Compounds

Abstract

The present invention provides novel compounds which are peptide hormone analogs and are useful in the treatment of conditions such as diabetes and obesity. Compounds of the general sequence listed in the specification have a tailored profile with respect to potency characteristics for GIP receptors. Administration of example peptides of the invention has been demonstrated in animal models about in vivo characteristics to result in increased weight loss. Preferred compounds achieve this without significantly reducing food intake.

Description

Technical Field

[0001] This disclosure relates to compounds that are peptide hormone analogs and can be used to treat conditions such as diabetes and obesity. Background Technology

[0002] According to the National Health and Nutrition Examination Survey (NHANES, 2009-2010), 33.0% of adults aged 20 and older in the United States were overweight, 35.7% were obese, and 6.3% were extremely obese. In addition, a large proportion of children in the United States are overweight or obese.

[0003] Obesity has complex and multifactorial causes. Growing evidence suggests that obesity is not a simple matter of self-control, but rather a complex condition involving appetite regulation and energy metabolism. Furthermore, obesity is associated with a variety of conditions linked to increased morbidity and mortality in populations. While the exact etiology of obesity is not yet fully established, genetic, metabolic, biochemical, cultural, and psychosocial factors are believed to play a role. Generally, obesity is described as a condition in which excess body fat puts an individual at health risk.

[0004] Strong evidence suggests that obesity is associated with increased morbidity and mortality. Disease risks, such as cardiovascular disease and type 2 diabetes, increase independently with increasing body mass index (BMI). In fact, for each point where BMI is greater than 24.9, this risk has been quantified as a five-percent increase in the risk of heart disease for women and a seven-percent increase for men (see Kenchaiah et al., *The New England Journal of Medicine* 347:305, 2002; Massie, *The New England Journal of Medicine* 347:358, 2002).

[0005] Diabetes is a chronic syndrome caused by insufficient insulin secretion or insulin resistance in target tissues, leading to impaired metabolism of carbohydrates, proteins, and fats. Diabetes occurs in two main forms: insulin-dependent diabetes mellitus (Type 1) and non-insulin-dependent diabetes mellitus (Type 2). Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is caused by the destruction of beta cells, resulting in insufficient levels of endogenous insulin. Type 2 diabetes, or non-insulin-dependent diabetes mellitus, is caused by a defect in the body's sensitivity to insulin and a relative insufficiency in insulin production. According to the National Diabetes Statistics Report, approximately 28.9 million adults aged 20 and older in the United States had diabetes in 2014 (estimates from the 2009–2012 National Health and Nutrition Examination Survey, applicable to 2012 U.S. Census data). In adults, 90% to 95% of diabetes cases are type 2 diabetes.

[0006] There is substantial evidence that weight loss in obese individuals can reduce important disease risk factors. Even minor weight loss (such as 10% of initial body weight in overweight and obese adults) has been associated with a reduction in risk factors such as high blood pressure, high cholesterol, and high blood sugar. Significant weight loss has been shown to be an effective cure for type 2 diabetes (Lim et al., Diabetologia, June 2011).

[0007] While diet and exercise offer simple ways to reduce weight gain, overweight and obese individuals often cannot adequately manage these factors to achieve effective weight loss. Drug therapies are available; the U.S. Food and Drug Administration (FDA) has approved several weight-loss medications that can be used as part of a comprehensive weight-loss program. However, many of these medications have serious adverse side effects. Bariatric surgery is an option for carefully selected patients with clinically severe obesity when less invasive methods fail and the patient is at high risk of obesity-related morbidity or mortality. However, these treatments are high-risk and suitable only for a limited number of patients. It's not just obese subjects who want to lose weight. People whose weight is within the recommended range (e.g., at the upper end of the recommended range) may wish to lose weight to get closer to their ideal weight. Therefore, there remains a need for medications that can be used to achieve weight loss in both overweight and obese subjects and those with normal weight.

[0008] Many approaches to developing agents that can be used to achieve weight loss involve gastrointestinal peptide hormones and their analogues. Glucose-dependent insulinotropic peptides (GIPs), also known as gastric inhibitory peptides or gastric inhibitory peptides, are gastrointestinal hormones belonging to a molecular class called incretins. GIPs are produced by K cells in the upper small intestine in response to food. The primary function of GIPs is to induce the release of insulin from the β cells of the pancreas after eating. Increased insulin secretion leads to a decrease in circulating glucose concentration.

[0009] In addition to its role as an incretin, GIP also inhibits apoptosis of pancreatic β-cells and promotes their proliferation. GIP is also known to stimulate glucagon secretion and fat accumulation. GIP receptors are present in other organs of the body, such as in the central nervous system, where GIP affects hippocampal memory formation and the regulation of appetite and satiety. GIP has also been proposed to play a role in bone remodeling by increasing bone formation while reducing bone breakdown.

[0010] Tirzepatide is the first drug that is a GIP analog that activates both GLP-1 and GIP receptors and was approved in the United States in May 2022 for medical use in the treatment of type 2 diabetes.

[0011] However, despite significant progress, the process of identifying substances for use as drugs remains a complex and, in many cases, unpredictable field. To be used as a therapeutic agent, a compound must possess a suitable range of properties. In addition to good efficacy against the biological target of interest, a compound must also exhibit favorable in vivo pharmacokinetic properties, low toxicity, and an acceptable distribution of side effects. For example, even with commercial agents such as liraglutide, side effects can include nausea and vomiting, and there are also concerns about thyroid cancer and pancreatitis.

[0012] Therefore, there remains a need for additional compounds that can be used to treat conditions and diseases such as diabetes and obesity. For example, it would be desirable to identify peptides with beneficial properties (such as improved activity distribution) and / or reduced side effects. For instance, it would be desirable to identify peptides that increase energy expenditure in subjects without significantly reducing food intake. If a compound reduces food intake less, it is expected to have fewer side effects, such as nausea. Or, additionally, it would be desirable to identify peptides that have these and other biological effects over a longer period. Compounds with longer durations of activity can be administered at lower frequencies and lower doses, which helps improve subject convenience, reduce side effects, and lower costs. Summary of the Invention

[0013] In a first aspect of the invention, a compound of the following formula is provided:

[0014] Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Xaa10–Ser11–Xaa12–Xaa13 – 23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29–Xaa30–Xaa31–Xaa32–Xaa33– Xaa34–Xaa35–Xaa36–Xaa37–Xaa38–Xaa39–Xaa40–Thr41–Gln42–Xaa43 [SEQ ID NO:1]

[0015] in:

[0016] Xaa1 is DTyr, His, Phe, or Tyr, or does not exist;

[0017] Xaa2 is either AIB or Ala, or it does not exist;

[0018] Xaa3 is Asp, Gln, Glu, or His;

[0019] Xaa7 is Ile, Thr, or Ser;

[0020] Xaa10 is either Tyr or His;

[0021] Xaa12 is either Ile or Lys;

[0022] Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn;

[0023] Xaa14 is Leu, Met, or NLeu;

[0024] Xaa17 is either Gln or Ile;

[0025] Xaa18 is Ala, Arg, or His;

[0026] Xaa19 is either Ala or Gln;

[0027] Xaa20 is AIB, Gln, His, or Lys;

[0028] Xaa21 is Ala, Asp, or Glu;

[0029] Xaa24 is Asn, Gln, or Glu;

[0030] Xaa25 is Arg, His, Trp, or Tyr;

[0031] Xaa27 is either Ile or Leu;

[0032] Xaa28 is either Ala or Asn;

[0033] Xaa29 is Gln, Gly, or Thr;

[0034] Xaa30 is Gly, Lys, or Lys*, or does not exist;

[0035] Xaa31 is Arg, Gly, or Pro, or it does not exist;

[0036] Xaa32 is Asn, Lys, or Lys*, or does not exist;

[0037] Xaa33 is Lys or Lys*, or does not exist;

[0038] Xaa34 is either Asn or Lys*;

[0039] Xaa35 is either an Asp or does not exist;

[0040] Xaa36 is either Trp or Lys*, or it does not exist;

[0041] Xaa37 is Lys or Lys*, or does not exist;

[0042] Xaa38 is His or does not exist;

[0043] Xaa39 is either Asn or Lys*, or it does not exist;

[0044] Xaa40 is Ile, Leu, or Lys*, or does not exist;

[0045] Xaa43 is either Lys* or does not exist;

[0046] Lys* is Lys whose ε-amino group is replaced by a group of the following formula:

[0047] Z–Xaa44–Xaa45–Xaa46–Xaa47–

[0048] in:

[0049] Xaa44 is Gly, Ser, Thr or does not exist;

[0050] Xaa45 is Gly, Ser, or does not exist;

[0051] Xaa46 is Asn, Gln, Gly, Ser, Thr or does not exist;

[0052] Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr or does not exist;

[0053] And Z is a group of the following formula:

[0054] (i): Or (ii): Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H;

[0055] Furthermore, the compounds of formula (I) or formula (II) contain a Lys* residue;

[0056] Or a derivative of the compound; or a salt or solvate of the compound or its derivative.

[0057] This document also provides a composition comprising the compounds, derivatives, salts or solvates of the present invention, as well as pharmaceutically acceptable carriers and optional additional therapeutic agents.

[0058] This document also provides compounds, derivatives, salts, or solvates of the present invention, or compositions comprising such compounds, derivatives, salts, or solvates and pharmaceutically acceptable carriers, which may be used as medicines, for example for the prevention or treatment of diabetes, obesity, heart disease, stroke, or non-alcoholic fatty liver disease, to improve insulin release in subjects, to improve carbohydrate metabolism in subjects, to improve lipid distribution in subjects, to reduce appetite, to reduce food intake, to reduce calorie intake, to improve glucose tolerance in subjects, and / or as cytoprotective agents, for example for the prevention or treatment of Parkinson's disease, Alzheimer's disease, and other types of neurodegeneration.

[0059] This article also provides a method for treating or preventing a subject's disease or condition or other undesirable physiological state, the method comprising, for example, administering a therapeutically effective amount of a compound, derivative, salt, or solvate of the present invention, or a composition comprising such a compound, derivative, salt, or solvate, and a pharmaceutically acceptable carrier, in a method for treating or preventing a subject's diabetes, obesity, heart disease, stroke, or non-alcoholic fatty liver disease, improving a subject's insulin release, improving a subject's carbohydrate metabolism, improving a subject's lipid distribution, improving a subject's glucose tolerance, reducing appetite, reducing food intake, reducing calorie intake, and / or providing cellular protection to a subject.

[0060] This document also provides the use of the compounds, derivatives, salts, or solvates of the present invention in the preparation of medicaments for the prevention or treatment of diabetes, obesity, heart disease, stroke, or non-alcoholic fatty liver disease; to improve insulin release in subjects; to improve carbohydrate metabolism in subjects; to improve lipid distribution in subjects; to improve glucose tolerance in subjects; to reduce appetite; to reduce food intake; to reduce calorie intake; and / or as cytoprotective agents, such as in the prevention or treatment of Parkinson's disease, Alzheimer's disease, and other types of neurodegenerative diseases.

[0061] This article also provides a method for reducing or preventing weight gain in a subject for cosmetic purposes, the method comprising administering an effective amount of the compound, derivative, salt or solvate of the present invention. Attached Figure Description

[0062] Figure 1 The amino acid sequences of exemplary compounds of the present invention are shown. The N-terminal residues of these compounds are presented on the left side of the table (indicated by columns titled "1").

[0063] Results from receptor activation assays (reporter gene assays), feeding, and pharmacokinetic studies showed that Figure 1 In the rightmost column.

[0064] sequence

[0065] The N-terminus of the amino acid sequence in this article is shown on the left, and in cases where the sequence spans multiple lines, the N-terminus is at the top left. Unless otherwise stated, the amino acid residues in the sequence are L-amino acids.

[0066] The amino acid sequences listed in this application are shown using standard letter abbreviations for amino acids. The non-natural amino acid 2-aminoisobutyric acid is commonly abbreviated as "AIB". Leucine is abbreviated as "NLeu".

[0067] The specific sequences given in this article are related to the specific embodiments of the present invention. Detailed Implementation

[0068] definition

[0069] To facilitate a review of the various embodiments of this disclosure, the following explanations of certain terms are provided:

[0070] Animals: Living multicellular vertebrates, including, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term "subject" includes both human subjects and livestock subjects. In a preferred embodiment of the invention, the subject is a human subject.

[0071] Appetite: An innate desire or craving for food. In one implementation, appetite is measured through a survey to assess the need for food. Increased appetite typically leads to increased eating behavior.

[0072] Appetite suppressants: compounds that reduce the desire for food. Commercially available appetite suppressants include, but are not limited to, amphetamine (diethylamine benzophenone), phentermine, masindole, phenylpropanolamine, fenfluramine, dexfenfluramine, and fluoxetine.

[0073] Body Mass Index (BMI): A mathematical formula used to measure body weight, sometimes also called the Quetelet index. It is calculated by dividing weight (in kg) by height. 2 (in meters) 2 BMI is calculated in units of 20 kg / m². Currently, a BMI of 20 kg / m² is considered "normal" for both men and women. 2 -24.9kg / m 2 In one implementation scheme, greater than 25 kg / m 2 BMI can be used to identify obese subjects. Grade I obesity (sometimes referred to as "overweight" rather than obese) corresponds to a BMI of 25 kg / m². 2 -29.9kg / m 2 Grade II obesity corresponds to a BMI of 30 kg / m². 2 -40kg / m 2 Furthermore, grade III obesity corresponds to a BMI greater than 40 kg / m². 2 (Jequier, *American Journal of Clinical Nutrition*, 45:1035-47, 1987). Ideal weight varies by species and individual, based on height, build, skeletal structure, and sex.

[0074] Cardiac protection refers to protecting heart cells (especially cardiomyocytes) from apoptosis, necrosis, cell death, or degeneration (loss of function). Cardiac protection is often most needed after a myocardial infarction, but it can also be used in subjects with ischemic heart disease (such as angina).

[0075] Cell protection refers to protecting cells from apoptosis, necrosis, cell death, or degeneration (loss of function).

[0076] Diabetes mellitus: A condition in which cells are unable to transport endogenous glucose across membranes due to a lack of endogenous insulin and / or insulin sensitivity defects. Diabetes mellitus is a chronic syndrome of impaired carbohydrate, protein, and fat metabolism caused by insufficient insulin secretion or insulin resistance in target tissues. It occurs in two main forms: insulin-dependent diabetes mellitus (IDDM, type I) and non-insulin-dependent diabetes mellitus (NIDDM, type II), which differ in etiology, pathology, genetics, age of onset, and treatment.

[0077] Both main forms of diabetes are characterized by the inability to deliver a sufficient amount of insulin and require precise timing for maintaining glucose homeostasis. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is caused by the destruction of beta cells, leading to insufficient levels of endogenous insulin. Type 2 diabetes, or non-insulin-dependent diabetes mellitus, results from a deficiency in the body's sensitivity to insulin and a relative insufficiency in insulin production.

[0078] Energy metabolism: The human body must consume a certain amount of energy to maintain normal metabolism. In civilized individuals, this amount is typically set at about 2,800 calories per day. If food consumption cannot provide this amount, it will lead to weight loss. However, energy metabolism is also regulated, and for example, the administration of glucagon is thought to increase the metabolic rate, thus requiring more food intake to achieve energy balance and maintain weight. Therefore, if food intake remains at a normal level, but energy metabolism increases, it will lead to weight loss.

[0079] Food intake: The amount of food consumed by an individual. Food intake can be measured by volume or weight. For example, food intake can be the total amount of food consumed by an individual. In feeding experiments, "food intake" is the weight of standardized food consumed by an animal over a 24-hour period. Alternatively, food intake can be the amount of protein, fat, carbohydrates, cholesterol, vitamins, minerals, or any other food component consumed by an individual. "Protein intake" refers to the amount of protein consumed by an individual. Similarly, "fat intake," "carbohydrate intake," "cholesterol intake," "vitamin intake," and "mineral intake" refer to the amount of protein, fat, carbohydrates, cholesterol, vitamins, or minerals consumed by an individual.

