood lipid profile at study start and at week 52 (serum lipid profile) using standard clinical methods.
The average dose of 52 Zhou Degu insulin is about 48 units/day.
A higher percentage of patients with randomly assigned GIP/GLP1 agonist achieved HbA1c of less than 7% (recommended goals for diabetics by the american diabetes association) or less than 5.7% (levels observed in non-diabetic populations) than patients with randomly assigned insulin digluc.
Example 2 clinical trials Using GIP/GLP1 agonists
The inclusion criteria listed in table 2 below include patients considered refractory to oral treatment for type 2 diabetes; however, oral diabetes treatment continued throughout the study. The study lasted 40 weeks.
Clinical trial 2, table 2
Table 2. Optional criteria example 2.
The study was designed to consist of a screening visit followed by a 3 week lead-in period. Thereafter, patients began a 40 week randomized double-blind study with GIP/GLP1 agonist or placebo as an additional therapy (add-on) to their previous treatment with insulin glargine (with or without metformin). The insulin glargine dose was titrated throughout the study using a validated "treatment-to-target algorism". Patients were followed at about weekly intervals and then about monthly. The study protocol included blood pressure measurements at each visit and lipid profiles at study start and at 40 weeks using standard clinical methods (serum lipid profile).
This study showed that as an additional therapy with clinical trial doses of titrated insulin glargine (with or without metformin) in adults with type 2 diabetes, the dose of GIP/GLP-1 agonist could be used to reduce HbA1c and body weight from baseline compared to placebo.
Example 3: clinical trials using GIP/GLP1 agonists
This study was a 4 week multiple escalation dose study that investigated the safety and tolerability of the GIP/GLP1 agonist of example 7 administered as a 4 weekly subcutaneous injection in type 2 diabetics as compared to placebo. The predetermined safety parameter to be studied comprises blood pressure.
The study included 4 cohorts treated with GIP/GLP-1 agonists. Queues 1 and 2 received 4 fixed doses of 0.3mg or 1mg, respectively. Queues 3 and 4 receive weekly doses in stepwise increments as shown in table 3.
Table 3: dosing regimen (in mg).
Criteria were established to recruit patients whose glycemic control was not well controlled by diet and exercise or stable doses of metformin. The baseline demographics of the enrolled patients are provided in table 4 below.
Total number of patients (N) 56
Average age, years 59.2
Sex (sex) 55.4% male and 44.6% female
Average body weight, kg 85.67
Average BMI, kg/m2 31.34
Mean HbA1 c%, percent 8.83
Average fasting blood glucose, mmol/L 10.58
Average duration of diabetes, year 10.99
Table 4: baseline demographics.
The blood pressure results are provided in table 5 below.
Mean systolic blood pressure BP (mm Hg): base line Day 29 (after last dose) N Average variation
Placebo 124.4 126.1 7 1.7
Queue 1 138.4 122.1 8 -16.3
Queue 2 120.9 115.3 8 -5.6
Queue 3 125.3 121.7 11 -3.6
Queue 4 123.6 120.4 14 -3.2
Mean diastolic pressure (mm Hg): base line Day 29 (after last dose)
Placebo 73.9 74.7 7 0.8
Queue 1 78.8 72.1 8 -6.7
Queue 2 76 73.8 8 -2.2
Queue 3 80.5 79.3 11 -1.2
Queue 4 77.3 74.7 14 -2.6
TABLE 5 blood pressure results
As seen in table 5, each GIP/GLP1 cohort had reduced mean systolic and diastolic blood pressure at the end of the study period, as compared to placebo.
Peptide synthesis
Example 4
Y-Aib-EGT-alpha MeF (2F) -TSDYSI-alpha MeL-LDEK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH 2 (SEQ ID NO：10).
The standard single letter amino acid code is used below to depict SEQ ID NO:10, except residues Aib2, αmef (2F) 6, αmel13, K17, aib20, D-Glu24 and Ser39, wherein the structure of these amino acid residues has been expanded:
the peptide backbone of example 4 was synthesized on a Symphony X peptide synthesizer (Gyros Protein Technologies.Tucson, AZ) using fluorenylmethoxycarbonyl (Fmoc)/t-butyl (t-Bu) chemistry.
The resin consisted of 1% DVB crosslinked polystyrene (Fmoc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) with a degree of substitution of 0.3-0.4 meq/g. Standard side chain protecting groups are used. Fmoc-Lys (Mtt) -OH was used for lysine at position 17 and Boc-Tyr (tBu) -OH was used for tyrosine at position 1. Fmoc groups were removed using 20% piperidine/DMF prior to each coupling step (2X 7 min). All standard amino acid couplings were performed using equimolar ratios of Fmoc amino acid (0.3 mM), diisopropylcarbodiimide (0.9 mM) and Oxyma (0.9 mM) at 9-fold molar excess over the theoretical peptide loading, with primary amine for 1 hour and secondary amine for 3 hours. The exception was coupling to a C.alpha. -methylated amino acid, which was coupled for 3 hours. After the synthesis of the peptide backbone was completed, the resin was washed thoroughly 6 times with DCM to remove residual DMF. The Mtt protecting group on the lysine at position 17 was selectively removed from the peptide resin using two treatments (2 x40 min treatments) of 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM.
Subsequent ligation of the fatty acid-linker moiety was achieved by coupling of 2- [2- (2-Fmoc-amino-ethoxy) -ethoxy ] -acetic acid (Fmoc-AEEA-OH, chemPep, inc.), fmoc-glutamic acid alpha-tert-butyl ester (Fmoc-Glu-OtBu, ark Pharm, inc.), mono-OtBu-eicosanedioic acid (WuXi AppTec, shanghai, china). For each coupling for a period of 1 hour a 3-fold excess of reagent was used (AA: pyAOP: DIPEA=1:1:1 mol/mol).
After the synthesis was completed, the peptide resin was washed with DCM and then dried thoroughly. The dried resin was treated with 10 ml of cleavage mixture (cleavage cocktail) (trifluoroacetic acid: water: triisopropylsilane, 95:2.5:2.5 v/v) at room temperature for 2 hours. The resin was filtered off, washed twice with 2 ml each of pure T' FA and the combined filtrates were treated with 5-fold excess volumes of cold diethyl ether (-20 ℃) to precipitate the crude peptide. The peptide/ether suspension was then centrifuged at 3500rpm for 2 minutes to form a solid mass, the supernatant was decanted, and the solid mass was triturated with ether two additional times and dried in vacuo. The crude peptide was dissolved in 20% acetonitrile/20% acetic acid/60% water and purified by RP-HPLC on a Luna 5 μm phenyl-hexyl prep column (21 x250mm, phenomenex) using a linear gradient of 100% acetonitrile and 0.1% tfa/water buffer system (30-50% acetonitrile in 60 minutes). The purity of the peptides was assessed using analytical RP-HPLC, with a confluence standard of > 95%. The main pool purity of compound 1 was found to be 98.0%. Subsequent lyophilization of the final major product pool yields the lyophilized peptide TFA salt. Molecular weight was determined by LC-MS (found: m+3= 1657.2; calculated m+3= 1657.0).
Example 5
Y-Aib-EGT-alpha MeF (2F) -TSDYSI-alpha MeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 16 -CO 2 H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH 2 (SEQ ID NO：11)
The standard single letter amino acid code is used below to depict SEQ ID NO:11, except residues Aib2, αmef (2F) 6, αmel13, orn16, K17, aib 20D-Glu 24 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO: the compound of 11 was prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3= 1642.6; calculated m+3= 1642.8).
Example 6
Example 6 is a compound represented by the following description:
Y-Aib-EGT-alpha MeF (2F) -TSDYSI-alpha MeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH 2 (SEQ ID NO：12)
The standard single letter amino acid code is used below to depict SEQ ID NO:12, except residues Aib2, αmef (2F) 6, αmel13, orn16, K17, aib20, D-Glu24 and Ser39, wherein the structure of these amino acid residues has been expanded:
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according to SEQ ID NO: the compound of 12 was prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3= 1651.8; calculated m+3= 1652.2).
Example 7
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy) ]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 16 -CO 2 H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH 2 (SEQ ID NO：13)
The standard single letter amino acid code is used below to depict SEQ ID NO:13, except residues Aib2, αmef (2F) 6, 4Pal10, αmel13, orn16, K17, aib20, D-Glu24 αmey25 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO: the compound of 13 was prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3= 1642.5; calculated m+3= 1642.1).
Example 8
Y-Aib-EGT- αMeF (2F) -TSDVSI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 16 -CO 2 H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH 2 (SEQ ID NO：14)
The standard single letter amino acid code is used below to depict SEQ ID NO:14, except residues Aib2, αmef (2F) 6, αmel13, orn16, K17, aib20, D-Glu24, αmey25 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO:14 are prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3= 1626.1; calculated m+3= 1626.1).
Example 8
Y-Aib-EGTFTSDYSILLDKK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH 2 (SEQ ID NO：21)
The standard single letter amino acid code is used below to depict SEQ ID NO:21, except residues Aib2, K17, aib20 and Ser39, wherein the structure of these amino acid residues has been extended:
According to SEQ ID NO: the compound of 21 was prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3= 1602.5; calculated m+3= 1602.8).
Example 10
Y-Aib-EGTFTSDYSI-alpha MeL-LDKK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH 2 (SEQ ID NO：22)
The standard single letter amino acid code is used below to depict SEQ ID NO:22, except residues Aib2, αmel13, K17, aib20 and Ser39, wherein the structure of these amino acid residues has been extended:
according to SEQ ID NO:22 was prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3= 1626.8; calculated m+3= 1626.8).
Example 11
(D-Tyr) -Aib-EGTFTSDYSI- αMeL-LDKK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH 2 (SEQ ID NO：23)
The standard single letter amino acid code is used below to depict SEQ ID NO:23, except residues D-Tyr1, aib2, αmel13, K17, aib20 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO: the compound of 23 was prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3= 1626.6; calculated m+3= 1626.8).
Example 12
(D-Tyr) -Aib-EGTFTSDYSI-alpha MeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-AFI-(D-Glu)-YLIAGGPSSGAPPPS-NH 2 (SEQ ID NO：24)
The standard single letter amino acid code is used below to depict SEQ ID NO:24, except residues D-Tyr1, aib2, αmel13, orn16, K17, aib20, D-Glu24 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO:24 was prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3= 1602.4; calculated m+3= 1602.8).