[0080] GIP: Glucose-dependent insulinotropic polypeptide (GIP), also known as gastric inhibitory polypeptide or gastric inhibitory peptide, is a 42-amino acid peptide released by K cells in the duodenum and jejunum in response to food intake. GIP, along with GLP-1, is a member of the incretin hormone peptide class.

[0081] The sequence of human GIP is: Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-A sp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln[SEQ ID NO:2].

[0082] GLP-1: Glucagon-like peptide-1 (GLP-1) is a transcription product of the proglucagon gene. The biologically active form of GLP-1 is called GLP-1. (7-37) and GLP-1 (7-36) The truncated form of -NH2 (the name -NH2 indicates an amino acid sequence in which the C-terminal amino acid has a –C(O)NH2 group that replaces the carboxylic acid group).

[0083] Human GLP-1 (7-37) The sequence is His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly [SEQ ID NO:3].

[0084] Human GLP-1 (7-36) The sequence of -NH2 is His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-–CONH2[SEQ ID NO:4].

[0085] Glucagon: Glucagon is a peptide derived from the proglucagon gene. It is a 29-amino acid polypeptide found in the human body, and its sequence is as follows:

[0086] His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr [SEQ ID NO: 5].

[0087] Neuroprotection refers to the protection of neurons within the nervous system (preferably the central nervous system) from apoptosis, necrosis, or degeneration (loss of function). Neuroprotective treatment, including those relating to various aspects of the present invention, may be necessary after brain injury (e.g., brain injury following physical trauma or non-traumatic injury such as stroke, brain tumor, infection, poisoning, hypoxia, ischemia, encephalopathy, or drug abuse).

[0088] Normal daily diet: The average food intake of an individual of a given species. A normal daily diet can be expressed in terms of calorie intake, protein intake, carbohydrate intake, and / or fat intake. A normal daily diet for humans typically consists of approximately 2,000, 2,400, or 2,800 calories to significantly more. Additionally, a normal daily diet for humans typically contains approximately 12g to 45g of protein, approximately 120g to 610g of carbohydrates, and approximately 11g to 90g of fat. A low-calorie diet will not exceed approximately 85% of a human individual's normal calorie intake, and preferably not more than approximately 70%.

[0089] In animals, calorie and nutritional requirements vary depending on the species and size. For example, in cats, the total calorie intake per pound, as well as the percentage distribution of protein, carbohydrates, and fat, varies with the cat's age and reproductive status. However, a general guideline for cats is 40 calories / pound / day (18.2 calories / kg / day). Approximately 30% to 40% should be from protein, approximately 7% to 10% from carbohydrates, and approximately 50% to 62.5% from fat intake. Those skilled in the art can readily identify a normal daily diet for an individual of any species.

[0090] Obesity: A condition where excess body fat can put a person at health risk (see Barlow and Dietz, *Pediatrics* 102:E29, 1998; *Obes Research* 6(Supplement 2):51S-209S, 1998, National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI)). Excess body fat results from an imbalance between energy intake and energy expenditure. For example, body mass index (BMI) can be used to assess obesity. In a common practice, a BMI of 25.0 kg / m² is defined as... 2 Up to 29.9 kg / m 2 He is overweight, with a BMI of 30 kg / m². 2 Or higher is obesity.

[0091] In another practice, waist circumference is used to assess obesity. In this practice, a waist circumference of 102 cm or more is considered obese in men, and 89 cm or more in women. Strong evidence suggests that obesity affects morbidity and mortality. For example, obese individuals have an increased risk of heart disease, non-insulin-dependent (type 2) diabetes, hypertension, stroke, cancers (e.g., endometrial, breast, prostate, and colon cancer), dyslipidemia, gallbladder disease, sleep apnea, decreased fertility, and osteoarthritis (see Lyznicki et al., *American Journal of Family Physicians* 63:2185, 2001).

[0092] Overweight: An individual whose weight exceeds their ideal weight. An overweight individual can be obese, but not necessarily obese. For example, an overweight individual is any individual who wishes to lose weight. By convention, an overweight individual is defined as someone with a BMI of 25.0 kg / m². 2 Up to 29.9 kg / m 2 Individuals.

[0093] Gastrin-regulatory hormone (OXM): Gastrin-regulatory hormone is the 37th amino acid peptide member of the glucagon superfamily. It comprises the entire 29-amino acid sequence of glucagon, with an eight-amino acid carboxyl-terminal extension. It is produced by tissue-specific processing of the proglucagon precursor in the brain and intestine. The human OXM sequence is as follows:

[0094] [SEQ ID NO:6].

[0095] Polyethylene glycolation and PEGylation: Polyethylene glycolation refers to the process of reacting a poly(alkylene glycol), preferably an activated poly(alkylene glycol), to form covalent bonds. Promoters, such as amino acids (e.g., lysine), can be used. Although "polyethylene glycolation" is generally performed using poly(ethylene glycol) or its derivatives (such as methoxylated poly(ethylene glycol)), the term is not limited herein to the use of methoxylated poly(ethylene glycol) and also includes the use of any other useful poly(alkylene glycol), such as poly(propylene glycol). The term PEGylation refers to compounds containing such poly(alkylene glycol) groups.

[0096] pI: pI is an abbreviation for isoelectric point. Sometimes an alternative abbreviation is IEP. It is the pH value at which a particular molecule carries no net charge. Proteins or peptides carry a net positive charge at pH values ​​below their pI, and a net negative charge at pH values ​​above their pI. Proteins and peptides can be separated based on their isoelectric points using a technique called isoelectric focusing, which is an electrophoretic method utilizing a pH gradient contained in a polyacrylamide gel.

[0097] Peripheral application: Application outside the central nervous system. Peripheral application does not include direct application to the brain. Peripheral application includes, but is not limited to, intravascular, intramuscular, subcutaneous, inhalation, oral, rectal, transdermal, or intranasal application.

[0098] Polypeptide: A polymer in which monomers are amino acid residues linked together by amide bonds. Unless the context otherwise indicates, the terms “polypeptide,” “peptide,” or “protein” as used herein cover any amino acid sequence and include modified sequences such as glycoproteins. The term “polypeptide” covers naturally occurring proteins as well as recombinant or synthetically produced proteins. The term “polypeptide fragment” refers to a portion of a polypeptide, such as a fragment exhibiting at least one useful sequence on a receptor. The term “functional fragment of a polypeptide” refers to all fragments of a polypeptide that retain its activity. Biofunctional peptides may also include fusion proteins, where the peptide of interest has been fused with another peptide that does not diminish its desired activity.

[0099] Subcutaneous administration: Subcutaneous administration is the application of a substance to the subcutaneous layer of fat between the dermis and the underlying tissue. Subcutaneous administration can be performed using a subcutaneous injection needle, for example, mounted on a syringe or "pen" type injection device. Other administration methods, such as microneedles, can also be used. Subcutaneous injection typically involves a certain degree of pain for the recipient. This pain can be masked by using local anesthetics or analgesics. However, a common method for reducing perceived injection pain is to distract the subject immediately before and during the injection. Pain can be minimized by using relatively small-gauge subcutaneous injection needles, by injecting relatively small volumes of substance, and by avoiding excessively acidic or alkaline compositions that may cause a "tingling" sensation at the injection site. Compositions with a pH between pH 4 and pH 10 are generally considered tolerable and comfortable.

[0100] Therapeutic effective amount: A dose sufficient to prevent disease progression or cause disease remission, or a dose capable of alleviating the signs or symptoms of the disease, or a dose capable of achieving the desired outcome. In some embodiments, the therapeutically effective amount of the compound of the present invention is an amount sufficient to inhibit or prevent weight gain, or an amount sufficient to reduce appetite.

[0101] The compounds of the present invention

[0102] The inventors have discovered that the exemplary compounds of the present invention have properties including causing weight loss in the body. These compounds also have a long half-life in the blood, meaning they can be administered conveniently at low frequencies.

[0103] Compared to GIP and previous GIP derivatives, the compounds of the present invention have a substituent at a lysine residue at one of a plurality of positions in the peptide sequence, the substituted lysine being functionalized at its ε-amino group, and the substituent group comprising a peptide sequence of up to 4 residues terminating at a group R-R1, wherein R1 is CO2H.

[0104] These are functionalizations that have not been studied before, and the beneficial properties discovered by the inventors have not been found before.

[0105] As described above, the compounds of the present invention have formula (I):

[0106] Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Xaa10–Ser11–Xaa12–Xaa13 – 23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29–Xaa30–Xaa31–Xaa32–Xaa33– Xaa34–Xaa35–Xaa36–Xaa37–Xaa38–Xaa39–Xaa40–Thr41–Gln42–Xaa43 [SEQ ID NO:1]

[0107] in:

[0108] Xaa1 is DTyr, His, Phe, or Tyr, or does not exist;

[0109] Xaa2 is either AIB or Ala, or it does not exist;

[0110] Xaa3 is Asp, Gln, Glu, or His;

[0111] Xaa7 is Ile, Thr, or Ser;

[0112] Xaa10 is either Tyr or His;

[0113] Xaa12 is either Ile or Lys;

[0114] Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn;

[0115] Xaa14 is Leu, Met, or NLeu;

[0116] Xaa17 is either Gln or Ile;

[0117] Xaa18 is Ala, Arg, or His;

[0118] Xaa19 is either Ala or Gln;

[0119] Xaa20 is AIB, Gln, His, or Lys;

[0120] Xaa21 is Ala, Asp, or Glu;

[0121] Xaa24 is Asn, Gln, or Glu;

[0122] Xaa25 is Arg, His, Trp, or Tyr;

[0123] Xaa27 is either Ile or Leu;

[0124] Xaa28 is either Ala or Asn;

[0125] Xaa29 is Gln, Gly, or Thr;

[0126] Xaa30 is Gly, Lys, or Lys*, or does not exist;

[0127] Xaa31 is Arg, Gly, or Pro, or it does not exist;

[0128] Xaa32 is Asn, Lys, or Lys*, or does not exist;

[0129] Xaa33 is Lys or Lys*, or does not exist;

[0130] Xaa34 is either Asn or Lys*;

[0131] Xaa35 is either an Asp or does not exist;

[0132] Xaa36 is either Trp or Lys*, or it does not exist;

[0133] Xaa37 is Lys or Lys*, or does not exist;

[0134] Xaa38 is His or does not exist;

[0135] Xaa39 is either Asn or Lys*, or it does not exist;

[0136] Xaa40 is Ile, Leu, or Lys*, or does not exist;

[0137] Xaa43 is either Lys* or does not exist;

[0138] Lys* is Lys whose ε-amino group is replaced by a group of the following formula:

[0139] Z–Xaa44–Xaa45–Xaa46–Xaa47–

[0140] in:

[0141] Xaa44 is Gly, Ser, Thr or does not exist;

[0142] Xaa45 is Gly, Ser, or does not exist;

[0143] Xaa46 is Asn, Gln, Gly, Ser, Thr or does not exist;

[0144] Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr or does not exist;

[0145] And Z is a group of the following formula:

[0146] (i): Or (ii):

[0147] Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H;

[0148] Furthermore, the compounds of formula (I) or formula (II) contain a Lys* residue.

[0149] Considering the residues in turn,

[0150] Xaa1 is selected from DTyr, His, Phe, or Tyr, or Xaa1 may not exist. Preferably, Xaa1 is selected from His, Phe, and Tyr. For example, Xaa1 is selected from His and Tyr, or alternatively, Xaa1 is selected from Phe and Tyr. For example, Xaa1 is Tyr. In a particularly preferred embodiment, Xaa1 is Tyr.

[0151] Xaa2 is selected from AIB or Ala, or may not exist. Preferably, Xaa2 is AIB.

[0152] Xaa3 is selected from Asp, Gln, Glu, or His. Preferably, Xaa3 is selected from Glu and Gln. For example, Xaa3 is Glu. Alternatively, Xaa3 is Gln. In a particularly preferred embodiment, Xaa3 is Glu.

[0153] Xaa7 is selected from Ile, Thr, or Ser. In one embodiment, Xaa7 is selected from Ile or Thr. In another embodiment, Xaa7 is selected from Ile or Ser. Preferably, Xaa7 is Ile.

[0154] Xaa10 is selected from Tyr or His. Preferably, Xaa10 is Tyr.

[0155] Xaa12 is selected from Ile or Lys. Preferably, Xaa12 is Ile.

[0156] Xaa13 is selected from AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn. In one embodiment, Xaa13 is selected from AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, or Val. Preferably, Xaa13 is selected from Ala, Gln, Thr, and Val. For example, Xaa3 is selected from Ala, Gln, and Val. For example, Xaa13 is selected from Ala and Gln, or alternatively, Xaa13 is selected from Ala and Val. In a particularly preferred embodiment, Xaa13 is Ala.

[0157] In another embodiment, Xaa13 is selected from Ala, Asp, Asn, and Ser. In a particularly preferred embodiment, Xaa13 is Ala.

[0158] According to certain implementation schemes, Xaa7 is selected from Ile or Thr, Xaa10 is Tyr, Xaa12 is Ile and Xaa13 is selected from AlB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr or Val.

[0159] Xaa14 is selected from Leu, Met, or NLeu. Preferably, Xaa14 is Leu.

[0160] Xaa17 is selected from Gln or Ile. Preferably, Xaa17 is Ile.

[0161] Xaa18 is selected from Ala, Arg, or His. Preferably, Xaa18 is selected from Ala and His. For example, Xaa18 is His. Alternatively, Xaa18 is Ala. In a particularly preferred embodiment, Xaa18 is His.

[0162] Xaa19 is selected from Ala or Gln. Preferably, Xaa19 is Gln.

[0163] Xaa20 is selected from AIB, Gln, His, or Lys. Preferably, Xaa20 is selected from AIB, Gln, and His. For example, Xaa20 is selected from AIB and Gln, or alternatively, Xaa20 is selected from Gln and His. In a particularly preferred embodiment, Xaa20 is Gln.

[0164] Xaa21 is selected from Ala, Asp, or Glu. Preferably, Xaa21 is selected from Asp and Glu. For example, Xaa21 is Asp. Alternatively, Xaa21 is Glu. In a particularly preferred embodiment, Xaa21 is Asp.

[0165] Xaa24 is selected from Asn, Gln, or Glu. Preferably, Xaa24 is selected from Asn and Gln. For example, Xaa24 is Asn. Alternatively, Xaa24 is Gln. In a particularly preferred embodiment, Xaa24 is Asn.

[0166] Xaa25 is selected from Arg, His, Trp, or Tyr. Preferably, Xaa25 is Trp.

[0167] Xaa27 is selected from Ile or Leu. Preferably, Xaa27 is Leu.

[0168] Xaa28 is selected from Ala or Asn. Preferably, Xaa28 is Ala.

[0169] Xaa29 is selected from Gln, Gly, or Thr. Preferably, Xaa29 is selected from Gln and Gly. For example, Xaa29 is Gln. Alternatively, Xaa29 is Gly. In a particularly preferred embodiment, Xaa29 is Gln.

[0170] Xaa30 is selected from Gly, Lys, or Lys*, or Xaa30 is not present. Preferably, Xaa30 is selected from Lys and Gly. For example, Xaa30 is Lys. Alternatively, Xaa30 is Gly. In a particularly preferred embodiment, Xaa30 is Lys.

[0171] Xaa31 is selected from Arg, Gly, or Pro, or Xaa31 may not exist. Preferably, Xaa31 is selected from Gly and Pro. For example, Xaa31 is Gly. Alternatively, Xaa31 is Pro. In a particularly preferred embodiment, Xaa31 is Gly.

[0172] Xaa32 is selected from Asn, Lys, or Lys*, or Xaa32 is not present. Preferably, Xaa32 is selected from Asn, Lys, and Lys*. For example, Xaa32 is selected from Lys and Lys*. Alternatively, Xaa32 is selected from Asn and Lys*. In a particularly preferred embodiment, Xaa32 is Lys*.

[0173] Xaa33 is Lys or Lys*; or Xaa33 does not exist. Preferably, Xaa33 is selected from Lys and Lys*. Alternatively, Xaa33 is Lys or does not exist. In a particularly preferred embodiment, Xaa33 is Lys.

[0174] Xaa34 is either Asn or Lys*; or Xaa34 does not exist. Preferably, Xaa34 is selected from Asn and Lys*, or Xaa34 does not exist. For example, Xaa34 is selected from Asn and Lys*. Alternatively, Xaa34 is Asn or does not exist. In a particularly preferred embodiment, Xaa34 is Asn.

[0175] Xaa35 is Asp; or Xaa35 does not exist. For example, Xaa35 is Asp. Alternatively, Xaa35 does not exist. In a preferred embodiment, Xaa35 is Asp.

[0176] Xaa36 is Trp or Lys*; or Xaa36 does not exist. Preferably, Xaa36 is Trp or does not exist. For example, Xaa36 is Trp. Alternatively, Xaa36 does not exist. In a particularly preferred embodiment, Xaa35 is Trp.

[0177] Xaa37 is Lys or Lys*; or Xaa37 does not exist. Preferably, Xaa37 is Lys or does not exist. For example, Xaa37 is Lys. Alternatively, Xaa37 does not exist. In a particularly preferred embodiment, Xaa37 is Lys.

[0178] Xaa38 is His, or Xaa38 does not exist. For example, Xaa38 is His. Alternatively, Xaa38 does not exist. In a particularly preferred embodiment, Xaa38 is His.

[0179] Xaa39 is Asn or Lys*; or Xaa39 does not exist. Preferably, Xaa39 is Asn or does not exist. For example, Xaa39 is Asn. Alternatively, Xaa39 does not exist. In a particularly preferred embodiment, Xaa39 is Asn.

[0180] Xaa40 is Ile, Leu, or Lys*; or Xaa40 does not exist. Preferably, Xaa40 is Ile or does not exist. For example, Xaa40 is Ile. Alternatively, Xaa40 does not exist. In a particularly preferred embodiment, Xaa40 is Ile.

[0181] Xaa41 is Thr, or Xaa41 does not exist. Preferably, Xaa41 is Thr.

[0182] Xaa42 is Gln, or Xaa42 does not exist. Preferably, Xaa42 is Gln.

[0183] Xaa43 is Lys*, or Xaa43 does not exist. Preferably, Xaa43 does not exist.

[0184] Linkage of Lys* substituents

[0185] In the compounds of this invention, the ε-amino group on Lys* is attached to the α-acid group of the Xaa47 residue of the molecule, such that the bond is an amide bond. If Xaa47 is absent, the ε-amino group on Lys* is attached to the α-acid group of the next present residue, or if no residue is present, it is attached to the α-acid group of the Z group.

[0186] In lysine residues, the ε-amino group is an amino group attached to the 6-carbon. According to standard IUPAC nomenclature, the atoms in lysine are numbered as follows, indicating the carbon atom number and the α to ε positions:

[0187]

[0188] The ε-amino group on Lys* in this paper refers to the amino group on the C-6 carbon atom shown.

[0189] According to the present invention, the substituent can be attached to a Lys residue at any position in the peptide sequence indicated by Lys* in formula (I). That is, the substituent can be attached to a Lys residue at one of positions Xaa30, Xaa32, Xaa33, Xaa34, Xaa36, Xaa37, Xaa39, Xaa40, or Xaa43. Preferred positions are selected from Xaa30, Xaa32, Xaa33, Xaa34, and Xaa43, for example, Xaa32, Xaa33, and Xaa43. In a particularly preferred embodiment, the substituent is attached to a Lys residue at position Xaa32.

[0190] The substituent groups in the compounds of this invention have the following formula:

[0191] Z–Xaa44–Xaa45–Xaa46–Xaa47–

[0192] Consider each residue in turn:

[0193] Xaa44 is selected from Gly, Ser, and Thr; or Xaa44 is not present. Preferably, Xaa44 is Thr, or Xaa44 is not present. For example, Xaa44 is Thr, or alternatively, Xaa44 is not present. In a particularly preferred embodiment, Xaa44 is not present.

[0194] Xaa45 is selected from Gly and Ser; or Xaa45 is not present. For example, Xaa45 is Gly or is not present. Alternatively, Xaa45 is Ser or is not present. Preferably, Xaa45 is Gly or is not present. In a particularly preferred embodiment, Xaa45 is not present.

[0195] Xaa46 is selected from Asn, Gln, Gly, Ser, and Thr; or Xaa46 is not present. Preferably, Xaa46 is selected from Asn, Gly, Ser, and Thr; or Xaa46 is not present. More preferably, Xaa46 is selected from Asn, Gly, and Ser; or Xaa46 is not present. For example, Xaa46 is selected from Asn and Ser; or Xaa46 is not present. Alternatively, Xaa46 is selected from Gly and Ser; or Xaa46 is not present. In a more preferred embodiment, Xaa46 is Ser or is not present. In a particularly preferred embodiment, Xaa46 is not present.

[0196] Xaa47 is selected from Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, and Thr; or Xaa47 is absent. Preferably, Xaa47 is selected from Gly, Gln, His, and Lys; or Xaa47 is absent. More preferably, Xaa47 is selected from Gly and Lys; or Xaa47 is absent. In a preferred embodiment, Xaa47 is Lys or is absent. In a particularly preferred embodiment, Xaa47 is Lys.

[0197] Group Z

[0198] The Z part of the compound is a group of the following formula:

[0199] (i): Or (ii): Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H.

[0200] Within the Z portion of the molecule, group R is an alkylene or alkenylene chain that is attached at one end to residue Xaa44 via an amide bond through a Glu residue (or, if Xaa44 is absent, then Xaa45, or if neither Xaa44 nor Xaa45 is present, then Xaa46, etc.; if all Xaa44- through Xaa47 are absent, then R is attached at one end to Lys*). At its other end, the alkylene or alkenylene chain R is attached to an acid group R1 (CO2H).

[0201] Option (i) above indicates the case where the Glu residue in the Z group is linked to the Lys* residue via a γ-carboxylic acid group of Glu. Option (ii) above indicates the case where the Glu residue in the Z group is linked to the Lys* residue via an α-carboxylic acid group of Glu. In a preferred embodiment of the invention, the Z portion of the compound has formula (i), i.e., the Glu residue in the Z group is linked to the Lys* residue via a γ-carboxylic acid group of Glu.

[0202] Typically, R has an even number of carbon atoms. For example, R can be an alkylene or alkenylene chain found in naturally occurring fatty acids. The chain length of root fatty acids is twice as long as the number of carbon atoms in the alkylene or alkenylene chain of R.

[0203] In a preferred embodiment, R is C 16 –C 18 Alkylene or alkenylene group. For example, R is a straight-chain alkylene or alkenylene group. For example, R is C 16 Or C 18 Straight-chain alkylene. For example, when R is C 16 When R is a group, it can be provided by the octadecanoic acid moiety. For example, when R is C 18 When the group is present, it can be provided by the eicosanoic acid moiety.

[0204] In a more preferred embodiment, R is C 18 Alkylene group.

[0205] In one embodiment of the present invention, it is preferred that:

[0206] Xaa1 is DTyr, His, Phe, or Tyr, or does not exist;

[0207] Xaa2 is either AIB or Ala, or it does not exist;

[0208] Xaa3 is Asp, Gln, Glu, or His;

[0209] Xaa7 is either Ile or Thr;

[0210] Xaa10 is Tyr;

[0211] Xaa12 is Ile;

[0212] Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, or Val;

[0213] Xaa14 is Leu, Met, or NLeu;

[0214] Xaa17 is either Gln or Ile;

[0215] Xaa18 is Ala, Arg, or His;

[0216] Xaa19 is either Ala or Gln;

[0217] Xaa20 is AIB, Gln, His, or Lys;

[0218] Xaa21 is Ala, Asp, or Glu;

[0219] Xaa24 is Asn, Gln, or Glu;

[0220] Xaa25 is Arg, His, Trp, or Tyr;

[0221] Xaa27 is either Ile or Leu;

[0222] Xaa28 is either Ala or Asn;

[0223] Xaa29 is Gln, Gly, or Thr;

[0224] Xaa30 is Gly, Lys, or Lys*, or does not exist;

[0225] Xaa31 is Arg, Gly, or Pro, or it does not exist;

[0226] Xaa32 is Asn, Lys, or Lys*, or does not exist;

[0227] Xaa33 is Lys or Lys*, or does not exist;

[0228] Xaa34 is either Asn or Lys*;

[0229] Xaa35 is either an Asp or does not exist;

[0230] Xaa36 is either Trp or Lys*, or it does not exist;

[0231] Xaa37 is Lys or Lys*, or does not exist;

[0232] Xaa38 is His or does not exist;

[0233] Xaa39 is either Asn or Lys*, or it does not exist;

[0234] Xaa40 is Ile, Leu, or Lys*, or does not exist;

[0235] Xaa43 is either Lys* or does not exist;

[0236] Lys* is Lys whose ε-amino group is replaced by a group of the following formula:

[0237] Z–Xaa44–Xaa45–Xaa46–Xaa47–

[0238] in:

[0239] Xaa44 is Gly, Ser, Thr or does not exist;

[0240] Xaa45 is Gly, Ser, or does not exist;

[0241] Xaa46 is Asn, Gln, Gly, Ser, Thr or does not exist;

[0242] Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr or does not exist;

[0243] And Z is a group of the following formula:

[0244] (i): Or (ii):

[0245] Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H;

[0246] Furthermore, the compounds of formula (I) or formula (II) contain a Lys* residue.

[0247] In one embodiment of the present invention, it is preferred that:

[0248] Xaa1 is His, Phe, or Tyr;

[0249] Xaa2 is an AIB;

[0250] Xaa3 is Glu, Gln, or His;

[0251] Xaa7 is Ile;

[0252] Xaa10 is Tyr;

[0253] Xaa12 is Ile;

[0254] Xaa13 is Ala, Gln, Thr, or Val;

[0255] Xaa14 is either Leu or Met;

[0256] Xaa17 is either Gln or Ile;

[0257] Xaa18 is either Ala or His;

[0258] Xaa19 is either Ala or Gln;

[0259] Xaa20 is AIB, Gln, His, or Lys;

[0260] Xaa21 is either Asp or Glu;

[0261] Xaa24 is Asn, Gln, or Glu;

[0262] Xaa25 is a Trp;

[0263] Xaa27 is Leu;

[0264] Xaa28 is either Ala or Asn;

[0265] Xaa29 is Gln, Gly, or Thr;

[0266] Xaa30 is Gly, Lys, or Lys*;

[0267] Xaa31 is Arg, Gly, or Pro;

[0268] Xaa32 is Asn, Lys, or Lys*;

[0269] Xaa33 is Lys or Lys*; or Xaa33 does not exist.

[0270] Xaa34 is either Asn or Lys*; or Xaa34 does not exist.

[0271] Xaa35 is Asp; or Xaa35 does not exist; Xaa36 is Trp; or Xaa36 does not exist; Xaa37 is Lys; or Xaa37 does not exist; Xaa38 is His; or Xaa38 does not exist; Xaa39 is Asn; or Xaa39 does not exist; Xaa40 is Ile; or Xaa40 does not exist; Xaa41 is Thr; or Xaa41 does not exist; Xaa42 is Gln; or Xaa42 does not exist; Xaa43 is Lys*; or Xaa43 does not exist; Z is (i): Where R is C 16 Or C 18 Alkylene chain and R1 is –CO2H;

[0272] Xaa44 is Thr, or Xaa44 does not exist;

[0273] Xaa45 is Gly, or Xaa45 does not exist;

[0274] Xaa46 is Asn, Gly, or Ser, or Xaa46 does not exist; and

[0275] Xaa47 is either Gly or Lys, or Xaa47 does not exist.

[0276] In a more preferred embodiment:

[0277] Xaa1 is Tyr;

[0278] Xaa2 is an AIB;

[0279] Xaa3 is either Glu or Gln;

[0280] Xaa7 is Ile;

[0281] Xaa10 is Tyr;

[0282] Xaa12 is Ile;

[0283] Xaa13 is Ala;

[0284] Xaa14 is Leu;

[0285] Xaa17 is Ile;

[0286] Xaa18 is His;

[0287] Xaa19 is Gln;

[0288] Xaa20 is either Gln or Lys;

[0289] Xaa21 is an Asp;

[0290] Xaa24 is either Asn or Gln;

[0291] Xaa27 is Leu;

[0292] Xaa28 is Ala;

[0293] Xaa29 is either Gln or Gly;

[0294] Xaa30 is either Gly or Lys;

[0295] Xaa31 is either Gly or Pro;

[0296] Xaa32 is Lys or Lys*;

[0297] Xaa33 is Lys or Lys*;

[0298] Xaa34 is an Asn; or Xaa34 does not exist.

[0299] Xaa35 is an Asp; or Xaa35 does not exist.

[0300] Xaa36 is a Trp; or Xaa36 does not exist.

[0301] Xaa37 is Lys; or Xaa37 does not exist.

[0302] Xaa38 is His; or Xaa38 does not exist;

[0303] Xaa39 is an Asn; or Xaa39 does not exist.

[0304] Xaa40 is Ile; or Xaa40 does not exist;

[0305] Xaa41 is Thr; or Xaa41 does not exist;

[0306] Xaa42 is Gln, or Xaa42 does not exist;

[0307] Xaa43 is Lys*; or Xaa43 does not exist.

[0308] Z is (i): Where R is C 18 Alkylene chain and R1 is –CO2H;

[0309] Xaa44 does not exist;

[0310] Xaa45 does not exist;

[0311] Xaa46 is Ser, or Xaa46 does not exist; and

[0312] Xaa47 is Lys, or Xaa47 does not exist.

[0313] For example, in such implementations:

[0314] Xaa3 is Glu;

[0315] Xaa20 is Gln;

[0316] Xaa24 is an Asn;

[0317] Xaa29 is Gln;

[0318] Xaa30 is Lys;

[0319] Xaa31 is Gly;

[0320] Xaa32 is Lys*;

[0321] Xaa33 is Lys;

[0322] Xaa34 is an Asn;

[0323] Xaa35 is an Asp;

[0324] Xaa36 is a Trp;

[0325] Xaa37 is Lys;

[0326] Xaa38 is His;

[0327] Xaa39 is an Asn;

[0328] Xaa40 is Ile;

[0329] Xaa41 is Thr;

[0330] Xaa42 is Gln.

[0331] Xaa43 does not exist;

[0332] Xaa46 does not exist; and

[0333] Xaa47 is either Lys or does not exist.

[0334] In such an implementation, Xaa47 is even more preferably Lys.

[0335] In another embodiment of the invention, it is preferred that:

[0336] Xaa1 is His, Phe, or Tyr;

[0337] Xaa2 is an AIB;

[0338] Xaa3 is Glu, Gln, or His;

[0339] Xaa7 is either Ile or Ser;

[0340] Xaa10 is either Tyr or His;

[0341] Xaa12 is either Ile or Lys;

[0342] Xaa13 is Ala, Asp, Asn, Gln, Ser, Thr, or Val; Xaa14 is Leu or Met;

[0343] Xaa17 is either Gln or Ile;

[0344] Xaa18 is either Ala or His;

[0345] Xaa19 is either Ala or Gln;

[0346] Xaa20 is AIB, Gln, His, or Lys;

[0347] Xaa21 is either Asp or Glu;

[0348] Xaa24 is Asn, Gln, or Glu;

[0349] Xaa25 is a Trp;

[0350] Xaa27 is Leu;

[0351] Xaa28 is either Ala or Asn;

[0352] Xaa29 is Gln, Gly, or Thr;

[0353] Xaa30 is Gly, Lys, or Lys*;

[0354] Xaa31 is Arg, Gly, or Pro;

[0355] Xaa32 is Asn, Lys, or Lys*;

[0356] Xaa33 is Lys or Lys*; or Xaa33 does not exist.

[0357] Xaa34 is either Asn or Lys*; or Xaa34 does not exist.

[0358] Xaa35 is an Asp; or Xaa35 does not exist.

[0359] Xaa36 is a Trp; or Xaa36 does not exist.

[0360] Xaa37 is Lys; or Xaa37 does not exist.

[0361] Xaa38 is His; or Xaa38 does not exist;

[0362] Xaa39 is an Asn; or Xaa39 does not exist.