Example 13
(D-Tyr) -Aib-EGTFTSDYSI- αMeL-LDKK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH 2 (SEQ ID NO：25)
The standard single letter amino acid code is used below to depict SEQ ID NO:25, except residues D-Tyr1, aib2, αmel13, K17, aib20, αmey25 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO:25 are prepared substantially as described in example 4. Molecular weight was determined by LC-MS (found: m+3= 1631.3; calculated m+3= 1631.5).
Example 14
(D-Tyr) -Aib-EGTFTSDYSI-alpha MeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH 2 (SEQ ID NO：26)
The standard single letter amino acid code is used below to depict SEQ ID NO:26, except residues D-Tyr1, aib2, αmel13, orn16, K17, aib20, αmey25 and Ser39, wherein the structure of these amino acid residues has been expanded:
According to SEQ ID NO: the compound of 26 was prepared essentially as described in the procedure of example 4. Molecular weight was determined by LC-MS (found: m+3=1626.5; calculated m+3= 1626.8).
Peptide synthesis
Example 15
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H)SSGAPPPS-NH 2 (SEQ ID NO：41).
The standard single letter amino acid code is used below to depict SEQ ID NO:41, except for residues Aib2, αmef (2F) 6, 4Pal10, αmel13, orn16, K17, aib20, D-Glu24, αmey25, K31 and Ser39, wherein the structure of these amino acid residues has been expanded:
the peptide backbone of example 15 was synthesized on a Symphony multiplexed peptide synthesizer (Gyros Protein Technologies.Tucson, AZ) using fluorenylmethoxycarbonyl (Fmoc)/t-butyl (t-Bu) chemistry.
The resin consisted of 1% DVB crosslinked polystyrene (Fmoc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) with a degree of substitution of 0.35 mmol/g. Standard side chain protecting groups are used. Fmoc-Lys (Mtt) -OH was used for the lysine residues at positions 17 and 31 and Boc-Tyr (tBu) -OH was used for the tyrosine residue at position 1. Fmoc groups were removed using 20% piperidine/DMF prior to each coupling step (2X 7 min). All standard amino acid couplings were performed with equimolar ratios of Fmoc amino acid (0.3 mM in DMF), diisopropylcarbodiimide (0.9 mM in DCM) and Oxyma (0.9 mM in DMF) at 9-fold molar excess over the theoretical peptide loading for 1 hour. The exception was coupling to a C.alpha. -methylated amino acid, which was coupled for 3 hours. After the synthesis of the peptide backbone was completed, the resin was washed thoroughly with DCM to remove residual DMF. The Mtt protecting group on the lysine residues at positions 17 and 31 was selectively removed from the peptide resin using 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM (3 x1 hour treatment), and the resin was washed thoroughly with DCM and DMF.
Subsequent ligation of the linker moiety was achieved by stepwise coupling of 2- [2- (2-Fmoc-amino-ethoxy) -ethoxy ] -acetic acid (Fmoc-AEEA-OH, chemPep, inc.) and Fmoc-glutamic acid alpha-tert-butyl ester (Fmoc-Glu-OtBu, ark Pharm, inc.) according to the procedure described above for standard coupling and deprotection reactions. After removal of the final Fmoc protecting group, mono-OtBu-tetradecanedioic acid (WuXi AppTec, shanghai, china) was coupled overnight using a 4-fold excess of fatty acid, diisopropylcarbodiimide and Oxyma (1:1:1 mol/mol) in 1:1 DCM/DMF. After the synthesis was completed, the peptide resin was washed with DCM and then thoroughly dried under vacuum.
The dried resin was treated with 10 ml of cleavage mixture (cleavage cocktail) (trifluoroacetic acid: water: triisopropylsilane, 95:2.5:2.5 v/v) at room temperature for 2 hours. The resin was filtered off, washed twice with 2 ml each of pure T' FA and the combined filtrates were treated with 5-fold excess volumes of cold diethyl ether (-20 ℃) to precipitate the crude peptide. The peptide/ether suspension was then centrifuged at 3500rpm for 2 minutes to form a solid mass, the supernatant was decanted, and the solid mass was triturated with ether two additional times and dried in vacuo. The crude peptide was dissolved in 20 ml of 20% acetonitrile/20% acetic acid/60% water and purified by RP-HPLC on a symmetry prep 7 μm C preparative column (19×300mm, waters) using a linear gradient of 100% acetonitrile and 0.1% tfa/water buffer system (35-55% acetonitrile over 60 minutes). The purity of the peptides was assessed using analytical RP-HPLC, with a confluence standard of > 95%. The main pool purity of example 14 was found to be 96.0%. Subsequent lyophilization of the final major product pool yields the lyophilized peptide TFA salt. Molecular weight was determined by LC-MS (found: m+3= 1853.9; calculated m+3= 1854.1).
Example 16
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：17)
The standard single letter amino acid code is used below to depict SEQ ID NO:17, except residues Aib2, αmef (2F) 6, 4Pal10, αmel13, orn16, K17, aib20, D-Glu24, αmey25, K31 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO: the compound of 17 was prepared essentially as described in the procedure of example 15 except that tert-butyl 4- (9-carboxy-nonyloxy) benzoate (WuXi AppTec, shanghai, china) was used in the final coupling step. Molecular weight was determined by LC-MS (found: m+3= 1887.1; calculated m+3= 1887.4).
Example 17
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：18)
The standard single letter amino acid code is used below to depict SEQ ID NO:18, except for residues Aib2, αmef (2F) 6, 4Pal10, αmel13, orn16, K17, aib20, D-Glu24, αmey25, K31 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO: the compound of 18 was prepared essentially as described in example 15 except that 4- (4-iodophenyl) butanoic acid (WuXi AppTec, shanghai, china) was used in the final coupling step. Molecular weight was determined by LC-MS (found: m+3= 1875.1; calculated m+3= 1875.2).
Example 18
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butyryl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：19)
The standard single letter amino acid code is used below to depict SEQ ID NO:19, except for residues Aib2, αmef (2F) 6, 4Pal10, αmel13, orn16, K17, aib20, D-Glu24, αmey25, K31 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO: the compound of 19 was prepared essentially as described in example 15 except that 4- (4-tert-butylphenyl) butanoic acid (WuXi AppTec, shanghai, china) was used in the final coupling step. Molecular weight was determined by LC-MS (found: m+3= 1828.3; calculated m+3= 1828.7).
Example 19
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 ) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 )SSGAPPPS-NH 2 (SEQ ID NO：19).
The standard single letter amino acid code is used below to depict SEQ ID NO:19, except for residues Aib2, αmef (2F) 6, 4Pal10, αmel13, orn16, K17, aib20, D-Glu24, αmey25, K31 and Ser39, wherein the structure of these amino acid residues has been expanded:
according to SEQ ID NO: the compound of 19 was prepared essentially as described in the procedure of example 15 except that lauric acid (Sigma Aldrich) was used in the final coupling step. Molecular weight was determined by LC-MS (found: m+3= 1815.1; calculated m+3= 1815.4).
Binding assays
Glucagon (called Gcg) is the reference standard for Eli Lilly and Company preparation. GLP-1,7-36-NH2 (referred to as GLP-1) was obtained from CPC Scientific (Sunnyvale, calif., 97.2% purity, 100. Mu.M aliquots in 100% DMSO). GIP 1-42 (called GIP) was prepared using peptide synthesis and HPLC chromatography as described above at Lilly Research Laboratories (> 80% purity, 100. Mu.M aliquots in 100% DMSO). [ 125 I]Radiolabelled Gcg, GLP-1 or GIP use 125 I]Lactoperoxidase preparation and obtained from Perkin Elmer (Boston, MA).
Stably transfected cell lines were prepared by subcloning the receptor cDNA into pcDNA3 expression plasmids and transfecting into Human Embryonic Kidney (HEK) 293 (hGcgR and hGLP-1R) or Chinese Hamster Ovary (CHO) (hGAPR) cells, followed by selection with geneticin (hGLP-1R and hGAPR) or hygromycin B (hGcgR).
Two methods were used to prepare crude cell membranes.
Method 1: frozen cell pellet on ice in Roche Complete containing 50mM Tris HCl,pH 7.5 and EDTA TM Cleavage in hypotonic buffer of protease inhibitor. Use equipmentThe glass Potter-Elvehjem homogenizer of the pestle destroyed the cell suspension 25. The homogenate was centrifuged at 1100x g for 10 min at 4 ℃. The supernatant was collected and stored on ice while the pellet was resuspended in homogenization buffer and re-homogenized as described above. The homogenate was centrifuged at 1100x g for 10 minutes. The second supernatant was combined with the first supernatant and centrifuged at 35000x g for 1 hour at 4 ℃. The resulting membrane pellet was resuspended in homogenization buffer containing about 1 to 3mg/mL protease inhibitor, flash frozen in liquid nitrogen, and stored as an aliquot in a-80 ℃ freezer until use.
Method 2: frozen cell pellet containing 50mM Tris HCl,pH 7.5, 1mM MgCl on ice 2 、Roche Complete TM EDTA-free protease inhibitor and 25 units/ml DNAse I (Invitrogen). Use equipmentThe glass Potter-Elvehjem homogenizer of the pestle breaks the cell suspension 20 to 25. The homogenate was centrifuged at 1800x g for 15 min at 4 ℃. The supernatant was collected and stored on ice while the pellet was resuspended in homogenization buffer (no DNAse I) and re-homogenized as described above. The homogenate was centrifuged at 1800x g for 15 min. The second supernatant was combined with the first supernatant and centrifuged at 1800 f x g for 15 min. The whole supernatant was then centrifuged at 25000x g for 30 minutes at 4 ℃. Re-suspending the resulting film mass to a concentration of about 1 to about 13mg/mL protease inhibitor in homogenization buffer (DNAse I free) and stored as aliquots in-80℃freezers until use.