[0363] Xaa40 is Ile; or Xaa40 does not exist;

[0364] Xaa41 is Thr; or Xaa41 does not exist;

[0365] Xaa42 is Gln, or Xaa42 does not exist;

[0366] Xaa43 is Lys*; or Xaa43 does not exist.

[0367] Z is (i): Where R is C 16 Or C 18 Alkylene chain and R1 is –CO2H;

[0368] Xaa44 is Thr, or Xaa44 does not exist;

[0369] Xaa45 is Gly, or Xaa45 does not exist;

[0370] Xaa46 is Asn, Gly, or Ser, or Xaa46 does not exist; and

[0371] Xaa47 is either Gly or Lys, or Xaa47 does not exist.

[0372] For example, in such implementations:

[0373] Xaa1 is Tyr;

[0374] Xaa2 is AlB;

[0375] Xaa3 is Glu;

[0376] Xaa7 is either Ile or Ser;

[0377] Xaa10 is either Tyr or His;

[0378] Xaa12 is either Ile or Lys;

[0379] Xaa13 is Asp, Asn, Ala, or Ser;

[0380] Xaa14 is Leu;

[0381] Xaa17 is Ile;

[0382] Xaa18 is His;

[0383] Xaa19 is Gln;

[0384] Xaa20 is Gln;

[0385] Xaa21 is an Asp;

[0386] Xaa24 is an Asn;

[0387] Xaa25 is a Trp;

[0388] Xaa27 is Leu;

[0389] Xaa28 is Ala;

[0390] Xaa29 is Gln;

[0391] Xaa30 is Lys;

[0392] Xaa31 is Gly;

[0393] Xaa32 is Lys;

[0394] Xaa33 is either Lys* or does not exist;

[0395] Xaa34 is either Lys* or does not exist;

[0396] Xaa35 does not exist;

[0397] Xaa36 does not exist;

[0398] Xaa37 does not exist;

[0399] Xaa38 does not exist;

[0400] Xaa39 does not exist;

[0401] Xaa40 does not exist;

[0402] Xaa41 does not exist;

[0403] Xaa42 does not exist;

[0404] Xaa43 does not exist;

[0405] Z is (i):

[0406] Where R is C 18 Alkylene chain and R1 is –CO2H;

[0407] Xaa44 does not exist;

[0408] Xaa45 does not exist;

[0409] Xaa46 is an Asn or does not exist; and

[0410] Xaa47 is either Lys or His, or it does not exist. For example, Xaa47 is either Lys or His.

[0411] As another example:

[0412] Xaa7 is Ile;

[0413] Xaa10 is Tyr;

[0414] Xaa12 is either Ile or Lys;

[0415] Xaa13 is either Ala or Asp;

[0416] Xaa33 is Lys*;

[0417] Xaa34 does not exist;

[0418] Xaa46 does not exist; and

[0419] Xaa47 is either Lys or does not exist. For example, Xaa47 is Lys.

[0420] In an embodiment of the first aspect of the invention, compounds of formula (I) or formula (II) are provided:

[0421] WX(I) or WY(II)

[0422] in

[0423] W is the amino acid sequence:

[0424] Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Xaa10–Ser11–Xaa12–Xaa13–Xaa14–Asp15–Lys 16–Xaa17–Xaa18–Xaa19–Xaa20–Xaa21–Phe22–Val23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29–[SEQ ID NO:7]

[0425] in:

[0426] Xaa1 is DTyr, His, Phe, or Tyr, or does not exist;

[0427] Xaa2 is either AIB or Ala, or it does not exist;

[0428] Xaa3 is Asp, Gln, Glu, or His;

[0429] Xaa7 is Ile, Thr, or Ser;

[0430] Xaa10 is either Tyr or His;

[0431] Xaa12 is either Ile or Lys;

[0432] Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn;

[0433] Xaa14 is Leu, Met, or NLeu;

[0434] Xaa17 is either Gln or Ile;

[0435] Xaa18 is Ala, Arg, or His;

[0436] Xaa19 is either Ala or Gln;

[0437] Xaa20 is AIB, Gln, His, or Lys;

[0438] Xaa21 is Ala, Asp, or Glu;

[0439] Xaa24 is Asn, Gln, or Glu;

[0440] Xaa25 is Arg, His, Trp, or Tyr;

[0441] Xaa27 is either Ile or Leu;

[0442] Xaa28 is either Ala or Asn; and

[0443] Xaa29 is Gln, Gly, or Thr;

[0444] X, when present, is an amino acid sequence:

[0445] –Xaa30–Xaa31–Xaa32–Xaa33–Asn34–Asp35–Xaa36–Xaa37–His38–Xaa39–Xaa40–Thr41–Gln42–Xaa43 [SEQ ID NO:8]

[0446] in:

[0447] Xaa30 is Gly, Lys, or Lys*;

[0448] Xaa31 is either Gly or Pro;

[0449] Xaa32 is Lys or Lys*;

[0450] Xaa33 is Lys or Lys*;

[0451] Xaa36 is either Trp or Lys*;

[0452] Xaa37 is Lys or Lys*;

[0453] Xaa39 is either Asn or Lys*;

[0454] Xaa40 is Ile, Leu, or Lys*; and

[0455] Xaa43 is either Lys* or does not exist;

[0456] Y, when present, is an amino acid sequence:

[0457] –Xaa30–Xaa31–Xaa32–Xaa33–Xaa34

[0458] in:

[0459] Xaa30 is Gly or Lys, or it does not exist;

[0460] Xaa31 is Arg, Gly, or Pro, or it does not exist;

[0461] Xaa32 is either Asn or Lys, or it does not exist;

[0462] Xaa33 is Lys, Lys*, or does not exist;

[0463] Xaa34 is either Lys* or does not exist;

[0464] Lys* is Lys whose ε-amino group is replaced by a group of the following formula: Z–Xaa44–Xaa45–Xaa46–Xaa47–

[0465] in:

[0466] Xaa44 is Gly, Ser, or Thr, or does not exist;

[0467] Xaa45 is Gly or Ser, or it does not exist;

[0468] Xaa46 is Asn, Gln, Gly, Ser, or Thr, or does not exist;

[0469] Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, or Thr, or does not exist;

[0470] And Z is a group of the following formula:

[0471] (i): Or (ii):

[0472] Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H;

[0473] Furthermore, the compounds of formula (I) or formula (II) contain a Lys* residue;

[0474] Or a derivative of the compound; or a salt or solvation of the compound or its derivative. In some embodiments of the invention, the compound is a compound of formula (I):

[0475] W–X(I)

[0476] Where W is the amino acid sequence:

[0477] Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Tyr10–Ser11–Ile12–Xaa13–Xaa14–Asp15–Lys 16–Xaa17–Xaa18–Xaa19–Xaa20–Xaa21–Phe22–Val23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29–[SEQ ID NO:9]

[0478] in:

[0479] Xaa1 is DTyr, His, Phe, or Tyr, or does not exist;

[0480] Xaa2 is either AIB or Ala, or it does not exist;

[0481] Xaa3 is Asp, Gln, Glu, or His;

[0482] Xaa7 is either Ile or Thr;

[0483] Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, or Val;

[0484] Xaa14 is Leu, Met, or NLeu;

[0485] Xaa17 is either Gln or Ile;

[0486] Xaa18 is Ala, Arg, or His;

[0487] Xaa19 is either Ala or Gln;

[0488] Xaa20 is AIB, Gln, His, or Lys;

[0489] Xaa21 is Ala, Asp, or Glu;

[0490] Xaa24 is Asn, Gln, or Glu;

[0491] Xaa25 is Arg, His, Trp, or Tyr;

[0492] Xaa27 is either Ile or Leu;

[0493] Xaa28 is either Ala or Asn; and

[0494] Xaa29 is Gln, Gly, or Thr;

[0495] And X is an amino acid sequence:

[0496] –Xaa30–Xaa31–Xaa32–Xaa33–Asn34–Asp35–Xaa36–Xaa37–His38–Xaa39–Xaa40–Thr41–Gln42–Xaa43 [SEQ ID NO:8]

[0497] in:

[0498] Xaa30 is Gly, Lys, or Lys*;

[0499] Xaa31 is either Gly or Pro;

[0500] Xaa32 is Lys or Lys*;

[0501] Xaa33 is Lys or Lys*;

[0502] Xaa36 is either Trp or Lys*;

[0503] Xaa37 is Lys or Lys*;

[0504] Xaa39 is either Asn or Lys*;

[0505] Xaa40 is Ile, Leu, or Lys*; and

[0506] Xaa43 is either Lys* or does not exist.

[0507] In a preferred embodiment, when the compound of the present invention is a compound of formula (I),

[0508] Xaa1 is His, Phe, or Tyr;

[0509] Xaa2 is an AIB;

[0510] Xaa3 is Gln, Glu, or His;

[0511] Xaa7 is Ile;

[0512] Xaa13 is Ala, Gln, Thr, or Val;

[0513] Xaa14 is either Leu or Met;

[0514] Xaa17 is either Gln or Ile;

[0515] Xaa18 is either Ala or His;

[0516] Xaa19 is either Ala or Gln;

[0517] Xaa20 is AIB, Gln, His, or Lys;

[0518] Xaa21 is either Asp or Glu;

[0519] Xaa24 is Asn, Gln, or Glu;

[0520] Xaa25 is a Trp;

[0521] Xaa27 is Leu;

[0522] Xaa28 is either Ala or Asn; and

[0523] Xaa29 is Gln, Gly, or Thr.

[0524] In such an implementation plan, an even better option is:

[0525] Xaa1 is Tyr;

[0526] Xaa2 is an AIB;

[0527] Xaa3 is Glu or Gln; and preferably Glu;

[0528] Xaa7 is Ile;

[0529] Xaa13 is Ala;

[0530] Xaa14 is Leu;

[0531] Xaa17 is Ile;

[0532] Xaa18 is His;

[0533] Xaa19 is Gln;

[0534] Xaa20 is Gln or Lys; and preferably Gln;

[0535] Xaa21 is an Asp;

[0536] Xaa24 is either Asn or Gln; and preferably Asn;

[0537] Xaa25 is a Trp;

[0538] Xaa27 is Leu;

[0539] Xaa28 is Ala; and

[0540] Xaa29 is Gln or Gly; and preferably Gln.

[0541] In a preferred embodiment, when the compound of the present invention is a compound of formula (I), Xaa30 is Lys or Lys*;

[0542] Xaa31 is Gly;

[0543] Xaa32 is Lys or Lys*;

[0544] Xaa33 is Lys or Lys*;

[0545] Xaa36 is either Trp or Lys*;

[0546] Xaa37 is Lys or Lys*;

[0547] Xaa39 is either Asn or Lys*;

[0548] Xaa40 is either Ile or Lys*; and

[0549] Xaa43 is either Lys* or does not exist.

[0550] In such an implementation plan, an even better option is:

[0551] Xaa30 is Lys;

[0552] Xaa32 is Lys*;

[0553] Xaa33 is Lys;

[0554] Xaa36 is a Trp;

[0555] Xaa37 is Lys;

[0556] Xaa39 is an Asn;

[0557] Xaa40 is Ile; and

[0558] Xaa43 does not exist.

[0559] In some embodiments of the present invention, the compound is a compound of formula (II):

[0560] W–Y(II)

[0561] Where W is the amino acid sequence:

[0562] Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Tyr10–Ser11–Ile12–Xaa13–Xaa14–Asp15–Lys 16–Xaa17–Xaa18–Xaa19–Xaa20–Xaa21–Phe22–Val23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29–[SEQ ID NO:9]

[0563] in:

[0564] Xaa1 is DTyr, His, Phe, or Tyr, or does not exist;

[0565] Xaa2 is either AIB or Ala, or it does not exist;

[0566] Xaa3 is Asp, Gln, Glu, or His;

[0567] Xaa7 is either Ile or Thr;

[0568] Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, or Val;

[0569] Xaa14 is Leu, Met, or NLeu;

[0570] Xaa17 is either Gln or Ile;

[0571] Xaa18 is Ala, Arg, or His;

[0572] Xaa19 is either Ala or Gln;

[0573] Xaa20 is AIB, Gln, His, or Lys;

[0574] Xaa21 is Ala, Asp, or Glu;

[0575] Xaa24 is Asn, Gln, or Glu;

[0576] Xaa25 is Arg, His, Trp, or Tyr;

[0577] Xaa27 is either Ile or Leu;

[0578] Xaa28 is either Ala or Asn; and

[0579] Xaa29 is Gln, Gly, or Thr;

[0580] And Y is the amino acid sequence:

[0581] –Xaa30–Xaa31–Xaa32–Xaa33–Xaa34

[0582] in:

[0583] Xaa30 is Gly or Lys, or it does not exist;

[0584] Xaa31 is Arg, Gly, or Pro, or it does not exist;

[0585] Xaa32 is either Asn or Lys, or it does not exist;

[0586] Xaa33 is either Lys or does not exist; and

[0587] Xaa34 is Lys*.

[0588] In another embodiment, when the compound of the present invention is a compound of formula (II),

[0589] Xaa1 is Tyr;

[0590] Xaa2 is AlB;

[0591] Xaa3 is Glu;

[0592] Xaa7 is Ile, Ser, or Thr;

[0593] Xaa10 is either Tyr or His;

[0594] Xaa12 is either Ile or Lys;

[0595] Xaa13 is AIB, Ala, Asn, Asp, Ser, or Tyr;

[0596] Xaa14 is Leu;

[0597] Xaa17 is either Gln or Ile;

[0598] Xaa18 is either Ala or His;

[0599] Xaa19 is either Ala or Gln;

[0600] Xaa20 is AIB, Gln, or Lys;

[0601] Xaa21 is Ala, Asp, or Glu;

[0602] Xaa24 is Asn, Gln, or Glu;

[0603] Xaa25 is Arg, His, Trp, or Tyr;

[0604] Xaa27 is either Ile or Leu;

[0605] Xaa28 is either Ala or Asn;

[0606] Xaa29 is Gln, Gly, or Thr;

[0607] Xaa30 is Gly or Lys, or it does not exist;

[0608] Xaa31 is Arg, Gly, or Pro, or it does not exist;

[0609] Xaa32 is either Asn or Lys, or it does not exist;

[0610] Xaa33 is either Lys or does not exist; and

[0611] Xaa34 is Lys*.

[0612] In a preferred embodiment, when the compound of the present invention is a compound of formula (I),

[0613] Xaa1 is His, Phe, or Tyr;

[0614] Xaa2 is an AIB;

[0615] Xaa3 is Gln, Glu, or His;

[0616] Xaa7 is Ile;

[0617] Xaa13 is Ala, Gln, Thr, or Val;

[0618] Xaa14 is either Leu or Met;

[0619] Xaa17 is either Gln or Ile;

[0620] Xaa18 is either Ala or His;

[0621] Xaa19 is either Ala or Gln;

[0622] Xaa20 is AIB, Gln, His, or Lys;

[0623] Xaa21 is either Asp or Glu;

[0624] Xaa24 is Asn, Gln, or Glu;

[0625] Xaa25 is a Trp;

[0626] Xaa27 is Leu;

[0627] Xaa28 is either Ala or Asn; and

[0628] Xaa29 is Gln, Gly, or Thr.

[0629] In such an implementation plan, an even better option is:

[0630] Xaa1 is Tyr;

[0631] Xaa2 is an AIB;

[0632] Xaa3 is Glu or Gln; and preferably Glu;

[0633] Xaa7 is Ile;

[0634] Xaa13 is Ala;

[0635] Xaa14 is Leu;

[0636] Xaa17 is Ile;

[0637] Xaa18 is His;

[0638] Xaa19 is Gln;

[0639] Xaa20 is Gln or Lys; and preferably Gln;

[0640] Xaa21 is an Asp;

[0641] Xaa24 is either Asn or Gln; and preferably Asn;

[0642] Xaa25 is a Trp;

[0643] Xaa27 is Leu;

[0644] Xaa28 is Ala; and

[0645] Xaa29 is Gln or Gly; and preferably Gln.

[0646] In a preferred embodiment, when the compound of the present invention is a compound of formula (II),

[0647] Xaa30 is either Lys or Gly;

[0648] Xaa31 is either Gly or Pro;

[0649] Xaa32 is either Lys or does not exist;

[0650] Xaa33 does not exist; and

[0651] Xaa34 is Lys*.