Binding assay method
Due to [ 125 I]High propanol content in stock, equilibrium binding dissociation constant (K) for various receptor/radioligand interactions determined by homologous competition binding analysis rather than saturation binding d ). K for receptor preparation assay d The values are as follows: hGcgR (3.9 nM), hGLP-1R (1.2 nM) and hGIPR (0.14 nM).
125 [I]Glucagon binding
Human Gcg receptor binding assays were performed using Scintillation Proximity Assay (SPA) format with wheat germ lectin (WGA) beads (Perkin Elmer). The binding buffer contained 25mM 4- (2-hydroxyethyl) -1-piperazine ethane sulfonic acid (HEPES), pH 7.4, 2.5mM CaCl 2 、1mM MgCl 2 0.1% (w/v) bacitracin (Research Products), 0.003% (w/v) polyoxyethylene sorbitan monolaurateAnd EDTA-free Roche Complete TM Protease inhibitors. Peptides and Gcg were thawed and serially diluted 3-fold in 100% dmso (10-point concentration response curve). Next, 5. Mu.L of serially diluted compound or DMSO was transferred to a +.A.A.5. Mu.L serial diluted compound or DMSO was transferred to a +.A.A.5.L serial diluted compound or DMSO was transferred to a.5.L serial diluted solution containing 45. Mu.L assay binding buffer or unlabeled Gcg control (non-specific binding or NSB, final 1. Mu.M)>3632 transparent bottom assay plate. Then 50. Mu.L was added using a Biotek Multiflo dispenser 125 I]Gcg (final 0.15 nM), 50. Mu.L human GcgR membrane (1.5. Mu.g/well) and 50. Mu.L WGA SPA beads (80 to 150. Mu.g/well). The plates were sealed and mixed for 1 min on a plate shaker (setting 6) and after incubation/sedimentation time of 12 hours at room temperature with PerkinElmer Trilux +.>The scintillation counter reads. Final determination of the tested peptides in response curvesThe concentration range is typically 1150nM to 0.058nM, and the control Gcg is 1000nM to 0.05nM.
125 [I]-GLP-1 binding
The SPA format with WGA beads was used for human GLP-1 receptor binding assays. The binding buffer contained 25mM HEPES,pH 7.4, 2.5mM CaCl 2 、1mM MgCl 2 0.1% (w/v) bacitracin, 0.003% (w/v)And EDTA-free Roche Complete TM Protease inhibitors. Peptides and GLP-1 were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, 5. Mu.L of serially diluted compound or DMSO is transferred to a +.A 5. Mu.L serial dilution of compound or DMSO is added to a solution containing 45. Mu.L assay binding buffer or unlabeled GLP-1 control (nonspecific binding or NSB, final 0.25. Mu.M)>3632 transparent bottom assay plate. Then 50. Mu.L was added using a Biotek Multiflo dispenser 125 I]GLP-1 (final 0.15 nM), 50. Mu.L human GLP-1R membrane (0.5. Mu.g/well) and 50. Mu.L WGA SPA beads (100 to 150. Mu.g/well). The plates were sealed and mixed for 1 min on a plate shaker (setting 6), after incubation/sedimentation time of 5 to 12 hours at room temperature with PerkinElmer Trilux +.>The scintillation counter reads. The final assay concentration of the peptide tested in the response curve is typically in the range 1150nM to 0.058nM, with control GLP-1 in the range 250nM to 0.013nM.
[125I]-GIP binding
The SPA format with WGA beads was used for the human GIP receptor binding assay. The binding buffer contained 25mM HEPES,pH 7.4, 2.5mM CaCl 2 、1mM MgCl 2 0.1% (w/v) bacitracin, 0.003% (w/v)And EDTA-free Roche Complete TM Protease inhibitors. Peptides and GIP were thawed and serially diluted 3-fold in 100% dmso (10-point concentration response curve). Next, 5. Mu.L of serially diluted compound or DMSO was transferred to a +.A 5. Mu.L serial dilution of compound or DMSO was added to a solution containing 45. Mu.L assay binding buffer or unlabeled GIP control (non-specific binding or NSB, final 0.25. Mu.M)>3632 transparent bottom assay plate. Then 50. Mu.L was added using a Biotek Multiflo dispenser 125 I]GIP (final 0.075-0.15 nM), 50 μl human GIPR membrane (3 μg/well) and 50 μl WGA SPA beads (100 to 150 μg/well). The plates were sealed and mixed for 1 min on a plate shaker (setting 6), after incubation/sedimentation time of 2.5 to 12 hours at room temperature with PerkinElmer Trilux->The scintillation counter reads. The final assay concentration of the tested peptides in the response curve is typically in the range 1150 to 0.058nM or 115nM to 0.0058nM, with a control GIP of 250nM to 0.013nM. />
Binding assay data analysis
Raw CPM data of concentration curves of peptide, gcg, GLP-1 or GIP were converted to percent inhibition by subtracting the non-specific binding (binding in the presence of excess unlabeled Gcg, GLP-1 or GIP, respectively) from the individual CPM values and dividing by the total binding signal (also corrected by subtracting the non-specific binding). Using four parameters (curve maximum, curve minimum, IC 50 Data was analyzed by Hill slope) non-linear regression program (Genedata Screener,12.0.4 edition, genedata AG, basal, switzerland). From absolute IC 50 The values are based on equation K i ＝IC 50 /(1+D/K d ) Calculation of affinity constant (K) i ) Where D is the concentration of radioligand used in the experiment, IC 50 Is the concentration that causes 50% inhibition of binding, and K d Is the equilibrium binding dissociation constant of the radioligand (as described above). K (K) i Reported as geometric mean, error expressed as Standard Error of Mean (SEM), and n is equal to the number of independent replicates (measured in assays performed on different days). Geometric mean valueThe following calculation was performed:
geometric mean=10 (arithmetic mean of logarithmic Ki values)
The Ki ratio (Ki of the natural control peptide/Ki of the test compound) was calculated for each receptor and each species. The Ki ratio is a rapid indicator of the apparent affinity of the peptide compared to the native control peptide. Ki ratio < 1 indicates that the test peptide has a lower affinity for the receptor than the native peptide (higher Ki value), while Ki ratio > 1 indicates that the test peptide has a higher affinity for the receptor than the native peptide (lower Ki value).
n=1/x means that only one value in the repetition total (x) is used to represent the average value. SEM is calculated only when there are unacceptable results of n=2 or greater. The mean is expressed as a geometric mean, and the Standard Error (SEM) and the number of repetitions (n) of the mean are shown in brackets.
TABLE 6 in vitro binding affinity (K) of the examples and comparative molecules shown for human GLP-1R, gcgR and GIPR i )
TABLE 7 in vitro binding affinity (K) of the examples and control molecules shown for human GLP-1R, gcgR and GIPR i )
Binding affinity
cAMP pharmacological function assay in the presence of casein
An additional set of cAMP assays were performed in HEK293 cells expressing human GLP-1 receptor (GLP-1R), gastric Inhibitory Peptide Receptor (GIPR), glucagon receptor (GcgR). Pharmacological activity of hGLP1R/GIPR peptides was assayed in HEK293 cells stably expressing the human GLP-1 receptor (GLP-1R), the Gastric Inhibitory Peptide Receptor (GIPR) or the GLP-2 receptor (GLP-2R). After supplementing 0.1% of caseinEach receptor overexpressing cell line (20. Mu.l) was treated with the test peptide in a 20. Mu.l assay volume in DMEM (Gibco Cat# 31053) with white (Sigma Cat#C4765), 250. Mu.M IBMX, 1X GlutaMAXTM (Gibco Cat#35050) and 20mM HEPES (HyClone Cat#SH 30237.01). After 60 minutes incubation at room temperature, the resulting increase in intracellular cAMP was quantified using a CisBio cAMP Dynamic HTRF assay kit (62 AM4 PEJ). Then, a lysis buffer containing cAMP-d2 conjugate (20. Mu.l) and an antibody anti-cAMP-Eu3+ -cryptate (20. Mu.l) was added to determine cAMP levels. After 1 hour incubation at room temperature, HTRF signals were detected using an Envision 2104 plate reader (PerkinElmer). Fluorescence emissions at 620nM and 665nM were measured and the ratio between 620nM and 665nM was calculated, then converted to nM cAMP per well using a cAMP standard curve. The dose response curves of the compounds were plotted as percent stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) and analyzed using a four parameter nonlinear regression fit with variable slope (Genedata Screener 13). The EC50 is the concentration of the compound that gives rise to half maximum simulation (half-maximal simulation) in the dose response curve. Deriving relative EC by nonlinear regression analysis (fitting to a four parameter logistic equation) using maximum percent response vs. added peptide concentration 50 Values.
The intrinsic efficacy of the example and control molecules was determined using a homogeneous time resolved fluorescence method in the presence of casein (instead of serum albumin) as a non-specific blocker that does not interact with the fatty acid moiety of the analytical molecule.
Intracellular cAMP levels were determined by extrapolation using a standard curve. The dose response curves of the compounds were plotted as percent stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) and analyzed using a four parameter nonlinear regression fit with variable slope (Genedata Screener 13). EC (EC) 50 Is the concentration of the compound that gives rise to half maximum simulation (half-maximal simulation) in the dose response curve. Each relative EC50 value used to calculate the geometric mean was determined from curve fitting.
Concentration response curves for compounds are plotted against minimum valuesThe percent stimulation normalized (buffer only) and maximum (maximum concentration of each control ligand) and analyzed using a four parameter nonlinear regression fit with variable slope (Genedata Screener). EC (EC) 50 Is the concentration of the compound that gives rise to half maximum simulation (half-maximal simulation) in the dose response curve.
EC 50 Summary statistics were calculated as follows:
geometric mean:
GM＝10^(log 10 transformed EC 50 Arithmetic mean of values).
Standard error of reported mean:
SEM = geometric mean x (log) 10 Transformed EC 50 The standard deviation of the values/square root of running number #) x10 log e
Logarithmic transformation considers EC falling on the multiplicative scale rather than the arithmetic scale 50 Values.
On each day of the run assay, the test peptides plus the native ligand GIP and GLP-1 were run with buffer alone as baseline (minimum) and the highest concentrations of the respective GIP and GLP-1 standards were used as maximum for calculation. To illustrate, test peptides were tested in 8 rounds of assays as shown in example 4. For the avoidance of doubt, hGIP amide and hGLP-1 amide EC50 in table 3 exemplify geometric mean values from a series of 18 determinations, and values vary daily compared to zero buffer. Thus, each example normalized the example assay run using the geometric mean of these values.