[0652] In such an implementation plan, an even better option is:

[0653] Xaa30 is Lys;

[0654] Xaa31 is Gly;

[0655] Xaa32 does not exist;

[0656] Xaa33 does not exist; and

[0657] Xaa34 is Lys*.

[0658] In a preferred embodiment, when the compound of the present invention is a compound of formula (II),

[0659] Xaa1 is Tyr;

[0660] Xaa2 is AlB;

[0661] Xaa3 is Glu;

[0662] Xaa7 is either Ile or Ser;

[0663] Xaa10 is either Tyr or His;

[0664] Xaa12 is either Ile or Lys;

[0665] Xaa13 is Asp, Asn, Ala, or Ser;

[0666] Xaa14 is Leu;

[0667] Xaa17 is Ile;

[0668] Xaa18 is His;

[0669] Xaa19 is Gln;

[0670] Xaa20 is Gln;

[0671] Xaa21 is an Asp;

[0672] Xaa24 is an Asn;

[0673] Xaa25 is a Trp;

[0674] Xaa27 is Leu;

[0675] Xaa28 is Ala;

[0676] Xaa29 is Gln;

[0677] Xaa30 is Lys;

[0678] Xaa31 is Gly;

[0679] Xaa32 is Lys;

[0680] Xaa33 is either Lys or does not exist; and

[0681] Xaa34 is Lys*;

[0682] Lys* is Lys whose ε-amino group is replaced by a group of the following formula: Z–Xaa44–Xaa45–Xaa46–Xaa47–

[0683] in:

[0684] Xaa44 does not exist;

[0685] Xaa45 does not exist;

[0686] Xaa46 is an Asn or does not exist; and

[0687] Xaa47 is either Lys or His;

[0688] Z is (i):

[0689] Where R is C 18 Alkylene chain and R1 is –CO2H;

[0690] For example,

[0691] Xaa10 is Tyr;

[0692] Xaa12 is either Ile or Lys;

[0693] Xaa13 is either Ala or Asp;

[0694] Xaa33 does not exist;

[0695] Xaa34 is Lys*;

[0696] Xaa46 does not exist; and

[0697] Xaa47 is Lys.

[0698] In a particularly preferred embodiment, the compound is Figure 1 One of the compounds of the present invention is listed in the table.

[0699] Derivatives and salts

[0700] The present invention provides compounds of formula (I), derivatives of such compounds, and salts or solvates of such compounds and derivatives.

[0701] The compounds, derivatives, and salts can be generated by recombination methods known in the art, or alternatively, by synthetic methods known in the art.

[0702] derivative

[0703] Although in some embodiments the invention relates to compounds of formula (I) rather than derivatives, in other embodiments the invention relates to derivatives of compounds of formula (I). The derivative may, for example, comprise one or more derivatizations selected from: amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, esterification, PEGylation, and fusion with another peptide or protein to form a fusion protein, such as the derivative comprising one or more derivatizations selected from: amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, esterification, and PEGylation. The structure may be modified at random positions within the molecule or at predetermined positions within the molecule, and may comprise one, two, three, or more linked chemical moieties.

[0704] In some embodiments, it is preferred that the primary peptide chains of the compounds of the present invention may be amidated at their C-termini. This modification is very common in nature, with approximately half of naturally occurring peptides (including certain gastrointestinal peptide hormones) readily amidated at their C-termini. The present invention includes all general and specific sequences disclosed herein, including amidated and non-amidated forms in the sequence listing and figures, wherein amidation is particularly preferably present at the C-terminus of the primary peptide sequence.

[0705] The derivative can be, for example, a fusion protein, in which the structure of formula (I) is fused to another protein or polypeptide (fusion chaperone) using recombinant methods known in the art. Alternatively, such a fusion protein can be synthesized synthetically by any known method. This fusion protein comprises the structure of formula (I). Any suitable peptide or protein can be used as a fusion chaperone (e.g., serum albumin, carbonic anhydrase, glutathione S-transferase, or thioredoxin, etc.). Such a fusion protein can be prepared by linking the carboxyl terminus of the fusion chaperone to the amino terminus of the structure of formula (I) or vice versa. Optionally, the structure of formula (I) can be linked to the fusion chaperone using a cleavable linker. The resulting cleavable fusion protein can be cleaved in vivo, thereby releasing the active form of the compound of the invention. Examples of such cleavable linkers include, but are not limited to, the linkers Asp-Asp-Asp-Asp-Tyr [SEQ ID NO:10], Gly-Pro-Arg, Ala-Gly-Gly, and His-Pro-Phe-His-Leu [SEQ ID NO:11], which can be cleaved by enterokinase, thrombin, ubiquitin lyase, and renin, respectively. For details, see, for example, U.S. Patent No. 6,410,707, the contents of which are incorporated herein by reference.

[0706] The derivatives of the present invention can be, for example, physiologically functional derivatives having the structure of formula (I). The term "physiologically functional derivative" is used herein to denote a chemical derivative of a compound of formula (I) that has the same physiological function as the corresponding unmodified compound. For example, the physiologically functional derivative can be converted in vivo into a compound of formula (I). According to the present invention, examples of physiologically functional derivatives include esters, amides, and carbamates; preferably esters and amides.

[0707] In addition to derivatization at Lys42, the compounds of the present invention can be further derivatized at other sites. For example, pharmaceutically acceptable esters and amides of the compounds of the present invention may include C-terminals linked at appropriate sites. 1-20 Alkyl-, C 2-20 alkenyl-, C 5-10 Aryl, C 5-10 Fragrance-C 1-20 Alkyl or amino acid-ester or amide group, said ester or amide group being formed, for example, by reacting an alkyl, alkenylaryl, aralkyl, or aminoalkyl group containing an alcohol or amino moiety with an acid moiety present in a compound of formula (I), or by reacting an alkyl, alkenylaryl, aralkyl, or aminoalkyl group containing an activated acyl group with an alcohol or amino group present in a compound of formula (I). Examples of suitable moieties are hydrophobic substituents having 4 to 26 carbon atoms, preferably 5 to 19 carbon atoms. Suitable lipid groups include fatty acids (e.g., lauroyl (C 12 H 23 Palmityl (C) 15 H 31 ), oil-based (C 15 H 29 ) or stearyl group (C 17 H 35 )) and bile acids (such as bile salts or deoxycholates).

[0708] Methods for esterifying thiol-containing compounds with fatty acid derivatives are disclosed in U.S. Patent Nos. 5,936,092, 6,093,692, and 6,225,445, the contents of which are incorporated herein by reference. The compounds of the present invention can be delivered to neuronal cells and tissues using fatty acid derivatives comprising the compounds of the present invention linked to fatty acids via disulfide bonds. Esterification significantly increases the absorption rate of the compounds relative to the absorption rate of the corresponding unesterified compounds and prolongs the blood and tissue retention of the compounds. Furthermore, the disulfide bonds in the esterified derivatives are relatively unstable in cells and thus promote the intracellular release of the molecules from the fatty acid moiety. Suitable lipid moieties are hydrophobic substituents having 4 to 26 carbon atoms (preferably 5 to 19 carbon atoms). Suitable lipid groups contain fatty acids (e.g., lauroyl (C 12 H 23 Palmityl (C) 15 H 31 ), oil-based (C 15 H 29 ) or stearyl group (C 17 H 35 And bile acids (e.g., bile salts or deoxycholates). While the lipid-functionalized compounds of the present invention may have benefits in certain situations, it is anticipated that in most cases, it will be simplest and preferred if the compounds of the present invention are not further derivatized, thus eliminating the need for additional lipid groups.

[0709] Cyclization methods include cyclization via disulfide bond formation and head-to-tail cyclization using cyclizing resins. Cyclic peptides may exhibit enhanced stability due to their conformational constraints, including increased resistance to enzymatic degradation. Cyclization can be particularly advantageous when the uncyclized peptide contains an N-terminal cysteine ​​group. Suitable cyclized peptides include monomeric and dimer head-to-tail cyclization structures. Cyclic peptides may contain one or more additional residues, particularly additional cysteine ​​residues bound for disulfide bond formation or side chains bound for resin-based cyclization.

[0710] The derivatives may be, for example, PEGylated structures of formula (I). Derivatives of the PEGylated compounds of the present invention may provide additional advantages, such as increased peptide solubility, stability and cycling time, or reduced immunogenicity (see U.S. Patent No. 4,179,337, the contents of which are incorporated herein by reference).

[0711] The chemical moiety used for the derivatization of the compounds of the present invention may also be selected from water-soluble polymers, such as polyethylene glycol, ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, etc. The polymer moiety used for the derivatization of the compounds of the present invention may have any molecular weight and may be branched or linear. For ease of handling and manufacture, the preferred molecular weight of the polyethylene glycol used for the derivatization of the compounds of the present invention is from about 1 kDa to about 100 kDa, the term "about" indicating that in the preparation of the polyethylene glycol, the weight of some molecules will be more or less than the specified molecular weight. Polymers of other molecular weights may be used, depending on the desired therapeutic regimen, such as the desired duration of sustained release, the effect on biological activity (if any), ease of handling, the degree or lack of antigenicity, and other known effects of polyethylene glycol on therapeutic proteins or analogues. For example, the average molecular weight of polyethylene glycol can be approximately 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, etc. 00, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000 or 100,000 kDa.

[0712] Salt

[0713] Salts of compounds of formula (I) and salts of derivatives of such compounds also constitute a part of this invention. In some embodiments, the salt is a salt of a compound of formula (I). In other embodiments, the salt is a salt of a derivative of a compound of formula (I).

[0714] The salts of the compounds of this invention comprise pharmaceutically acceptable salts, i.e., salts suitable for use in pharmaceuticals. However, salts having non-pharmaceutically acceptable counterions are also within the scope of this invention, for example, as intermediates in the preparation of said compounds.

[0715] Suitable salts according to the invention comprise salts formed from organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts comprise salts formed from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and hydroxyethanesulfonic acid. Other acids (such as oxalic acid) may also be used as intermediates to obtain analogues of the invention in their final form.

[0716] Pharmaceutically acceptable salts formed from bases include ammonium salts; alkali metal salts, such as potassium and sodium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed from organic bases, such as dicyclohexylamine and N-methyl-D-glucosamine.

[0717] solvates

[0718] Those skilled in the art of organic chemistry and / or medicinal chemistry will understand that many organic compounds can form complexes with solvents, in which the organic compound reacts or precipitates or crystallizes. Such complexes are called "solvates." For example, complexes with water are called "hydrates." The present invention also covers solvates of compounds of formula (I), solvates of derivatives of said compounds, and solvates of salts of said derivatives.

[0719] Those skilled in the art of organic chemistry and / or medicinal chemistry will also recognize that many organic compounds can exist in different forms, including amorphous materials and / or one or more crystalline forms. These different physical forms of organic compounds are referred to as polymorphs. This invention also covers all such different physical forms of compounds of formula (I), as well as different physical forms of derivatives and salts of said compounds.

[0720] Bioactivity

[0721] The compounds of the present invention are active against the human GIP receptor and can be considered as GIP receptor agonists. This can be evaluated, for example, by in vitro or cell binding assays or reporter gene assays. For example, when tested according to the assays described in the Examples section below, the preferred compounds of the present invention exhibit at least 1 / 50 of the activity of human GIP against the human GIP receptor, preferably at least 1 / 30, 1 / 20, 1 / 10, 1 / 5, 1 / 3, or 1 / 2 of the activity of human GIP.

[0722] Methods for assessing GIP receptor activity are well known. For example, homogeneous time-resolved fluorescence (RJ Samms et al., GIPR agonism in obese mice via telpoide-mediated weight-independent insulin sensitization, J. Clin. Invest., 2021, 131(12):e146353) detects changes in cAMP accumulation in response to Gs-coupled G protein-coupled receptor (GPCR) activation. Specific methods are described below.

[0723] The preferred compounds of the present invention effectively promote insulin release / secretion. This can be assessed, for example, by in vitro or in vivo assays. Methods for assessing insulin release are well known.

[0724] The compounds of the present invention satisfy some, or more preferably all, of the following criteria:

[0725] 1) It has sustained biological activity against human GIP receptors, thereby leading to appetite suppression;

[0726] 2) Activity that promotes insulin release;

[0727] 3) It exhibits high solubility in aqueous solutions at pH 3.0–8.0, allowing for the administration of effective doses in small-volume injections (resulting in lower injection pain). Solubility can be easily assessed via simple in vitro tests.

[0728] 4) Long duration of in vivo activity (evaluated in human or animal models) so that the frequency of injection does not exceed once daily, and preferably, not more than twice a week, or more preferably, not more than once a week, while still producing acceptable therapeutic or cosmetic benefits.

[0729] 5) Good weight loss (as assessed in human subjects or animal models, where the assessment can be accomplished by co-administration of a GLP1r agonist).

[0730] According to certain embodiments of the present invention (particularly embodiments relating to weight loss, obesity, carbohydrate metabolism, and diabetes), the compounds, derivatives, and salts of the present invention have one, several, or all of the following characteristics:

[0731] A. It has sufficient solubility between pH 3.0 and pH 8.0, thereby allowing the effective dose to be administered in volumes of less than 1 mL, less than 0.5 mL, or less than 0.3 mL;

[0732] B. Activates cAMP signaling in cells that overexpress human GIP receptor;

[0733] C. One, several, or all of the other 1 to 5 features listed above.

[0734] Pharmacokinetics, duration of action, and solubility

[0735] When administered subcutaneously, the compounds of this invention exhibit effective and prolonged duration of action in vivo. To achieve this, the compounds are required to possess both good activity against the biological target and excellent pharmacokinetic properties.

[0736] The compounds of the present invention have a therapeutically useful duration of action, and their beneficial effects are observed for several days as described in the experiments below. The half-life of the compounds of the present invention was evaluated in a porcine PK model. It was found that the preferred compounds of the present invention have a half-life equivalent to or longer than that of smeglutide. In addition to exhibiting a long in vivo half-life, the compounds of the present invention also exhibit good storage stability, with no significant degradation observed after storage in solution at 4°C for 4 weeks.

[0737] Poor water solubility is a known problem with lipid-containing molecules. In contrast, the compounds of the present invention have very good solubility.

[0738] Symptoms

[0739] The present invention also provides compounds, derivatives or salts of the invention for use as medicaments, or compositions comprising said compounds, derivatives or salts, as well as pharmaceutically acceptable carriers and optional additional therapeutic agents.

[0740] The present invention also provides a method for treating or preventing a disease or condition or other undesirable physiological state in a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, or salt of the present invention, or a composition comprising said compound, derivative, or salt, and a pharmaceutically acceptable carrier and optionally additional therapeutic agents. Preferably, said compound, derivative, salt, or composition is administered subcutaneously.

[0741] According to certain implementations, the disease or condition or other undesirable physiological state is diabetes or obesity, especially diabetes (e.g., type 2 diabetes).

[0742] According to certain implementations, the disease or condition or other undesirable physical condition may be an overweight physical condition.

[0743] Subjects administered the compound may be overweight, e.g., obese. Alternatively or otherwise, the subject may have diabetes, e.g., insulin resistance or glucose intolerance, or both. The subject may have diabetes, e.g., type 2 diabetes. The subject may be overweight (e.g., obese) and have diabetes (e.g., type 2 diabetes).

[0744] In addition, or alternatively, participants may have or may be at risk of having any of the following conditions where obesity or being overweight is a risk factor. Such conditions include, but are not limited to, heart disease, cardiovascular disease (e.g., hypertension), atherosclerosis, congestive heart failure, and dyslipidemia; stroke; gallbladder disease; osteoarthritis; sleep apnea; reproductive disorders such as polycystic ovary syndrome; cancers such as breast cancer, prostate cancer, colon cancer, endometrial cancer, kidney cancer, and esophageal cancer; varicose veins; acanthosis nigricans; eczema; exercise intolerance; insulin resistance; hypertensive hypercholesterolemia; gallstones; osteoarthritis; orthopedic trauma; insulin resistance such as type 2 diabetes and syndrome X; and thromboembolic diseases (see Kopelman, Nature 404:635-43, 2000; Rissanen et al., British Medical Journal 301, 835, 1990).