TABLE 8 functional activation of hGLP-1R, hGIPR, hGcgR in the presence of 0.1% casein
As demonstrated by the data in table 8, the example compounds stimulated cAMP from human GLP-1R and GIPR in the presence of 0.1% casein.
Amino acid sequence
SEQ ID NO：1
GIP (human)
SEQ ID NO：2
GLP-1 (7-36) (human)
SEQ ID NO：3
R 1 X 1 X 2 X 3 GTX 6 TSDX 10 X 11 X 12 X 13 X 14 D-X 16 X 17 AX 1 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31
SEQ ID NO：4
PX 32 X 33 X 34 -R 2
SEQ ID NO：5
PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2
SEQ ID NO：6
PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2
SEQ ID NO：7
K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 -R 2
SEQ ID NO：8
K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2
SEQ ID NO：9
K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2
SEQ ID NO：10
Example 3
Y-Aib-EGT-alpha MeF (2F) -TSDYSI-alpha MeL-LDEK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH 2
SEQ ID NO：11
Example 4
Y-Aib-EGT-alpha MeF (2F) -TSDYSI-alpha MeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 16 -CO 2 H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH 2
SEQ ID NO：12
Example 5
Y-Aib-EGT-alpha MeF (2F) -TSDYSI-alpha MeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH 2
SEQ ID NO：13
Example 6
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 16 -CO 2 H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH 2
SEQ ID NO：14
Example 7
Y-Aib-EGT- αMeF (2F) -TSDVSI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 16 -CO 2 H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH 2
SEQ ID NO：15
PSSG-R 2
SEQ ID NO：16
PSSGAPPPS-R 2
SEQ ID NO：17
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) SSGAPPPS-NH 2
SEQ ID NO：18
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy) ]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) SSGAPPPS-NH 2
SEQ ID NO：19
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butyryl)) AQ-Aib-EFI- (D-Glu) -alpha MeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)) SSGAPPPS-NH 2
SEQ ID NO：20
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 ) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 )SSGAPPPS-NH 2
SEQ ID NO：21
Y-Aib-EGTFTSDYSILLDKK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH 2
SEQ ID NO：22
Y-Aib-EGTFTSDYSI-alpha MeL-LDKK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH 2
SEQ ID NO：23
(D-Tyr) -Aib-EGTFTSDYSI- αMeL-LDKK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH 2
SEQ ID NO：24
(D-Tyr) -Aib-EGTFTSDYSI-alpha MeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-AFI-(D-Glu)-YLIAGGPSSGAPPPS-NH 2
SEQ ID NO：25
(D-Tyr) -Aib-EGTFTSDYSI- αMeL-LDKK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH 2
SEQ ID NO：26
(D-Tyr) -Aib-EGTFTSDYSI-alpha MeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH 2
SEQ ID NO：27
X 1 X 2 EGTX 6 TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30
SEQ ID NO：28
X 31 SSG
SEQ ID NO：29
X 31 SSG-R 3
SEQ ID NO：30
X 31 SSGX 35 PPPX 39
SEQ ID NO：31
X 31 SSGX 35 PPPX 39 R 3
SEQ ID NO：32
X 31 SSGX 35 PPPX 39 X 40
SEQ ID NO：33
X 31 SSGX 35 PPPX 39 X 40 R 3
SEQ ID NO：34
PSSG
SEQ ID NO：35
PSSG-R 3
SEQ ID NO：36
PSSGX 35 PPPX 39
SEQ ID NO：37
PSSGX 35 PPPX 39 R 3
SEQ ID NO：38
PSSGX 35 PPPX 39 X 40
SEQ ID NO：39
PSSGX 35 PPPX 39 X 40 R 3
SEQ ID NO：40
X 1 X 2 EGTX 6 TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30
SEQ ID NO：41
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H)SSGAPPPS-NH 2
Sequence listing
<110> Eli Lilly and Company
<120> GIP/GLP1 dual agonist treatment methods
<130> X22989
<150> US 63/150,408
<151> 2021-02-17
<160> 41
<170> PatentIn version 3.5
<210> 1
<211> 42
<212> PRT
<213> Chile person
<400> 1
Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 2
<211> 30
<212> PRT
<213> Chile person
<220>
<221> MOD_RES
<222> (30)..(30)
<223> amidation
<400> 2
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210> 3
<211> 31
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MOD_RES
<222> (1)..(1)
<223> R1 is a modification of the N-terminal group, wherein the modification is selected from Ac and the absence of
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is selected from Y, H, D-Tyr, F, desH and desY
<220>
<221> MISC_FEATURE
<222> (1)..(31)
<223> q is selected from 14, 15, 16, 17, 18, 19 and 20; and R2 is a modification of the C-terminal group, wherein the modification is NH2 or is absent; or a pharmaceutically acceptable salt thereof; wherein if X30 is G-R2, then X31 is
<220>
<221> MISC_FEATURE
<222> (1)..(31)
<223> wherein not more than one of X10, X12, X13, X14, X16, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39 and X40 may be a substituent containing a fatty acid
<220>
<221> MISC_FEATURE
<222> (1)..(31)
<223> wherein not more than one of X30, X34, X39 and X40 may be C
<220>
<221> MISC_FEATURE
<222> (1)..(31)
<223> wherein if one of X30, X34, X39 and X40 is C, none of X10, X12, X13, X14, X16, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39 and X40 is a substituent containing a fatty acid
<220>
<221> MISC_FEATURE
<222> (2)..(2)
Xaa at position 2 is selected from Aib, α -MeP, A, P and D-Ala; or X1 and X2 combine to form desH- ψ [ NHCO ] -Aib
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa at position 3 is selected from E, N, aad and cTA
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is selected from F, alpha-MeF and alpha-MeF (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
Xaa at position 10 <223> is selected from A, L, H, 3Pal, 4Pal, V, Y, E, α -MeF (2F), I, α -MeY, Q, D-His, D-Tyr, cTA, and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (γ -Glu) -CO- (CH 2) qCO2
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa at position 11 is selected from S, alpha-MeS and D-Ser
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa at position 12 is selected from I, S, D-Ile and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (13)..(13)
Xaa at position 13 <223> is selected from Nle, aib, L, α -MeL and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (γ -Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa at position 14 is selected from L and K, wherein K is conjugated to a C16-C22 fatty acid, wherein said fatty acid is conjugated to said K, optionally via a linker
<220>
<221> MISC_FEATURE
<222> (16)..(16)
Xaa at position 16 <223> is selected from K, E, orn, dab, dap, S, T, H, aib, α -MeK, R and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (γ -Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa at position 17 is selected from K, Q, I and an amino acid conjugated to a C16-C22 fatty acid, wherein said fatty acid is conjugated to said amino acid optionally via a linker
<220>
<221> MISC_FEATURE
<222> (19)..(19)
Xaa at position 19 is selected from Q, A and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
Xaa at position 20 is selected from Aib, Q, H, R, K, α -MeK and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (γ -Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (21)..(21)
Xaa at position 21 is selected from H, aad, D, aib, T, A, E, I and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (22)..(22)
Xaa at position 22 is selected from F and alpha-MeF
<220>
<221> MISC_FEATURE
<222> (23)..(23)
Xaa at position 23 is selected from I, L, A, G, F, H, E, V and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (24)..(24)
Xaa at position 24 is selected from S, aad, D-Glu, E, aib, H, V, A, Q, D, P and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (25)..(25)
Xaa at position 25 is selected from Y and alpha-MeY
<220>
<221> MISC_FEATURE
<222> (26)..(26)
Xaa at position 26 is selected from L, α -MeL and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (γ -Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (27)..(27)
Xaa at position 27 is selected from L, I and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (28)..(28)
Xaa at position 28 is selected from E, A, S, D-Glu and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (29)..(29)
Xaa at position 29 <223> is selected from Aib, G, A and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) qCO2H
<220>
<221> MISC_FEATURE
<222> (30)..(30)
Xaa at position 30 is selected from C, G, G-R2 and K (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> absence of Xaa at position 31 or selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9
<400> 3
Xaa Xaa Xaa Gly Thr Xaa Thr Ser Asp Xaa Xaa Xaa Xaa Xaa Asp Xaa
1 5 10 15
Xaa Ala Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
<210> 4
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (γ -Glu) -CO- (CH 2) q-CO2H ];
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa at position 3 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-C O H ]
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa at position 4 is selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> R2 is a modification of the C-terminal group, wherein the modification is NH2 or is absent
<400> 4
Pro Xaa Xaa Xaa
1
<210> 5
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa at position 3 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa at position 4 is selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is A or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa at position 7 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa at position 8 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is selected from C, S and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> R2 is a modification of the C-terminal group, wherein the modification is NH2 or is absent
<400> 5
Pro Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 6
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa at position 3 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa at position 4 is selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is A or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa at position 7 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa at position 8 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is selected from C, S and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is selected from C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is selected from C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<400> 6
Pro Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 7
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Lys at position 1 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa at position 3 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa at position 4 is selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> R2 is a modification of the C-terminal group, wherein the modification is NH2 or absent;
<400> 7
Lys Xaa Xaa Xaa
1
<210> 8
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Lys at position 1 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa at position 3 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa at position 4 is selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is A or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa at position 7 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa at position 8 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is selected from C, S and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> R2 is a modification of the C-terminal group, which modification is NH2 or is absent
<400> 8
Lys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 9
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Lys at position 1 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa at position 3 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa at position 4 is selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is A or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa at position 7 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa at position 8 is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is selected from C, S and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is selected from C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) q-CO2H ]
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> R2 is a modification of the C-terminal group, wherein the modification is NH2 or is absent
<400> 9
Lys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 10
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-methyl-F (2F)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 18-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 10
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Glu
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Tyr Leu Ile Glu Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 11
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-methyl-F (2F)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 13 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2-gamma-Glu-CO- (CH 2) 16-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 11
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Tyr Leu Ile Glu Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 12
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-methyl-F (2F)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 18-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 12
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Tyr Leu Ile Glu Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 13
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-methyl-F (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is 4Pal
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 16-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Tyr
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 13
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Xaa Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Xaa Leu Ile Glu Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 14
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-methyl-F (2F)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 16-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Tyr
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 14
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Val Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Xaa Leu Ile Glu Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 15
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MOD_RES
<222> (4)..(4)
<223> Gly is modified with R2, wherein R2 is a modification of the C-terminal group, wherein said modification is NH2 or is absent
<400> 15
Pro Ser Ser Gly
1
<210> 16
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MOD_RES
<222> (9)..(9)