[0745] Other conditions associated with obesity include depression, anxiety, panic attacks, migraines, PMS, chronic pain states, fibromyalgia, insomnia, impulsivity, obsessive-compulsive disorder, and myoclonus. Certain neurological disorders and neurodegenerative diseases are also associated with obesity. Furthermore, obesity is a recognized risk factor for increased complications from general anesthesia (see, for example, Kopelman, *Nature* 404:635-43, 2000). Generally, obesity reduces lifespan and carries a significant risk of comorbidities as listed above.

[0746] Other diseases or conditions associated with obesity include: birth defects, increased incidence of neural tube defects and carpal tunnel syndrome (CTS) in obese pregnant women; chronic venous insufficiency (CVI); daytime sleepiness; deep vein thrombosis (DVT); end-stage renal disease (ESRD); gout; fever; impaired immune response; impaired respiratory function; infertility; liver disease; lower back pain; obstetric and gynecological complications; pancreatitis; abdominal hernia; acanthosis nigricans; endocrine disorders; chronic hypoxia and Hypercapnia; dermatologic effects; elephantiasis; gastroesophageal reflux; heel spurs; lower extremity edema; mammegaly, which causes considerable problems such as bra strap pain, skin lesions, neck pain, chronic odor, and infection in the skin folds under the breast; large anterior abdominal wall masses, such as peritonitis with frequent panniculitis, which hinders walking, causes frequent infections, odor, difficulty dressing, and lower back pain; musculoskeletal disorders; pseudotumor of the brain (or benign intracranial hypertension), and sliding hiatal hernia.

[0747] In some implementations, the disease or condition may be non-alcoholic fatty liver disease.

[0748] According to certain embodiments, the disease or condition or other undesirable physiological state may be an undesirable weight (although not obese or overweight). Subjects may be subjects of normal weight (this includes, but is not limited to, subjects who were previously overweight or obese and subjects who wish to prevent returning to an unhealthy weight). Subjects may be subjects who desire weight loss, such as female and / or male subjects who desire a change in appearance. In some cases where the subject's weight is normal, aspects of the invention may relate to cosmetic treatments rather than therapeutic treatments.

[0749] The present invention also provides a method for reducing a subject's appetite, reducing a subject's food intake, reducing a subject's calorie intake, improving a subject's insulin release, improving a subject's carbohydrate metabolism, and / or improving a subject's glucose tolerance, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention. Such methods may relate to treating subjects with a prediabetic state (e.g., insulin insensitivity) or prediabetes.

[0750] The present invention also provides a method for improving lipid distribution in a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention. The present invention further provides a method for alleviating symptoms or conditions that can be relieved by reducing nutrient utilization, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention.

[0751] The compounds, derivatives, salts, or compositions of the present invention can be used for weight control and treatment (e.g., reducing or preventing obesity), specifically for any one or more of the following: preventing and reducing weight gain; inducing and promoting weight loss; and reducing obesity as measured by body mass index. The compounds, derivatives, salts, or compositions of the present invention can be used to maintain any one or more of the following: desired weight, desired body mass index, desired appearance, and good health.

[0752] This invention can also be used to treat, prevent, improve, or alleviate symptoms or conditions caused, complicated, or aggravated by relatively high nutrient utilization. The term "symptoms or conditions that can be alleviated by reducing caloric (or nutrient) utilization" is used herein to refer to any symptom or condition in a subject that is caused by, complicated by, or aggravated by relatively high nutrient utilization, or that can be alleviated by reducing nutrient utilization (e.g., by reducing food intake). Subjects with insulin resistance, impaired glucose tolerance, or any form of diabetes (e.g., type 1, type 2, or gestational diabetes) may also benefit from the methods according to the invention.

[0753] Symptoms or conditions associated with increased calorie intake include, but are not limited to, insulin resistance, glucose intolerance, obesity, diabetes (including type 2 diabetes), eating disorders, insulin resistance syndrome, and Alzheimer's disease.

[0754] An article published in the *Journal of Cereb. Blood Flow Metab.* on April 13, 2011 (Teramoto S et al.) discussed the use of GLP-1 and exendin-4 in conferring cardioprotective effects after myocardial infarction and demonstrated that exendin-4 could provide neuroprotection against cerebral ischemia-reperfusion injury. The study showed that mice receiving intravenous exendin-4 60 minutes after focal cerebral ischemia exhibited significantly reduced infarct volume and improved functional deficits, as well as suppressed oxidative stress, inflammatory responses, and cell death after reperfusion. This study provides evidence that the protective effect of exendin-4 is mediated by increasing intracellular cAMP levels and suggests that exendin-4 may be useful in the treatment of acute ischemic stroke.

[0755] Therefore, the present invention also provides a method for providing cellular protection (such as providing cardiac protection, providing neuroprotection, and / or treating or preventing neurodegeneration) to a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention.

[0756] In some embodiments, the compounds, derivatives, salts, or compositions of the present invention can be used to treat or prevent diseases or conditions or other undesirable physiological states, such as neurodegeneration. This neurodegeneration may be caused by apoptosis, necrosis, or loss of function of neurons (preferably in the CNS). The neurodegeneration to be treated or prevented may be neurodegeneration following brain injury (e.g., brain injury following physical trauma or non-traumatic injury such as stroke, tumor, hypoxia, poisoning, infection, ischemia, encephalopathy, or drug abuse). Alternatively or additionally, it may be applicable to neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Geiger's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, other demyelinating diseases, Alzheimer's disease, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette syndrome, Guillain-Barré syndrome, Wilson's disease, Pick's disease, neuroinflammatory diseases, encephalitis, encephalomyelitis, meningitis). This treatment aims to prevent or treat neurodegenerative diseases in subjects with inflammation, other central nervous system infections, prions, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia-telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatal substantia nigra degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscin deposition. Preferably, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Gayle's disease (amyotrophic lateral sclerosis), and Huntington's disease. In this case, the treatment will be considered to have a neuroprotective effect. According to certain preferred embodiments, the treatment has a neuroprotective effect after cerebral ischemia, or has a neuroprotective effect in subjects with neurodegenerative diseases or diagnosed as susceptible to neurodegenerative diseases.

[0757] According to other embodiments, the disease or condition or other undesirable physiological state is cardiac degeneration (specifically, myocardial degeneration due to apoptosis, necrosis, or loss of function of cardiomyocytes), in which case the compounds, derivatives, salts, or compositions according to the invention provide cardiac protection. According to certain preferred embodiments, the treatment has a protective effect on myocardial function after myocardial infarction.

[0758] The present invention also provides compounds, derivatives, salts, or compositions thereof for the treatment of obesity or diabetes.

[0759] The present invention also provides compounds, derivatives, salts, or compositions thereof for increasing energy expenditure, improving insulin release, improving glucose tolerance, and / or improving carbohydrate metabolism in subjects. Such uses may relate to treating subjects with a prediabetic state (e.g., insulin insensitivity) or prediabetes.

[0760] The present invention also provides compounds, derivatives, salts, or compositions thereof for reducing appetite in subjects, reducing food intake in subjects, reducing calorie intake in subjects, improving insulin release in subjects, and / or improving glucose tolerance in subjects. Such uses may relate to treating subjects with a prediabetic state (e.g., insulin insensitivity) or prediabetes.

[0761] The present invention also provides compounds, derivatives, salts, or compositions of the invention for use as cytoprotective agents (e.g., for treating or preventing neurodegeneration, providing neuroprotection, and / or providing cardioprotection). For example, the compounds, derivatives, salts, or compositions can be used for myocardial protection in subjects after myocardial infarction, or for neuroprotection in subjects after cerebral ischemia or stroke, or for neuroprotection in subjects suffering from chronic neurodegenerative diseases. Various features of the compounds, derivatives, salts, or compositions for neuroprotective or cardioprotective uses may be as outlined above regarding the methods of the present invention.

[0762] In cases of neuroprotection, the subject may have previously experienced brain injury, stroke, or other events causing cerebral ischemia. Alternatively, the subject may have a chronic neurodegenerative disease or have been diagnosed as susceptible to chronic neurodegenerative diseases. In cases of cardiac protection, the subject may have previously experienced events causing myocardial ischemia, such as myocardial infarction and angina. According to some embodiments, the compounds, derivatives, salts, or compositions of the present invention may be administered as soon as possible after the subject has experienced a suspected myocardial infarction. According to some embodiments, the compounds, derivatives, salts, or compositions of the present invention may be administered as soon as possible after the subject has experienced a suspected stroke.

[0763] The present invention also provides the use of the compounds, derivatives, salts or compositions of the present invention in the preparation of a medicament for treating obesity or diabetes in a subject, who may be as described above with reference to other aspects of the invention.

[0764] This invention also provides the use of the compounds, derivatives, or salts of this invention in the preparation of medicaments for improving insulin release in subjects, for improving glucose tolerance in subjects, and / or for improving carbohydrate metabolism in subjects. Such uses may relate to treating subjects with a prediabetic state (e.g., insulin insensitivity) or prediabetes.

[0765] The present invention also provides the use of the compounds, derivatives, salts or compositions of the present invention in the preparation of medicaments for reducing appetite in subjects, reducing food intake in subjects, reducing calorie intake in subjects, improving insulin release in subjects and / or improving glucose tolerance in subjects.

[0766] The present invention also provides the use of the compounds, derivatives, salts or compositions of the present invention in the preparation of medicaments for providing cellular protection (e.g., prevention or treatment of neurodegeneration, providing neuroprotection and / or providing cardioprotection) to a subject, who may be as described above with reference to other aspects of the invention.

[0767] According to some embodiments, the compounds, derivatives, salts, or compositions of the present invention are administered parenterally. According to other embodiments, the compounds, derivatives, salts, or compositions of the present invention are administered subcutaneously, intravenously, intramuscularly, intranasally, transdermally, or sublingually. According to other embodiments, the compounds, derivatives, salts, or compositions of the present invention are administered orally. In a preferred embodiment, the compounds, derivatives, salts, or compositions of the present invention are administered subcutaneously.

[0768] The compounds, derivatives, salts, or compositions of the present invention are preferably used to treat human subjects. However, although the compounds, derivatives, salts, or compositions of the present invention are generally used to treat human subjects, they may also be used to treat similar or identical conditions in other vertebrates, such as other primates; farm animals, such as pigs, cattle, and poultry; loitering animals, such as horses; or companion animals, such as dogs and cats.

[0769] Composition

[0770] The compounds of formula (I) or their derivatives and / or salts are preferably present in pharmaceutical formulations or compositions. Therefore, the present invention provides a composition comprising the compounds, derivatives, or salts of the present invention, as well as pharmaceutically acceptable excipients and optionally another therapeutic ingredient. Compositions comprising compounds, derivatives, or salts are suitable for therapeutic use. According to certain preferred embodiments, the composition is present in a syringe or other administration device for subcutaneous administration to humans. According to certain preferred embodiments, the composition has a pH of 3.0–8.0. The compositions of the present invention may be in the form of pharmaceutical formulations as described below.

[0771] The pharmaceutical formulations according to the invention comprise formulations suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intra-articular), inhalation (including fine dust or mist that can be produced by various types of metered-dose pressurized aerosols, nebulizers, or blowers), rectal, and topical (including skin, transdermal, transmucosal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend, for example, on the recipient's condition and illness.

[0772] Formulations can be conveniently presented in unit dosage forms and can be prepared by any method known in the pharmaceutical industry. All methods involve the step of binding the active ingredient with a carrier that constitutes one or more excipients. Typically, formulations are prepared by uniformly and tightly binding the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0773] Formulations of the present invention suitable for oral administration may be available in the following forms: discrete units, such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be presented in pellets, saccharides, or pastes. Various pharmaceutically acceptable carriers and their formulations are described in standard formulation discussions, for example, EW Martin's Remington's Pharmaceutical Sciences. See also Wang, YJ, and Hanson, MA, Journal of Parenteral Science and Technology, Technical Report No. 10, Supplement 42:2S, 1988, the contents of which are incorporated herein by reference.

[0774] Tablets can be prepared by compression or molding, optionally with one or more excipients. Active ingredients (such as powders or granules) in free-flowing form, optionally mixed with binders, lubricants, inert diluents, surfactants, or dispersants, can be prepared by compression in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to allow slow or controlled release of the active ingredient. The compounds of the present invention can be administered, for example, in a form suitable for immediate or prolonged release. Immediate or prolonged release can be achieved by using a suitable pharmaceutical composition comprising the compounds of the present invention, or, specifically, in the case of prolonged release, by using a device such as a subcutaneous implant or an osmotic pump. The compounds of the present invention can also be administered via liposomes.

[0775] Preferably, the compositions according to the invention are suitable for subcutaneous administration, for example, by injection. According to some embodiments, the compositions may contain metal ions, such as copper, iron, aluminum, zinc, nickel, or cobalt ions. The presence of such ions can limit solubility and thus delay absorption from the subcutaneous application site into the circulatory system.

[0776] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for volume impartation, alginate or sodium alginate as a suspending agent, methylcellulose as a thickener, and sweeteners or flavoring agents, such as those known in the art; and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, expanders, disintegrants, diluents, and lubricants, such as those known in the art. Such compositions may also contain penetration enhancers. The compounds of the present invention may also be delivered orally via sublingual and / oral administration. Molded tablets, compressed tablets, or freeze-dried tablets are exemplary forms that may be used. Exemplary compositions comprise compositions formulated with rapidly dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations may also contain high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). These formulations may also contain excipients that aid mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and controlled-release agents, such as polypropylene copolymers (e.g., Carbopol 934). For ease of manufacture and use, lubricants, flow aids, flavoring agents, colorants, and stabilizers may also be added.

[0777] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. These formulations may be present in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions where a sterile liquid carrier (e.g., saline or water for injection) is added immediately before use. Temporary injectable solutions and suspensions can be prepared from the aforementioned types of sterile powders, granules, and tablets. Exemplary compositions for parenteral administration comprise injectable solutions or suspensions that may contain, for example, suitable non-toxic, parenteral-acceptable diluents or solvents (such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution); or other suitable dispersants or wetting agents and suspending agents (containing synthetic monoglycerides or diglycerides) and fatty acids (containing oleic acid or cremaphores). The aqueous carrier may be, for example, an isotonic buffer solution with a pH of about 3.0 to about 8.0, preferably about 3.5 to about 7.4 (e.g., 3.5 to 6.0, e.g., 3.5 to about 5.0). Useful buffers include sodium citrate-citric acid and sodium phosphate-phosphate, as well as sodium acetate / acetic acid buffers. The composition preferably does not contain any compounds known to be harmful to peptide compounds.

[0778] Excipients that may be included are, for example, other proteins, such as human serum albumin or plasma preparations. If desired, the pharmaceutical composition may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, preservatives, and pH buffers, for example, sodium acetate or sorbitol monolaurate.

[0779] Exemplary compositions for nasal aerosol or inhalation administration comprise a solution in saline solution, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, and / or other solubilizers or dispersants as known in the art. Conveniently, in compositions for nasal aerosol or inhalation administration, the compounds of the present invention can be delivered from a pressurized pack or nebulizer in the form of an aerosol spray when using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In the case of pressurized aerosols, the dosage unit can be determined by providing a valve for delivering the amount of the metered dose. Capsules and cartridges (e.g., gelatinous) for inhalers or blowpipes can be configured as powder mixtures containing the compound and a suitable powder matrix (e.g., lactose or starch). In a specific, non-limiting example, the compounds of the present invention are administered as an aerosol via an aerosol adapter (also called an actuator) from a metering valve. Optionally, it also includes a stabilizer and / or porous particles for deep lung delivery (see, for example, U.S. Patent No. 6,447,743).

[0780] Formulations for rectal administration may be presented as retention enemas or suppositories in combination with substances such as cocoa butter, synthetic glycerides, or polyethylene glycol. This carrier is typically solid at room temperature but liquefies and / or dissolves in the rectal lumen to release the drug.