<223> Ser is modified with R2, wherein R2 is a modification of the C-terminal group, wherein the modification is NH2 or is absent
<400> 16
Pro Ser Ser Gly Ala Pro Pro Pro Ser
1 5
<210> 17
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-methyl-F (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is 4Pal
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Tyr
<220>
<221> MOD_RES
<222> (31)..(31)
<223> Lys at position 31 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 17
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Xaa Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Xaa Leu Ile Glu Gly Gly Lys Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 18
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-methyl-F (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is 4Pal
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) - (4- (4-iodophenyl) butanoyl)
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Tyr
<220>
<221> MOD_RES
<222> (31)..(31)
<223> Lys at position 31 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) - (4- (4-iodophenyl) butanoyl)
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 18
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Xaa Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Xaa Leu Ile Glu Gly Gly Lys Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 19
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-methyl-F (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is 4Pal
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Tyr
<220>
<221> MOD_RES
<222> (31)..(31)
<223> Lys at position 31 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 19
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Xaa Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Xaa Leu Ile Glu Gly Gly Lys Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 20
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-Me-F (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is 4Pal
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 10-CH3
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Tyr
<220>
<221> MOD_RES
<222> (31)..(31)
<223> Lys at position 31 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 10-CH3
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 20
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Xaa Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Xaa Leu Ile Glu Gly Gly Lys Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 21
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 18-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 21
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys
1 5 10 15
Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Ile Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 22
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 18-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 22
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Glu Tyr Leu Ile Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 23
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is D-Tyr
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 18-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 23
Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Glu Tyr Leu Ile Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 24
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is D-Tyr
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 18-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 24
Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Ala Phe Ile Xaa Tyr Leu Ile Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 25
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is D-Tyr
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 18-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Tyr
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 25
Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Glu Xaa Leu Ile Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 26
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is D-Tyr
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 18-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Tyr
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 26
Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Glu Xaa Leu Ile Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 27
<211> 30
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is Y or R1Y, wherein R1 is Ac modification of the N-terminal amino group
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-Me-F or alpha-Me-F (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
Xaa at position 10 is 4Pal, Y, α -Me-F (2F), α -Me-L, α -Me-V, ac c, ac5c, ac6c, bip, 1Nal, 2Nal, OMeY, hTyr, nle, V, 4CPhe, chG, chA, bzt, 2FA, 4TAA, 2TA, 3TA or KZ1; z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa at position 11 is S, alpha-Me-S, aib, G, dap, ac5c or Tle
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa at position 12 is I or KZ1; wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-L or alpha-Me-F
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa at position 17 is Q, I or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa at position 20 is Aib, orn, 4Pal, α -Me-F, ac5c or Ac6c
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa at position 21 is E, KZ, G, orn or 4Pal; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (22)..(22)
<223> Xaa at position 22 is F, 2ClPhe, 3ClPhe, 2FPhe, 3,5FPhe, 1Nal, 2Nal, alpha-Me-F (2F), chA, bzt and alpha-Me-F
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu, E, G or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is Y, α -Me-F, and KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (28)..(28)
<223> Xaa at position 28 is E, orn or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa at position 30 is G, orn, KZ1, K (Z1) R6, ornR2 or GR2; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> R2 is X31, SEQ ID NO 28, SEQ ID NO 29, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32 or SEQ ID NO 33; and modification of the C-terminal group, wherein the modification is NH2
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> R6 is SEQ ID NO 34, SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38 or SEQ ID NO 39; and modification of the C-terminal group, wherein the modification is NH2
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> R3 is a modification with a C-terminal group, wherein the modification is NH2;
wherein two and only two of X10, X12, X17, X21, X24, X25, X28, X30, X31 and X40 are KZ1 or K (Z1) R6
<400> 27
Xaa Xaa Glu Gly Thr Xaa Thr Ser Asp Xaa Xaa Xaa Xaa Leu Asp Xaa
1 5 10 15
Xaa Ala Gln Xaa Xaa Xaa Ile Xaa Xaa Leu Ile Xaa Gly Xaa
20 25 30
<210> 28
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is P or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<400> 28
Xaa Ser Ser Gly
1
<210> 29
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is P or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MOD_RES
<222> (4)..(4)
<223> Gly at position 4 is G-R3; wherein R3 is a modification of the C-terminal group, wherein the modification is NH2
<400> 29
Xaa Ser Ser Gly
1
<210> 30
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is X31, wherein X31 is P or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is X35, wherein X35 is A or Orn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is X39, wherein X39 is S or Orn
<400> 30
Xaa Ser Ser Gly Xaa Pro Pro Pro Xaa
1 5
<210> 31
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is X31, wherein X31 is P or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is X35, wherein X35 is A or Orn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is X39, wherein X39 is S or Orn
<220>
<221> MOD_RES
<222> (9)..(9)
<223> X at position 9 is modified with R3, wherein R3 is a modification of the C-terminal group, wherein the modification is NH2
<400> 31
Xaa Ser Ser Gly Xaa Pro Pro Pro Xaa
1 5
<210> 32
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is X31, wherein X31 is P or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is X35, wherein X35 is A or Orn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is X39, wherein X39 is S or Orn
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is X40, wherein X40 is KZ1, wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<400> 32
Xaa Ser Ser Gly Xaa Pro Pro Pro Xaa Xaa
1 5 10
<210> 33
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is X31, wherein X31 is P or KZ1; wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is X35, wherein X35 is A or Orn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is X39, wherein X39 is S or Orn
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is X40, wherein X40 is KZ1, wherein Z1 is R5 or R4R5; wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MOD_RES
<222> (10)..(10)
<223> Xaa at position 10 is modified with R3, wherein R3 is a modification of the C-terminal group, wherein the modification is NH2
<400> 33
Xaa Ser Ser Gly Xaa Pro Pro Pro Xaa Xaa
1 5 10
<210> 34
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 34
Pro Ser Ser Gly
1
<210> 35
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MOD_RES
<222> (4)..(4)
<223> Gly is modified by R3, wherein R3 is a modification of the C-terminal group, wherein said modification is NH2
<400> 35
Pro Ser Ser Gly
1
<210> 36
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is X35, wherein X35 is A or Orn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is X39, wherein X39 is S or Orn
<400> 36
Pro Ser Ser Gly Xaa Pro Pro Pro Xaa
1 5
<210> 37
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is X35, wherein X35 is A or Orn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is X39, wherein X39 is S or Orn
<220>
<221> MOD_RES
<222> (9)..(9)
<223> Xaa at position 9 is modified with R3, wherein R3 is a modification of the C-terminal group, wherein the modification is NH2
<400> 37
Pro Ser Ser Gly Xaa Pro Pro Pro Xaa
1 5
<210> 38
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is X35, wherein X35 is A or Orn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is X39, wherein X39 is S or Orn
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is X40, wherein X40 is KZ1, wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<400> 38
Pro Ser Ser Gly Xaa Pro Pro Pro Xaa Xaa
1 5 10
<210> 39
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa at position 5 is X35, wherein X35 is A or Orn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa at position 9 is X39, wherein X39 is S or Orn
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is X40, wherein X40 is KZ1, wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MOD_RES
<222> (10)..(10)
<223> Xaa at position 10 is modified with R3, wherein R3 is a modification of the C-terminal group, wherein the modification is NH2
<400> 39
Pro Ser Ser Gly Xaa Pro Pro Pro Xaa Xaa
1 5 10
<210> 40
<211> 30
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa at position 1 is Y or R1Y, wherein R1 is Ac modification of the N-terminal amino group
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-Me-F or alpha-Me-F (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is 4Pal, Y, α -Me-F (2F), α -Me-L, α -Me-V, ac c, ac5c, ac6c, bip, 1Nal, 2Nal, OMeY, hTyr, nle, V, 4CPhe, chG, chA, bzt, 2FA, 4TAA, 2TA, 3TA or KZ1, wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa at position 11 is Ac5c, S, alpha-Me-S, aib, G, dap or Tle
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa at position 12 is I or KZ1, wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-L or alpha-Me-F
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa at position 17 is Q, I or KZ1, wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa at position 20 is Aib, orn, 4Pal, α -Me-F, ac5c or Ac6c
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa at position 21 is E, KZ, G, orn or 4Pal, wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (22)..(22)
<223> Xaa at position 22 is F, 2ClPhe, 3ClPhe, 2FPhe, 3,5FPhe, 1Nal, 2Nal, alpha-Me-F (2F), chA, bzt or alpha-Me-F
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu, E, G or KZ1; wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (25)..(25)
Xaa at position 25 is Y, α -Me-F or KZ1; wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (28)..(28)
<223> Xaa at position 28 is E, orn or KZ1; wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa at position 30 is G, orn, KZ1 or GR2; wherein Z1 is R5 or R4R5, wherein R4 is a linker and R5 is a fatty acid; r2 is SEQ ID NO. 28, SEQ ID NO. 29, SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32 or SEQ ID NO. 33
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> R3 is a modification of the C-terminal group, wherein the modification is NH2;
wherein two and only two of X10, X12, X17, X21, X24, X25, X28, X30, X31 and X40 are KZ1
<400> 40
Xaa Xaa Glu Gly Thr Xaa Thr Ser Asp Xaa Xaa Xaa Xaa Leu Asp Xaa
1 5 10 15
Xaa Ala Gln Xaa Xaa Xaa Ile Xaa Xaa Leu Ile Xaa Gly Xaa
20 25 30
<210> 41
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa at position 2 is Aib
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa at position 6 is alpha-Me-F (2F)
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa at position 10 is 4Pal
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa at position 13 is alpha-Me-Leu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa at position 16 is Orn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Lys at position 17 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 12-CO2H
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa of position 20 is Aib
<220>
<221> MISC_FEATURE
<222> (24)..(24)
<223> Xaa at position 24 is D-Glu
<220>
<221> MISC_FEATURE
<222> (25)..(25)
<223> Xaa at position 25 is alpha-Me-Y
<220>
<221> MOD_RES
<222> (31)..(31)
<223> Lys at position 31 was chemically modified by conjugation of the epsilon-amino group of the Lys side chain with (2- [2- (2-amino-ethoxy) -ethoxy ] -acetyl) 2- (gamma-Glu) -CO- (CH 2) 12-CO2H
<220>
<221> MOD_RES
<222> (39)..(39)
Ser amidation of position 39 <223 ]
<400> 41
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Xaa Ser Ile Xaa Leu Asp Xaa
1 5 10 15
Lys Ala Gln Xaa Glu Phe Ile Xaa Xaa Leu Ile Glu Gly Gly Lys Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35

Claims (76)

1. A method of treating refractory type 2 diabetes in a patient in need thereof, comprising administering to the patient an effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof once a week.
2. The method of claim 1, wherein the patient has type 2 diabetes for at least 8 years.
3. The method of any one of claims 1 or 2, wherein the HbA1c target of the patient is less than 7%.
4. A method according to any one of claims 1 to 3, wherein the HbA1c target of the patient is equal to or less than 5.7%.
5. The method of any one of claims 1 to 4, wherein the patient has a HbA1c of greater than 10%.
6. The method of any one of claims 1 to 4, wherein the patient has a HbA1c of greater than 11%.
7. The method of any one of claims 1 to 6, wherein the patient is at least 46 years old.
8. The method of any one of claims 1 to 7, wherein the patient is at least 60 years old.
9. The method of any one of claims 1 to 8, wherein the patient is taking an SGLT2 inhibitor.
10. The method of any one of claims 1 to 9, wherein the patient is taking metformin.
11. The method of any one of claims 1 to 10, wherein basal insulin is not administered to the patient.
12. The method of any one of claims 1 to 11, wherein the patient fails to reach their HbA1c target upon administration of metformin and an SGLT2 inhibitor.
13. The method of any one of claims 1 to 12, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is treated for at least 40 weeks.
14. The method of any one of claims 1-13, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered to the patient for at least 50 weeks.
15. The method of any one of claims 1-14, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered to the patient for at least 2 years.
16. The method of any one of claims 1 to 15, wherein the patient is non-obese.
17. The method of any one of claims 1 to 16, wherein the patient has co-morbid hypertension.
18. The method of any one of claims 1 to 17, wherein the patient has co-morbid low HDL-C.
19. The method of any one of claims 1 to 15 or 16 to 18, wherein the patient has co-morbid obesity.
20. The method of any one of claims 1 to 19, wherein the patient has at least two cardiovascular risk factors.
21. The method of any one of claims 1 to 19, wherein the patient is free of cardiovascular risk factors.
22. The method of any one of claims 1 to 21, wherein the patient has type 2 diabetes for at least 10 years.
23. A method of treating hypertension in a patient in need thereof comprising administering to the patient an effective amount of a GIP/GLP1 agonist or a pharmaceutically acceptable salt thereof once a week.
24. The method of claim 23, wherein the patient has type 2 diabetes for at least 8 years.
25. The method of any one of claims 23 or 24, wherein the patient has refractory type 2 diabetes.
26. The method of any one of claims 24 or 25, wherein the HbA1c target of the patient is less than 7%.
27. The method of any one of claims 23 to 26, wherein the HbA1c target of the patient is equal to or less than 5.7%.
28. The method of any one of claims 23 to 27, wherein the patient has HbA1c of greater than 10%.
29. The method of any one of claims 23 to 28, wherein the HbA1c of the patient is greater than 11%.
30. The method of any one of claims 23 to 29, wherein the patient is at least 46 years old.
31. The method of any one of claims 23 to 30, wherein the patient is at least 60 years old.
32. The method of any one of claims 23 to 31, wherein the patient is taking an SGLT2 inhibitor.
33. The method of any one of claims 23 to 32, wherein the patient is taking metformin.
34. The method of any one of claims 23 to 33, wherein basal insulin is not administered to the patient.
35. The method of any one of claims 23 to 34, wherein the patient fails to reach their HbA1c target upon administration of metformin and an SGLT2 inhibitor.
36. The method of any one of claims 23-35, wherein the GIP/GLP1 agonist treatment is continued for at least 40 weeks.
37. The method of any one of claims 23 to 36, wherein the patient has co-morbid obesity.
38. The method of any one of claims 23 to 37, wherein the patient is non-obese.
39. The method of any one of claims 23 to 38, wherein the patient has co-morbid low HDL-C.
40. The method of any one of claims 23 to 39, wherein the patient has at least two cardiovascular risk factors.
41. The method of any one of claims 23 to 40, wherein the hypertension is a hypertensive crisis.
42. The method of any one of claims 23 to 41, wherein the method prevents hypertensive crisis.
43. The method of any one of claims 23 to 42, wherein the method prevents stroke.
44. A method of raising HDL-C in a patient in need thereof, comprising administering to the patient an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, once a week.
45. The method of claim 44, wherein the patient has type 2 diabetes for at least 8 years.
46. The method of any one of claims 44 or 45, wherein the patient has refractory type 2 diabetes.
47. The method of any one of claims 44 to 56, wherein the patient is at least 46 years old.
48. The method of any one of claims 44 to 47, wherein the patient is at least 60 years old.
49. The method of any one of claims 44 to 48, wherein the patient is taking an SGLT2 inhibitor.
50. The method of any one of claims 44 to 49, wherein the patient is taking metformin.
51. The method of any one of claims 44 to 50, wherein no basal insulin is administered to the patient.
52. The method of any one of claims 44-51, wherein the GIP/GLP1 agonist treatment is continued for at least 40 weeks.
53. The method of any one of claims 44-52, wherein the patient is non-obese.
54. The method of any one of claims 44 to 53, wherein said patient has at least two cardiovascular risk factors.
55. The method of any one of claims 44 to 54, wherein the patient has co-morbid hypertension.
56. The method of any one of claims 44-53, wherein the GIP/GLP1 agonist is administered for at least 50 weeks.
57. The method of any one of claims 44-56, wherein the once weekly administration of the GIP/GLP1 agonist is for at least 2 years.
58. The method of any one of claims 1 to 22, wherein the GIP/GLP1 agonist compound has the formula:
R 1 X 1 X 2 X 3 GTX 6 TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 (SEQ ID NO：3)
wherein:
R 1 no Ac modification or N-terminal amino group;
X 1 selected from Y, H, D-Tyr, F, desH and desY;
X 2 selected from Aib, αmep, a, P and D-Ala;
or X 1 And X 2 Combine to form desH- ψ [ NHCO ] ]-Aib；
X 3 Selected from E, N, aad and cTA;
X 6 selected from F, αmef and αmef (2F);
X 10 selected from A, L, H, 3Pal, 4Pal, V, Y, E, αMeF (2F), I, αMeY, Q, D-His, D-Tyr, cTA and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 11 Selected from S, αMeS and D-Ser;
X 12 selected from I, S, D-Ile and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 13 Selected from Nle, aib, L, αmel and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 14 Selected from L and K, wherein K is conjugated to C 16 -C 22 A fatty acid, wherein the fatty acid is conjugated to the K, optionally via a linker;
X 16 selected from K, E, orn, dab, dap, S, T, H, aib, αMeK, R and K (2- [2- (2-amino-ethoxy) -ethoxy]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 17 Selected from K, Q, I and conjugation to C 16 -C 22 An amino acid of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker;
X 19 selected from Q, A and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 20 Selected from Aib, Q, H, R, K, αMeK and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 21 Selected from H, aad, D, aib, T, A, E, I and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 22 Selected from F and αmef;
X 23 selected from I, L, A, G, F, H, E, V and K (2- [2- (2-amino-ethoxy) -ethoxy ] ]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 24 Selected from S, aad, D-Glu, E, aib, H, V, A, Q, D, P and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 25 Selected from Y and αmey;
X 26 selected from L, alpha MeL and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 27 Selected from L, I and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 28 Selected from E, A, S, D-Glu and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 29 Selected from Aib, G, A and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 30 Selected from C, G, G-R 2 And K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H；
X 31 Absence or selection of PX 32 X 33 X 34 -R 2 (SEQ ID NO：4)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO：5)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 6), K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 -R 2 (SEQ ID NO: 7), K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 8) and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 9); wherein:
X 32 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 33 Is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 34 Selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 35 Is A or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 36 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ] ]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 37 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 38 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 39 Selected from C, S and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 40 Selected from C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
q is selected from 14, 15, 16, 17, 18, 19 and 20; and
R 2 is a modification of the C-terminal group, wherein the modification is NH 2 Or is absent;
wherein if X 30 Is G-R 2 X is then 31 Absence of;
wherein X is 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 19 、X 20 、X 21 、X 23 、X 24 、X 26 、X 27 、X 28 、X 29 、X 30 、X 31 、X 32 、X 33 、X 34 、X 35 、X 36 、X 37 、X 38 、X 39 And X 40 May be a fatty acid-containing substituent; and
wherein X is 30 、X 34 、X 39 And X 40 May be C; and
wherein if X 30 、X 34 、X 39 And X 40 One is C, then X 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 19 、X 20 、X 21 、X 23 、X 24 、X 26 、X 27 、X 28 、X 29 、X 30 、X 31 、X 32 、X 33 、X 34 、X 35 、X 36 、X 37 、X 38 、X 39 And X 40 None of which contains a substituent of a fatty acid.