[0781] Formulations for topical application in the oral cavity (e.g., via the buccal or sublingual route) comprise lozenges containing active ingredients in a flavoring matrix (such as sucrose and gum arabic or tragacanth) and soft lozenges containing active ingredients in a matrix (such as gelatin and glycerin or sucrose and gum arabic). Exemplary compositions for topical application comprise a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0782] Preferred unit dose formulations are formulations containing an effective dose of the above-mentioned active ingredient or an appropriate portion thereof.

[0783] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may contain other agents conventional in the art, and formulations suitable for oral administration may contain flavoring agents, in relation to the types of formulations under discussion.

[0784] The compounds, derivatives, and salts of the present invention can also be suitably administered as sustained-release systems. Suitable examples of sustained-release systems of the present invention include suitable polymeric materials, such as semi-permeable polymer matrices in the form of molded articles, such as membranes or microcapsules; suitable hydrophobic materials, such as emulsions in acceptable oils; or ion exchange resins; and slightly soluble derivatives of the compounds of the present invention, such as slightly soluble salts. Sustained-release systems can be administered orally; rectally; parenterally; intracerebrospinal; intravaginally; intraperitoneally; topically, such as as powders, ointments, gels, drops, or transdermal patches; buccally; or as oral or nasal sprays.

[0785] Formulations for administration can be suitably formulated to provide controlled release of the compounds, derivatives, and salts of the present invention. For example, pharmaceutical compositions may be in particulate form, comprising one or more of the following: biodegradable polymers, polysaccharide gels and / or bioadhesive polymers, amphiphilic polymers, and agents capable of altering the interfacial properties of the particles of the compounds of the present invention. Certain biocompatibility characteristics exhibited by these compositions allow for the controlled release of the active substance, see U.S. Patent No. 5,700,486, the contents of which are incorporated herein by reference.

[0786] Controlled-release compositions are preferred for indications such as the treatment of obesity and / or diabetes, where maximizing the time interval between injections is desirable. However, for indications such as providing neuroprotection or cardioprotection (e.g., after suspected myocardial infarction or stroke), where it is desirable to achieve therapeutic plasma concentrations of the active agent within the shortest possible time, immediate-release formulations are preferred. In this case, a dosing regimen comprising administering one dose of the immediate-release formulation of the active agent (i.e., as soon as possible after suspected myocardial infarction or stroke) followed by one dose of the controlled-release formulation of the active agent may be preferred.

[0787] The compounds, derivatives, or salts of the present invention can be delivered by a pump (see Langer, ibid.; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201, 1987; Buchwald et al., Surgery 88:507, 1980; Saudek et al., New England Journal of Medicine 321:574, 1989) or by continuous subcutaneous infusion (e.g., using a micropump). Intravenous solution bags may also be used. A key factor in selecting an appropriate dose is the result obtained, such as a reduction in total body weight or the ratio of fat to muscle mass, or by other criteria deemed appropriate by the practitioner for measuring the control or prevention of obesity or obesity-related conditions. Other controlled-release systems are discussed in Langer's commentary (Science 249:1527-1533, 1990), which is incorporated herein by reference. In another aspect of this disclosure, the compounds of the invention are delivered via implanted pumps, as described, for example, in U.S. Patent Nos. 6,436,091, 5,939,380, and 5,993,414, the contents of which are incorporated herein by reference.

[0788] Implantable drug infusion devices are used to provide patients with a long-term, fixed dose or infusion of a drug or any other therapeutic agent. Essentially, such devices can be classified as active or passive. The compounds, derivatives, or salts of the present invention can be formulated into long-acting formulations. Such long-acting reservoir formulations can be administered via implantation (e.g., subcutaneously or intramuscularly); or via intramuscular injection. Thus, for example, the active ingredient can be formulated with suitable polymeric or hydrophobic materials, such as as an emulsion in an acceptable oil; or as an ion exchange resin; or as a slightly soluble derivative, such as a slightly soluble salt.

[0789] The therapeutically effective amount of the active agent of the present invention can be administered in single-pulse doses, bolus doses, or pulse doses administered over time. Thus, in a pulse dose, a bolus administration of the active agent is provided, followed by a period without further administration of the active agent to the subject, and then a second bolus administration. In specific, non-limiting examples, pulse doses are administered over a one-day, a one-week, or a one-month course of treatment.

[0790] Combination therapy

[0791] In some embodiments, a therapeutically effective amount of the compound, derivative, salt, or composition of the present invention is administered together with a therapeutically effective amount of one or more other therapeutic agents. The compound, derivative, or salt may be administered, for example, simultaneously with one or more other therapeutic agents, or may be administered sequentially or separately. Therefore, the present invention provides compounds, derivatives, or salts of the present invention for use as medicaments, wherein said compounds, derivatives, or salts are used together with a therapeutically effective amount of one or more other therapeutic agents (e.g., simultaneously, sequentially, or separately). In some embodiments, the active agent of the present invention is formulated together with one or more other therapeutic agents and administered in a single dose.

[0792] In some embodiments, one or more additional therapeutic agents are additional antidiabetic, appetite-suppressing, food-reducing, plasma glucose-lowering, or plasma lipid-altering agents. Specific, non-limiting examples of additional appetite suppressants include amphetamine (diethylamine benzophenone), phentermine, masindole and phenylpropanolamine, fenfluramine, dexfenfluramine, benzodiazepine, amphetamine, sibutramine, rimonaban, topiramate, fluoxetine, bupirocin, zonisamide, naltrexone, orlistat and cetirizine. Other specific, non-limiting examples of antidiabetic agents include metformin, phenformin, rosiglitazone, pioglitazone, troglitazone, repaglinide, nateglinide, tolbutamide, acesulfame potassium, tolazoline, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, fibroblast growth factor 21, miglitol, acarbose, exenatide, pramlintide, vildagliptin, and sitagliptin.

[0793] In a preferred embodiment, one or more additional therapeutic agents are GLP-1 receptor agonists. In another preferred embodiment, one or more additional therapeutic agents are amylin receptor agonists. In yet another preferred embodiment, one or more additional therapeutic agents are glucagon receptor agonists.

[0794] In an alternative embodiment, the additional therapeutic agent is a GLP-1 receptor agonist and an amylin receptor agonist. In another alternative embodiment, the additional therapeutic agent is a GLP-1 receptor agonist and a glucagon receptor agonist. In yet another alternative embodiment, the additional therapeutic agent is an amylin receptor agonist and a glucagon receptor agonist.

[0795] In another alternative implementation, the additional therapeutic agents are GLP-1 receptor agonists, amylin receptor agonists, and glucagon receptor agonists.

[0796] In alternative embodiments, one or more additional therapeutic agents are additional cardioprotective agents or neuroprotective agents. Specific, non-limiting examples of additional cardioprotective agents include aspirin, N-acetylcysteine, phenylethylamine, coenzyme Q10, vitamin E, vitamin C, L-carnitine, carvedilol, and dexrazoxane. Specific, non-limiting examples of neuroprotective agents include statins (such as simvastatin), steroids (such as progesterone), minocycline, resveratrol, and vitamin E. Examples of agents used to treat Parkinson's disease include anticholinergics, pramipexole, bromocriptine, levodopa, carbidopa, rasagiline, amantadine, and ropinirole.

[0797] dose

[0798] Whenever an effect such as appetite suppression, reduced food intake, or reduced calorie intake is desired, the compounds, derivatives, salts, or compositions of the present invention may be applied, or applied at a time slightly earlier than the time when the desired effect is desired (such as, but not limited to, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 90 minutes, or about 120 minutes before the time when the desired effect is desired).

[0799] The therapeutically effective amount of the active agent of the present invention will depend on the molecule used, the subject being treated, the severity and type of disease, and the manner and route of administration. For example, the therapeutically effective amount of the compound of the present invention can range from about 0.01 μg per kilogram of body weight to about 1 g per kilogram of body weight, for example from about 0.1 μg per kilogram of body weight to about 20 mg per kilogram of body weight, for example from about 1 μg per kilogram of body weight to about 5 mg per kilogram of body weight, or from about 5 μg per kilogram of body weight to about 1 mg per kilogram of body weight.

[0800] In one embodiment of the invention, the compounds, derivatives, or salts of the invention may be administered to a subject at a concentration of 0.5 nmol to 1,333 nmol per kg of body weight, for example, 1 nmol to 1,333 nmol per kg of body weight, for example, 2 nmol to 1,000 nmol per kg of body weight, for example, 4 nmol to 1,333 nmol per kg of body weight, for example, 5 nmol to 1,000 nmol per kg of body weight, for example, 10 nmol to 750 nmol per kg of body weight, for example, 20 nmol to 500 nmol per kg of body weight, and particularly 30 nmol to 240 nmol per kg of body weight. In a preferred embodiment, the highly active compounds of the invention are administered to a subject at a concentration of 0.2 nmol to 10 nmol per kg of body weight, for example, 0.5 nmol to 5.0 nmol per kg of body weight, for example, 1.0 nmol to 2.0 nmol per kg of body weight, for example, 1.5 nmol per kg of body weight. For a 75 kg subject, such a dose corresponds to 37.5 nmol to 100 μmol, for example 75 nmol to 100 μmol, for example 150 nmol to 100 μmol, for example 300 nmol to 100 μmol, for example 375 nmol to 75 μmol, for example 750 nmol to 56.25 μmol, for example 1.5 μmol to 37.5 μmol, and particularly 2.25 μmol to 18 μmol. In a preferred embodiment of the highly active compound of the invention, for a 75 kg subject, such a dose corresponds to 15 nmol to 750 nmol, for example 37.5 nmol to 375.0 nmol, for example 75 nmol to 150 nmol, for example 112.5 nmol. The invention also considers dose ranges defined by any particular dose described herein.

[0801] Based on the potency of the specific compound used, the route of delivery of the compound, and the age, weight, sex, and physiological condition of the subject, those skilled in the art can readily determine the exact dosage.

[0802] For compounds with a long blood half-life, the above-mentioned doses may be administered, for example, once or twice a month, or once, twice, three or four times a week. For preferred compounds, the dose may be administered at a frequency not exceeding once a week. Alternatively, for compounds with a shorter blood half-life, the above-mentioned doses may be administered, for example, once, twice, three or four times a day, or once or twice a week. In some embodiments, the dose may be administered every 2 days, every 3 days, or every 4 days. According to some embodiments, the dose may be administered shortly before each meal.

[0803] Example

[0804] The invention is further described with reference to the following non-limiting examples.

[0805] Materials and methods

[0806] peptide synthesis

[0807] Peptide synthesis was performed on a tricyclic amide linking resin. Amino acids were linked using the Fmoc strategy. For the Xaa1 to Xaa43 moieties, each amino acid was added sequentially from the C-terminus to the N-terminus. Peptide coupling was mediated using a reagent (e.g., HBTU). In the presence of a scavenger, the peptide was cleaved from the resin using trifluoroacetic acid. In a second stage, the lysine residue to be substituted was functionalized at its ε-amino group after deprotection of the ε-amino group. The chain on the substituted lysine residue was then sequentially constructed using the same amino acid linking chemistry.

[0808] The peptides were purified by reversed-phase HPLC. All purified peptides underwent quality control, and HPLC confirmed that the purity of the peptides was greater than 90% in most cases using two buffer systems. MALDI-MS revealed the expected molecular ions.

[0809] Exemplary synthesis

[0810] Exemplary compound 91 was prepared using standard Fmoc chemistry as follows (GIP reference number 117):

[0811] 1. Resin Preparation: A DCM (20 mL) solution of 1-chloro-2-[chloro(diphenyl)methyl]benzene resin (0.3 mmol, 1.00 equivalent, substitution value 1.08 mmol / g) and Fmoc-Gln(Trt)-OH (1.0 equivalent) was added to DIEA (4.0 equivalent) and stirred with N2 at 25 °C for 2.5 h. The mixture was then filtered to obtain the resin.

[0812] 2. Deprotection: Add a 20% piperidine DMF solution (25.00 mL) to the resin and stir the mixture with N2 at 20 °C for 15 min. Wash the resin with DMF (25.00 mL × 5) and filter to obtain the resin.

[0813] 3. Coupling: A solution of HBTU (2.85 equivalents) and Fmoc-Thr(tBu)-OH (3.00 equivalents) in DMF (20 mL) was added to the resin along with DIEA (6.00 equivalents) and stirred with N2 at 20 °C for 30 min. The resin was then washed with DMF (20.0 mL × 5).

[0814] 4. Repeat steps 2 and 3 using the reagents in Table 1 to couple the following amino acids (3-42):

[0815] Table 1 :

[0816]

[0817]

[0818]

[0819] 5. After coupling with tert-butyl carbonate, add 3% H2N·NH2 / DMF and allow to react for 30 min. Repeat the reaction, then drain and wash with DMF (20.0 mL × 5).

[0820] 6. Repeat steps 2 and 3 using the reagents in Table 2 to couple the remaining amino acids (43-45):

[0821] Table 2 :

[0822]

[0823] These groups 43-45 are Figure 1 And residues 47 and Z in the structural definition in the claims.

[0824] *Because the C-1 acid group of the protected glutamate reagent 44 is protected by tBu, it reacts with lysine 43 at its C-5 acid site. When Z is (i), it is the Fmoc-Glu-OtBu reagent, which provides the glutamate residue moiety in the Z part of the compound:

[0825]

[0826] Peptide cleavage and purification :

[0827] 7. The resin was washed with MeOH (20.0 mL × 2) and vacuum dried to obtain 3 g of peptide resin. Then, 30 mL of lysis buffer (92.5% TFA / 2.5% 3-Mpr / 2.5% TIS / 2.5% H2O) was added to the flask containing the peptide resin with protected side chains at 20 °C, and the mixture was stirred for 2 h. The peptide was precipitated with cold isopropyl ether (300 mL) and centrifuged (3000 rpm, 2 min). The peptide precipitate was washed twice more with isopropyl ether (300 mL). The crude peptide was vacuum dried for 2 h and its identity was confirmed by LCMS.

[0828] 8. The residue was purified by preparative HPLC (TFA conditions; 30 °C, A: 0.075% TFA / H2O, B: CH3CN) to give the title compound (244.5 mg, 43.2 μmol, 14.4% yield, 98.3% purity, TFA) as a white solid, and its identity was confirmed by LCMS.

[0829] Equivalent methods were used for all other peptides described herein. The sequence and other structural features of example peptides are shown below. Figure 1 As shown in the figure, the Lys* residue is substituted at its ε-amino group by the group Z–Xaa44–Xaa45–Xaa46–Xaa47– (blanks in the columns discussed indicate the absence of this residue), and Z is a group having the following structure:

[0830] (i): Or (ii):

[0831] Where R is C8-C 28 alkylene or alkenylene groups; and

[0832] R1 is CO2H.

[0833] The number of carbon atoms in the alkylene or alkenylene group of R (n, n = 8–28) is within the range of Figure 1 The integer part is indicated in the column titled "n(R=Cn)". In the illustrated embodiment, n is 14, 16, or 18.

[0834] Figure 1 Some of the exemplary compounds in the figure are repeat preparations of compounds listed elsewhere in the figure, and they are indicated as such as "dupl" in columns titled "Notes".

[0835] Receptor potency of peptides against human GIP receptor overexpressed in HEK cells

[0836] Bioactivity was assessed by stimulating cAMP production in a human embryonic kidney (HEK) cell line overexpressing the SNAP-tagged human GIP receptor with peptide stimulation. Receptor expression was induced 24 hours prior to use by adding tetracycline to the cell culture medium. On the day of assay, cells were cultured at 8 × 10⁶ cells / day. -5 Cells were seeded at a density of [number] cells / mL into 96-well half-area plates in serum-free medium. After peptide stimulation for 30 min and further lysis for 1 h, cAMP levels in the cells were quantified using a commercial cAMP kit (Cisbio) via HTRF (homogeneous time-resolved fluorescence). Plates were read on a SpectraMax i3x multi-mode detection platform reader, and concentration-response curves were plotted using a Graph Pad Prism 8.0 (or higher). EC was generated for each peptide. 50The value was then compared with the control group for that day.