59. The method of any one of claims 23 to 43, wherein the GIP/GLP1 agonist compound has the formula:
R 1 X 1 X 2 X 3 GTX 6 TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 (SEQ ID NO：3)
wherein:
R 1 no Ac modification or N-terminal amino group;
X 1 selected from Y, H, D-Tyr, F, desH and desY;
X 2 selected from Aib, αmep, a, P and D-Ala;
or X 1 And X 2 Combine to form desH- ψ [ NHCO ]]-Aib；
X 3 Selected from E, N, aad and cTA;
X 6 selected from F, αmef and αmef (2F);
X 10 selected from A, L, H, 3Pal, 4Pal, V, Y, E, αMeF (2F), I, αMeY, Q, D-His, D-Tyr, cTA and K (2- [2- (2-amino-ethoxy) ]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 11 Selected from S, αMeS and D-Ser;
X 12 selected from I, S, D-Ile and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 13 Selected from Nle, aib, L, αmel and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 14 Selected from L and K, wherein K is conjugated to C 16 -C 22 A fatty acid, wherein the fatty acid is conjugated to the K, optionally via a linker;
X 16 selected from K, E, orn, dab, dap, S, T, H, aib, αMeK, R and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 17 Selected from K, Q, I and conjugation to C 16 -C 22 An amino acid of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker;
X 19 selected from Q, A and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 20 Selected from Aib, Q, H, R, K, αMeK and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 21 Selected from H, aad, D, aib, T, A, E, I and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 22 Selected from F and αmef;
X 23 selected from I, L, A, G, F, H, E, V and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 24 Selected from S, aad, D-Glu, E, aib, H, V, A, Q, D, P and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 25 Selected from Y and αmey;
X 26 selected from L, αMeL and K (2- [2- (2-amino-ethoxy) ] Ethoxy group]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 27 Selected from L, I and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 28 Selected from E, A, S, D-Glu and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 29 Selected from Aib, G, A and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 30 Selected from C, G, G-R 2 And K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H；
X 31 Absence or selection of PX 32 X 33 X 34 -R 2 (SEQ ID NO：4)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO：5)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 6), K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 -R 2 (SEQ ID NO: 7), K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 8) and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 9); wherein:
X 32 is S or K [ (2- [2- (2-amino-ethoxy)Base group]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 33 Is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 34 Selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 35 Is A or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 36 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 37 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 38 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 39 Selected from C, S and K [ (2- [2- (2-amino-ethoxy) -ethoxy ] ]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 40 Selected from C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
q is selected from 14, 15, 16, 17, 18, 19 and 20; and
R 2 is a modification of the C-terminal group, wherein the modification is NH 2 Or is absent;
wherein if X 30 Is G-R 2 X is then 31 Absence of;
wherein X is 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 19 、X 20 、X 21 、X 23 、X 24 、X 26 、X 27 、X 28 、X 29 、X 30 、X 31 、X 32 、X 33 、X 34 、X 35 、X 36 、X 37 、X 38 、X 39 And X 40 May be a fatty acid-containing substituent; and
wherein X is 30 、X 34 、X 39 And X 40 May be C; and
wherein if X 30 、X 34 、X 39 And X 40 One is C, then X 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 19 、X 20 、X 21 、X 23 、X 24 、X 26 、X 27 、X 28 、X 29 、X 30 、X 31 、X 32 、X 33 、X 34 、X 35 、X 36 、X 37 、X 38 、X 39 And X 40 None of which contains a substituent of a fatty acid.
60. The method of any one of claims 44 to 57, wherein the GIP/GLP1 agonist compound has the formula:
R 1 X 1 X 2 X 3 GTX 6 TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 (SEQ ID NO：3)
wherein:
R 1 no Ac modification or N-terminal amino group;
X 1 selected from Y, H, D-Tyr, F, desH and desY;
X 2 selected from Aib, αmep, a, P and D-Ala;
or X 1 And X 2 Combine to form desH- ψ [ NHCO ]]-Aib；
X 3 Selected from E, N, aad and cTA;
X 6 selected from F, αmef and αmef (2F);
X 10 selected from A, L, H, 3Pal, 4Pal, V, Y, E, αMeF (2F), I, αMeY, Q, D-His, D-Tyr, cTA and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 11 Selected from S, αMeS and D-Ser;
X 12 selected from I, S, D-Ile and K (2- [2- (2-amino-ethoxy) -ethoxy ] ]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 13 Selected from Nle, aib, L, αmel and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 14 Selected from L and K, wherein K is conjugated to C 16 -C 22 A fatty acid, wherein the fatty acid is conjugated to the K, optionally via a linker;
X 16 selected from K, E, orn, dab, dap, S, T, H, aib, αMeK, R and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 17 Selected from K, Q, I and conjugation to C 16 -C 22 An amino acid of a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker;
X 19 selected from Q, A and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 20 Selected from Aib, Q, H, R, K, αMeK and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 21 Selected from H, aad, D, aib, T, A, E, I and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 22 Selected from F and αmef;
X 23 selected from I, L, A, G, F, H, E, V and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 24 Selected from S, aad, D-Glu, E, aib, H, V, A, Q, D, P and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 25 Selected from Y and αmey;
X 26 selected from L, alpha MeL and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 27 Selected from L, I and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 28 Selected from E, A, S, D-Glu and K (2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 29 Selected from Aib, G, A and K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H；
X 30 Selected from C, G, G-R 2 And K (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H；
X 31 Absence or selection of PX 32 X 33 X 34 -R 2 (SEQ ID NO：4)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO：5)、PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 6), K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 -R 2 (SEQ ID NO: 7), K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 8) and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 9); wherein:
X 32 is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 33 Is S or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 34 Selected from G, C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 35 Is A or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 36 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 37 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 38 Is P or K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 39 Selected from C, S and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
X 40 Selected from C and K [ (2- [2- (2-amino-ethoxy) -ethoxy ]]Acetyl group 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]；
q is selected from 14, 15, 16, 17, 18, 19 and 20; and
R 2 Is a modification of the C-terminal group, wherein the modification is NH 2 Or is absent;
wherein if X 30 Is G-R 2 X is then 31 Absence of;
wherein X is 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 19 、X 20 、X 21 、X 23 、X 24 、X 26 、X 27 、X 28 、X 29 、X 30 、X 31 、X 32 、X 33 、X 34 、X 35 、X 36 、X 37 、X 38 、X 39 And X 40 May be a fatty acid-containing substituent; and
wherein X is 30 、X 34 、X 39 And X 40 May be C; and
wherein if X 30 、X 34 、X 39 And X 40 One is C, then X 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 19 、X 20 、X 21 、X 23 、X 24 、X 26 、X 27 、X 28 、X 29 、X 30 、X 31 、X 32 、X 33 、X 34 、X 35 、X 36 、X 37 、X 38 、X 39 And X 40 None of which contains a substituent of a fatty acid.
61. The method of any one of claims 1 to 22, wherein the GIP/GLP1 agonist compound has the formula:
X 1 X 2 EGTX 6 TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30 (SEQ ID NO：27)
wherein the method comprises the steps of
X 1 Selected from Y and R 1 Y；
R 1 Ac modification of the N-terminal amino group;
X 2 is Aib;
X 6 selected from αmef and αmef (2F);
X 10 selected from 4Pal, Y, αMeF (2F), αMeL, αMeV, ac4c, ac5c, ac6c, bip, 1Nal, 2Nal, OMeY, hTyr, nle, V, 4CPhe, chG, chA, bzt, 2FA, 4TAA, 2TA, 3TA and KZ 1 ；
X 11 Selected from S, α MeS, aib, G, dap, ac5c and tlie;
X 12 selected from I and KZ 1 ；
X 13 Selected from αmel and αmef;
X 16 is Orn;
X 17 selected from Q, I and KZ 1 ；
X 20 Selected from Aib, orn, 4Pal, αmef, ac5c, and Ac6c;
X 21 selected from E, KZ 1 G, orn and 4Pal;
X 22 selected from F, 2ClPhe, 3ClPhe, 2FPhe, 3,5FPhe, 1Nal, 2Nal, αMeF (2F), chA, bzt and αMeF;
X 24 selected from D-Glu, E, G and KZ 1 ；
X 25 Selected from Y, αMeY, αMeF and KZ 1 ；
X 28 Selected from E, orn and KZ 1 ；
X 30 Selected from G, orn, KZ 1 、K(Z 1 )R 6 、OrnR 2 And GR (glass fiber reinforced plastics) 2 ；
R 2 Selected from X 31 、X 31 SSG(SEQ ID NO：28)、X 31 SSG-R 3 (SEQ ID NO：29)、X 31 SSGX 35 PPPX 39 (SEQ ID NO：30)、X 31 SSGX 35 PPPX 39 R 3 (SEQ ID NO：31)、X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO：32)、X 31 SSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 33) and modification of the c-terminal group, wherein the modification is NH 2 ；
R 6 Selected from PSSG (SEQ ID NO: 34), PSSG-R 3 (SEQ ID NO：35)、PSSGX 35 PPPX 39 (SEQ ID NO：36)、PSSGX 35 PPPX 39 R 3 (SEQ ID NO：37)、PSSGX 35 PPPX 39 X 40 (SEQ ID NO：38)、PSSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 39) and modification of the c-terminal group, wherein the modification is NH 2 ；
X 31 Selected from P and KZ 1 ；
X 35 Selected from A and Orn;
X 39 selected from S and Orn;
X 40 is KZ 1 ；
R 3 Is a modification of the C-terminal group, wherein the modification is NH 2 ；
Wherein X is 10 、X 12 、X 17 、X 21 、X 24 、X 25 、X 28 、X 30 、X 31 And X 40 Is KZ 1 Or K (Z) 1 )R 6 ；
Z 1 Selected from R 5 and-R 4 R 5 ；
R 4 Is a joint; and
R 5 is a fatty acid.