[0837] In vivo efficacy study: Single-dose feeding study in male mice

[0838] Male mice (Charles River Ltd, Margate, UK) were used in the animal experiments. Mice housed individually in IVC cages were randomly assigned to treatment groups, stratified by body weight. Mice were fasted overnight prior to injection. All peptide solutions were freshly prepared immediately before administration. Control animals were administered 5% v / v water and 95% NaCl (0.9% w / v). Treatment groups received a single subcutaneous injection of a combination of 10 nmol–45 nmol / kg body weight of a GIP analogue and 1 nmol–1.5 nmol / kg body weight of GLP-1r agonist G7097 (prepared in water for injection). Body weight was measured in grams (g) at injection (early photoperiod; 0900–1000), and each mouse was refeeded with a known amount of food. Subsequent measurements of remaining food and body weight were taken 72 h post-administration. Animals had free access to water throughout the study period.

[0839] Results for exemplary compounds 1 to 110 are shown in Figure 1 In this study, mice were fasted overnight and administered the drug early in the light period, followed by a known amount of food. Mice were given a single subcutaneous injection of a combination of subtherapeutic doses of the GLP-1r agonist G7097 (0.5 nmol / kg–1 nmol / kg) and an exemplary compound (4.5 nmol / kg–30 nmol / kg). Figure 1 In the table, "n" indicates the number of tests conducted on the compound in question. Each test typically involves administering the compound to a group of 5 animals. The compounds are assessed for their tendency to inhibit food intake and their ability to induce changes in body weight. The sum of their effects is reported as a single value. Figure 1 The value is referred to as "x" to indicate efficacy. To score efficacy, the difference in mean food intake, measured in grams, compared to the vehicle control was measured at at least two of the following time points: 24 h, 48 h, and 72 h post-administration. This difference in mean food intake was then multiplied by the difference in mean body weight, measured in grams, compared to the vehicle control at at least two of the following time points: 24 h, 48 h, and 72 h post-administration. The higher the number, the more effective the analogue.

[0840] PK Measurement for Half-Life Assessment

[0841] Göttingen miniature pigs received a single subcutaneous injection of the test compound at the start of the study (0 hours). Blood samples were repeatedly collected from the pigs over the next 216 hours, plasma was separated and stored at -20°C to -80°C. Mass spectrometry was used to quantify the plasma concentration of the compound. Calculations were performed from t... max To C max The time taken to half of the time is used to represent the half-life of the compound (t). 1 / 2 Typically, the presented t 1 / 2 It is the average value of two different animals.

[0842] result

[0843] Figure 1 This is a table providing the amino acid sequences and other structural information of exemplary compounds of the present invention. For example, the amino acid sequence of exemplary compound number 1 is as follows [SEQ ID NO:12]:

[0844]

[0845]

[0846] Furthermore, the Lys* residue at position 43 carries a group on its ε-amino group.

[0847] Z–Gly–Ser–Gly–

[0848] Where Z is a group in the following formula:

[0849]

[0850] Where R is C 18 Straight-chain alkylene groups; and

[0851] R1 is CO2H.

[0852] The figure also summarizes the results of in vivo feeding efficacy studies using the example peptides of the invention as discussed above.

[0853] To the right of the column displaying feeding scores, the graph shows receptor potency data for peptides, for example, at GIP receptors overexpressed in human embryonic kidney (HEK) cells. Bioactivity was assessed by the potency of peptide stimulation to produce cAMP in HEK cells as described above.

[0854] As can be seen from the figures, mice that were fasted overnight and administered a combination of the example peptide of the present invention and the GLP-1r agonist G7097 achieved reduced weight gain or weight loss compared to mice administered G7097 alone or to control animals. This supports the claim that the compounds of the present invention are particularly effective in improving metabolism and that the compounds can be used to treat conditions such as obesity.

[0855] half life :

[0856] The half-life of selected compounds of the present invention was measured. Results in hours are shown... Figure 1 The rightmost part of the table is marked as t 1 / 2 In the list.

[0857] In the foregoing description, when reference is made to integers or elements having known, obvious, or foreseeable equivalents, such equivalents are incorporated herein as if set forth separately. The true scope of the invention should be determined with reference to the claims, which should be interpreted as encompassing any such equivalents. The reader will also understand that integers or features of the invention described as preferred, advantageous, convenient, etc., are optional and do not limit the scope of the independent claims. Furthermore, it should be understood that while such optional integers or features may be beneficial in some embodiments of the invention, they may be undesirable and therefore not present in other embodiments.

Claims

1. A compound of the following formula: Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Xaa10–Ser11– Xaa12–Xaa13–Xaa14–Asp15–Lys16–Xaa17–Xaa18–Xaa19–Xaa20– Xaa21–Phe22–Val23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29– Xaa30–Xaa31–Xaa32–Xaa33–Xaa34–Xaa35–Xaa36–Xaa37–Xaa38– Xaa39–Xaa40–Xaa41–Xaa42–Xaa43 [SEQ ID NO:1] in: Xaa1 is DTyr, His, Phe, or Tyr, or does not exist; Xaa2 is either AIB or Ala, or it does not exist; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is either Tyr or His; Xaa12 is either Ile or Lys; Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn; Xaa14 is Leu, Met, or NLeu; Xaa17 is either Gln or Ile; Xaa18 is Ala, Arg, or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is either Ile or Leu; Xaa28 is either Ala or Asn; Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, or Lys*, or does not exist; Xaa31 is Arg, Gly, or Pro, or it does not exist; Xaa32 is Asn, Lys, or Lys*, or does not exist; Xaa33 is Lys or Lys*, or does not exist; Xaa34 is either Asn or Lys*, or it does not exist; Xaa35 is either an Asp or does not exist; Xaa36 is either Trp or Lys*, or it does not exist; Xaa37 is Lys or Lys*, or does not exist; Xaa38 is His or does not exist; Xaa39 is either Asn or Lys*, or it does not exist; Xaa40 is Ile, Leu, or Lys*, or does not exist; Xaa41 is Thr or does not exist; Xaa42 is Gln or does not exist; Xaa43 is either Lys* or does not exist; Lys* is Lys whose ε-amino group is replaced by a group of the following formula: Z–Xaa44–Xaa45–Xaa46–Xaa47– in: Xaa44 is Gly, Ser, Thr or does not exist; Xaa45 is Gly, Ser, or does not exist; Xaa46 is Asn, Gln, Gly, Ser, Thr or does not exist; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr or does not exist; And Z is a group of the following formula: (i): Or (ii): Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H; Furthermore, the compounds of formula (I) or formula (II) contain a Lys* residue; Or a derivative of the compound; or a salt or solvate of the compound or its derivative.

2. The compound, derivative, salt, or solvate according to claim 1, wherein the compound is a compound of formula (I) or formula (II): W–X(I) or W–Y(II) in W is the amino acid sequence: Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Xaa10–Ser11– Xaa12–Xaa13–Xaa14–Asp15–Lys16–Xaa17–Xaa18–Xaa19–Xaa20– Xaa21–Phe22–Val23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29– [SEQ ID NO:7] in: Xaa1 is DTyr, His, Phe, or Tyr, or does not exist; Xaa2 is either AIB or Ala, or it does not exist; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is either Tyr or His; Xaa12 is either Ile or Lys; Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn; Xaa14 is Leu, Met, or NLeu; Xaa17 is either Gln or Ile; Xaa18 is Ala, Arg, or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is either Ile or Leu; Xaa28 is either Ala or Asn; and Xaa29 is Gln, Gly, or Thr; X, when present, is an amino acid sequence: –Xaa30–Xaa31–Xaa32–Xaa33–Asn34–Asp35–Xaa36–Xaa37–His38–Xaa39–Xaa40–Thr41–Gln42–Xaa43 [SEQ ID NO:8] in: Xaa30 is Gly, Lys, or Lys*; Xaa31 is either Gly or Pro; Xaa32 is Lys or Lys*; Xaa33 is Lys or Lys*; Xaa36 is either Trp or Lys*; Xaa37 is Lys or Lys*; Xaa39 is either Asn or Lys*; Xaa40 is Ile, Leu, or Lys*; and Xaa43 is either Lys* or does not exist; Y, when present, is an amino acid sequence: –Xaa30–Xaa31–Xaa32–Xaa33–Xaa34 in: Xaa30 is Gly or Lys, or it does not exist; Xaa31 is Arg, Gly, or Pro, or it does not exist; Xaa32 is either Asn or Lys, or it does not exist; Xaa33 is Lys, Lys*, or does not exist; and Xaa34 is either Lys* or does not exist; Lys* is Lys whose ε-amino group is replaced by a group of the following formula: Z–Xaa44–Xaa45–Xaa46–Xaa47– in: Xaa44 is Gly, Ser, or Thr, or does not exist; Xaa45 is Gly or Ser, or it does not exist; Xaa46 is Asn, Gln, Gly, Ser, or Thr, or does not exist; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, or Thr, or does not exist; And Z is a group of the following formula: (i): Or (ii): Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H; Furthermore, the compounds of formula (I) or formula (II) contain a Lys* residue; Or a derivative of the compound; or a salt or solvate of the compound or its derivative.

3. The compound, derivative, salt, or solvate according to claim 2, wherein: Xaa1 is His, Phe, or Tyr; Xaa2 is an AIB; Xaa3 is Gln, Glu, or His; Xaa7 is either Ile or Ser; Xaa10 is either Tyr or His; Xaa12 is either Ile or Lys; Xaa13 is Ala, Gln, Thr, Val, Asp, or Asn; Xaa14 is either Leu or Met; Xaa17 is either Gln or Ile; Xaa18 is either Ala or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is either Asp or Glu; Xaa24 is Asn, Gln, or Glu; Xaa25 is a Trp; Xaa27 is Leu; Xaa28 is either Ala or Asn; and Xaa29 is Gln, Gly, or Thr.

4. The compound, derivative, salt, or solvate according to claim 3, wherein: Xaa1 is Tyr; Xaa2 is an AIB; Xaa3 is either Glu or Gln; Xaa7 is either Ile or Ser; Xaa10 is either Tyr or His; Xaa12 is either Ile or Lys; Xaa13 is Ala, Asp, or Asn; Xaa14 is Leu; Xaa17 is Ile; Xaa18 is His; Xaa19 is Gln; Xaa20 is either Gln or Lys; Xaa21 is an Asp; Xaa24 is either Asn or Gln; Xaa25 is a Trp; Xaa27 is Leu; Xaa28 is Ala; and Xaa29 is either Gln or Gly.

5. The compound, derivative, salt, or solvate according to claim 4, wherein: Xaa3 is Glu; Xaa20 is Gln; Xaa24 is an Asn; and Xaa29 is Gln.

6. The compound, derivative, salt or solvate according to any one of claims 2 to 5, wherein the compound is a compound of formula (I).

7. The compound, derivative, salt, or solvate according to claim 6, wherein: Xaa30 is Lys or Lys*; Xaa31 is Gly; Xaa32 is Lys or Lys*; Xaa33 is Lys or Lys*; Xaa36 is either Trp or Lys*; Xaa37 is Lys or Lys*; Xaa39 is either Asn or Lys*; Xaa40 is either Ile or Lys*; and Xaa43 is either Lys* or does not exist.

8. The compound, derivative, salt, or solvate according to claim 7, wherein: Xaa30 is Lys; Xaa32 is Lys*; Xaa33 is Lys; Xaa36 is a Trp; Xaa37 is Lys; Xaa39 is an Asn; Xaa40 is Ile; and Xaa43 does not exist.

9. The compound, derivative, salt or solvate according to any one of claims 2 to 5, wherein the compound is a compound of formula (II).

10. The compound, derivative, salt, or solvate according to claim 9, wherein: Xaa30 is either Lys or Gly; Xaa31 is either Gly or Pro; Xaa32 is either Lys or does not exist; Xaa33 is Lys, Lys*, or does not exist; and Xaa34 is either Lys* or does not exist.

11. The compound, derivative, salt, or solvate according to claim 10, wherein: Xaa30 is Lys; Xaa31 is Gly; Xaa32 is either Lys or does not exist; Xaa33 is Lys, Lys*, or does not exist; and Xaa34 is either Lys* or does not exist.

12. The compound, derivative, salt, or solvate according to claim 1, wherein the compound, derivative, salt, or solvate has an amino acid sequence corresponding to any one of the amino acid sequences listed in the table of FIG1.

13. A derivative of a compound according to any one of claims 1 to 12, or a salt or solvation of such a derivative, wherein the derivative or a salt or solvation comprises one or more derivatizations selected from: amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, esterification, polyethylene glycolation, and fusion with another peptide or protein to form a fusion protein.

14. The compound, derivative, salt, or solvate according to any one of claims 1 to 13, wherein the compound, derivative, salt, or solvate is used together with another therapeutic agent for simultaneous, sequential, or separate administration.

15. The compound, derivative, salt, or solvate of claim 14, wherein the additional therapeutic agent is a GLP-1 receptor agonist or an amylin analogue.

16. A composition comprising a compound, derivative, salt or solvate according to any one of claims 1 to 15, and a pharmaceutically acceptable carrier.

17. The composition of claim 16, wherein the composition is present in a syringe or other application device for subcutaneous administration to a human.

18. The compound, derivative, salt, or solvate according to any one of claims 1 to 15, or the composition according to claim 16 or claim 17, wherein the compound, derivative, salt, or solvate or the composition is used as a pharmaceutical.

19. A method for treating or preventing a disease or condition or other undesirable physiological state in a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, salt or solvate according to any one of claims 1 to 15, or a composition according to claim 16 or 17.

20. The compound, derivative, salt, or solvate of any one of claims 1 to 15, or the composition of claim 16 or 17, wherein the compound, derivative, salt, or solvate or the composition is used in the prevention or treatment of diabetes, obesity, heart disease, stroke, and non-alcoholic fatty liver disease, to improve insulin release in a subject, to improve carbohydrate metabolism in a subject, to improve lipid distribution in a subject, to reduce appetite, to reduce food intake, to reduce calorie intake, to improve glucose tolerance in a subject, and / or as a cytoprotective agent.

21. The compound, derivative, salt, or solvate or composition used as a cell protectant according to claim 20, wherein the compound, derivative, salt, or composition is used in the prevention or treatment of neurodegeneration, providing neuroprotection, and / or providing cardioprotection.

22. The compound, derivative, salt, or solvate or composition used as a cell protectant according to claim 21, wherein the compound, derivative, salt, or composition is used to provide cardiac protection to a subject after myocardial infarction.

23. The compound, derivative, salt, or solvate or composition used as a cell protectant according to claim 22, wherein the compound, derivative, salt, or composition is used to provide neuroprotection for a subject suffering from or diagnosed at risk of chronic neurodegenerative disease.

24. The compound, derivative, salt, or solvate or composition used according to claim 23, wherein the chronic neurodegenerative disease is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Gregg's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, other demyelinating related diseases, Alzheimer's disease, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette syndrome, Gibbs disease, etc. Lambaré syndrome, Wilson's disease, Pick's disease, neuroinflammatory diseases, encephalitis, encephalomyelitis, meningitis, other central nervous system infections, prions, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia-telangiectasia, spinal dystrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatal nigra degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscin deposition disease.

25. A method for treating or preventing diabetes, obesity, heart disease, stroke, or non-alcoholic fatty liver disease in a subject, improving insulin release in a subject, improving carbohydrate metabolism in a subject, improving lipid distribution in a subject, improving glucose tolerance in a subject, reducing appetite, reducing food intake, reducing calorie intake, and / or providing cellular protection to a subject, said method comprising administering a therapeutically effective amount of a compound, derivative, salt, or solvate according to any one of claims 1 to 15, or a composition according to claim 16 or claim 17.

26. Use of any compound, derivative, salt or solvate of claims 1 to 15 in the preparation of a medicament for the prevention or treatment of diabetes, obesity, heart disease, stroke and non-alcoholic fatty liver disease, improvement of insulin release in a subject, improvement of carbohydrate metabolism in a subject, improvement of lipid distribution in a subject, improvement of glucose tolerance in a subject, reduction of appetite, reduction of food intake, reduction of calorie intake, and / or as a cytoprotective agent.

27. A method for reducing or preventing weight gain in a subject for cosmetic purposes, the method comprising administering an effective amount of a compound, derivative, salt, or solvate according to any one of claims 1 to 15, or a composition according to claim 16 or 17.

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