62. The method of any one of claims 23 to 43, wherein the GIP/GLP1 agonist compound has the formula:
X 1 X 2 EGTX 6 TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30 (SEQ ID NO：27)
wherein the method comprises the steps of
X 1 Selected from Y and R 1 Y；
R 1 Ac modification of the N-terminal amino group;
X 2 is Aib;
X 6 selected from αmef and αmef (2F);
X 10 selected from 4Pal, Y, αMeF (2F), αMeL, αMeV, ac4c, ac5c, ac6c, bip, 1Nal, 2Nal, OMeY, hTyr, nle, V, 4CPhe, chG, chA, bzt, 2FA, 4TAA, 2TA, 3TA and KZ 1 ；
X 11 Selected from S, α MeS, aib, G, dap, ac5c and tlie;
X 12 selected from I and KZ 1 ；
X 13 Selected from αmel and αmef;
X 16 is Orn;
X 17 selected from Q, I and KZ 1 ；
X 20 Selected from Aib, orn, 4Pal, αmef, ac5c, and Ac6c;
X 21 selected from E, KZ 1 G, orn and 4Pal;
X 22 selected from F, 2ClPhe, 3ClPhe, 2FPhe, 3,5FPhe, 1Na1, 2Nal, αMeF (2F), chA, bzt and αMeF;
X 24 selected from D-Glu, E, G and KZ 1 ；
X 25 Selected from Y, αMeY, αMeF and KZ 1 ；
X 28 Selected from E, orn and KZ 1 ；
X 30 Selected from G, orn, KZ 1 、K(Z 1 )R 6 、OrnR 2 And GR (glass fiber reinforced plastics) 2 ；
R 2 Selected from X 31 、X 31 SSG(SEQ ID NO：28)、X 31 SSG-R 3 (SEQ ID NO：29)、X 31 SSGX 35 PPPX 39 (SEQ ID NO：30)、X 31 SSGX 35 PPPX 39 R 3 (SEQ ID NO：31)、X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO：32)、X 31 SSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 33) and modification of the c-terminal group, wherein the modification is NH 2 ；
R 6 Selected from PSSG (SEQ ID NO: 34), PSSG-R 3 (SEQ ID NO：35)、PSSGX 35 PPPX 39 (SEQ ID NO：36)、PSSGX 35 PPPX 39 R 3 (SEQ ID NO：37)、PSSGX 35 PPPX 39 X 40 (SEQ ID NO：38)、PSSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 39) and modification of the c-terminal group, wherein the modification is NH 2 ；
X 31 Selected from P and KZ 1 ；
X 35 Selected from A and Orn;
X 39 selected from S and Orn;
X 40 is KZ 1 ；
R 3 Is a modification of the C-terminal group, wherein the modification is NH 2 ；
Wherein X is 10 、X 12 、X 17 、X 21 、X 24 、X 25 、X 28 、X 30 、X 31 And X 40 Is KZ 1 Or K (Z) 1 )R 6 ；
Z 1 Selected from R 5 and-R 4 R 5 ；
R 4 Is a joint; and
R 5 is a fatty acid.
63. The method of any one of claims 44 to 57, wherein the GIP/GLP1 agonist compound has the formula:
X 1 X 2 EGTX 6 TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30 (SEQ ID NO：27)
wherein the method comprises the steps of
X 1 Selected from Y and R 1 Y；
R 1 Ac modification of the N-terminal amino group;
X 2 is Aib;
X 6 selected from αmef and αmef (2F);
X 10 selected from 4Pal, Y, αMeF (2F), αMeL, αMeV, ac4c, ac5c, ac6c, bip, 1Nal, 2Nal, OMeY, hTyr, nle, V, 4CPhe, chG, chA, bzt, 2FA, 4TAA, 2TA, 3TA and KZ 1 ；
X 11 Selected from S, α MeS, aib, G, dap, ac5c and tlie;
X 12 Selected from I and KZ 1 ；
X 13 Selected from αmel and αmef;
X 16 is Orn;
X 17 selected from Q, I and KZ 1 ；
X 20 Selected from Aib, orn, 4Pal, αmef, ac5c, and Ac6c;
X 21 selected from E, KZ 1 G, orn and 4Pal;
X 22 selected from F, 2ClPhe, 3ClPhe, 2FPhe, 3,5FPhe, 1Nal, 2Nal, αMeF (2F), chA, bzt and αMeF;
X 24 selected from D-Glu, E, G and KZ 1 ；
X 25 Selected from Y, αMeY, αMeF and KZ 1 ；
X 28 Selected from E, orn and KZ 1 ；
X 30 Selected from G, orn, KZ 1 、K(Z 1 )R 6 、OrnR 2 And GR (glass fiber reinforced plastics) 2 ；
R 2 Selected from X 31 、X 31 SSG(SEQ ID NO：28)、X 31 SSG-R 3 (SEQ ID NO：29)、X 31 SSGX 35 PPPX 39 (SEQ ID NO：30)、X 31 SSGX 35 PPPX 39 R 3 (SEQ ID NO：31)、X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO：32)、X 31 SSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 33) and modification of the c-terminal group, wherein the modification is NH 2 ；
R 6 Selected from PSSG (SEQ ID NO: 34), PSSG-R 3 (SEQ ID NO：35)、PSSGX 35 PPPX 39 (SEQ ID NO：36)、PSSGX 35 PPPX 39 R 3 (SEQ ID NO：37)、PSSGX 35 PPPX 39 X 40 (SEQ ID NO：38)、PSSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO: 39) and modification of the c-terminal group, wherein the modification is NH 2 ；
X 31 Selected from P and KZ 1 ；
X 35 Selected from A and Orn;
X 39 selected from S and Orn;
X 40 is KZ 1 ；
R 3 Is a modification of the C-terminal group, wherein the modification is NH 2 ；
Wherein X is 10 、X 12 、X 17 、X 21 、X 24 、X 25 、X 28 、X 30 、X 31 And X 40 Is KZ 1 Or K (Z) 1 )R 6 ；
Z 1 Selected from R 5 and-R 4 R 5 ；
R 4 Is a joint; and
R 5 is a fatty acid.
64. The method of any one of claims 1 to 22, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is a peptide selected from the group consisting of SEQ ID NO: 10. SEQ ID NO: 11. SEQ ID NO: 12. SEQ ID NO:13 and SEQ ID NO:14 or a pharmaceutically acceptable salt thereof.
65. The method of any one of claims 23 to 43, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is a peptide selected from the group consisting of SEQ ID NO: 10. SEQ ID NO: 11. SEQ ID NO: 12. SEQ ID NO:13 and SEQ ID NO:14 or a pharmaceutically acceptable salt thereof.
66. The method of any one of claims 44-57, wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is a peptide selected from the group consisting of SEQ ID NOs: 10. SEQ ID NO: 11. SEQ ID NO: 12. SEQ ID NO:13 and SEQ ID NO:14 or a pharmaceutically acceptable salt thereof.
67. The method of any one of claims 1 to 22, wherein the GIP/GLP1 agonist compound or pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID NO: 21. SEQ ID NO: 22. SEQ ID NO: 23. SEQ ID NO: 24. SEQ ID NO:25 and SEQ ID NO:26.
68. the method of any one of claims 23 to 43, wherein the GIP/GLP1 agonist compound or pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID NO: 21. SEQ ID NO: 22. SEQ ID NO: 23. SEQ ID NO: 24. SEQ ID NO:25 and SEQ ID NO:26.
69. the method of any one of claims 44-57, wherein the GIP/GLP1 agonist compound or pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID NO: 21. SEQ ID NO: 22. SEQ ID NO: 23. SEQ ID NO: 24. SEQ ID NO:25 and SEQ ID NO:26.
70. the method of any one of claims 1 to 22, wherein the GIP/GLP1 agonist is a compound selected from the group consisting of
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H)SSGAPPPS-NH 2 (SEQ ID NO：41)，
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：17)，
Y-Aib-EGT-aMeF (2F) -TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：18)，
Y-Aib-EGT-aMeF (2F) -TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butyryl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO: 19), and
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy) ]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 )SSGAPPPS-NH 2 (SEQ ID NO：19)。
71. The method of any one of claims 23 to 43, wherein the GIP/GLP1 agonist is a compound selected from the group consisting of
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H)SSGAPPPS-NH 2 (SEQ ID NO：41)，
Y-Aib-EGT-aMeF (2F) -TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：17)，
Y-Aib-EGT-aMeF (2F) -TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：18)，
Y-Aib-EGT-aMeF (2F) -TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy) ]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butyryl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO: 19), and
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 )SSGAPPPS-NH 2 (SEQ ID NO：19)。
72. The method of any one of claims 44 to 57, wherein the GIP/GLP1 agonist is a compound selected from the group consisting of
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H)SSGAPPPS-NH 2 (SEQ ID NO：41)，
Y-Aib-EGT-aMeF (2F) -TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (10- (4-carboxyphenoxy) decanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：17)，
Y-Aib-EGT-aMeF (2F) -TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy) ]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-iodophenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO：18)，
Y-Aib-EGT-aMeF (2F) -TSD-4Pal-SI-aMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butyryl)) AQ-Aib-EFI- (D-Glu) -aMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 - (gamma-Glu) - (4- (4-tert-butylphenyl) butanoyl)) SSGAPPPS-NH 2 (SEQ ID NO: 19), and
Y-Aib-EGT- αMeF (2F) -TSD-4Pal-SI- αMeL-LD-Orn-K ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3) AQ-Aib-EFI- (D-Glu) - αMeY-LIEGGK ((2- [2- (2-amino-ethoxy)]Acetyl group 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 )SSGAPPPS-NH 2 (SEQ ID NO：19)。
73. The method of any one of claims 1 to 22, wherein the GIP/GLP1 agonist is guanosine 5' - (gamma-thio) triphosphate at the GLP-1r hek293 cell membrane [ 35 S]A compound exhibiting partial agonism in a (gtpγs) binding assay is co-administered with a compound exhibiting 35% or less partial agonism in a GLP-CHO cell β -inhibitor recruitment assay.
74. The method of any one of claims 1 to 22, wherein the GIP/GLP1 agonist is at GLP- 1R HEK293 cell membrane guanosine 5' - (gamma-thio) triphosphate- [ 35 S]A compound exhibiting partial agonism in a (gtpγs) binding assay is co-administered with a compound exhibiting 35% or less partial agonism in a GLP-CHO cell β -inhibitor recruitment assay.
75. The method of any one of claims 23 to 43, wherein the GIP/GLP1 agonist is guanosine 5' - (gamma-thio) triphosphate at the GLP-1R HEK293 cell membrane [ 35 S]A compound exhibiting partial agonism in a (gtpγs) binding assay is co-administered with a compound exhibiting 35% or less partial agonism in a GLP-CHO cell β -inhibitor recruitment assay.
76. The method of any one of claims 44 to 57, wherein the GIP/GLP1 agonist is guanosine 5' - (gamma-thio) triphosphate at the GLP-1R HEK293 cell membrane [ 35 S]A compound exhibiting partial agonism in a (gtpγs) binding assay is co-administered with a compound exhibiting 35% or less partial agonism in a GLP-CHO cell β -inhibitor recruitment assay.
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