compound

Abstract

The present invention provides novel compounds that are peptide hormone analogs and are useful for treating disorders such as diabetes and obesity.The compounds of the general sequence listed herein have tailored profiles of potency at the GIP receptor.Regarding in vivo properties, administration of exemplary peptides of the present invention has been shown to result in improved weight loss in animal models.Preferred compounds achieve this without significantly reducing food intake.

Description

[Technical Field]

[0001] The present disclosure relates to compounds that are peptide hormone analogs and are useful in the treatment of disorders such as diabetes and obesity. [Background technology]

[0002] According to the National Health and Nutrition Examination Survey (NHANES, 2009-2010), 33.0% of US adults aged 20 years and older are overweight, 35.7% are obese, and 6.3% are very obese. Furthermore, a large percentage of children in the US are overweight or obese.

[0003] The causes of obesity are complex and multifactorial. There is increasing evidence that obesity is not a simple problem of self-control, but rather a complex disorder involving appetite regulation and energy metabolism. Furthermore, obesity is associated with a variety of conditions that are associated with increased morbidity and mortality in the population. The etiology of obesity has not been conclusively established, but genetic, metabolic, biochemical, cultural, and psychosocial factors are thought to contribute. Generally, obesity has been described as a condition in which excess body fat puts an individual at risk for health.

[0004] There is strong evidence that obesity is associated with increased morbidity and mortality. Disease risk, such as cardiovascular disease risk and type 2 diabetes risk, increases independently with increasing body mass index (BMI). In fact, this risk has been quantified as a 5 percent increase in heart disease risk for women and a 7 percent increase in heart disease risk for men for each point of BMI above 24.9 (see Kenchaiah et al., N.Engl.J.Med.347:305,2002; Massie, N.Engl.J.Med.347-358(2002)).

[0005] Diabetes mellitus (DDM) is a chronic syndrome characterized by impaired carbohydrate, protein, and fat metabolism due to insufficient insulin secretion or insulin resistance in target tissues. It occurs in two major forms: insulin-dependent diabetes mellitus (type I diabetes) and non-insulin-dependent diabetes mellitus (type II diabetes). Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is caused by beta cell destruction, resulting in insufficient levels of endogenous insulin. Type II diabetes, or non-insulin-dependent diabetes, results from both impaired sensitivity to insulin and a relative deficiency in insulin production. According to the 2014 National Diabetes Statistics Report, approximately 28.9 million U.S. adults aged 20 years and older have diabetes (based on estimates from the 2009–2012 National Health and Nutrition Examination Survey and 2012 U.S. Census data). Among adults, 90–95% of cases of diabetes are type II diabetes.

[0006] There is strong evidence that weight loss in obese individuals reduces important disease risk factors. Even modest weight loss, such as 10% of initial body weight in both overweight and obese adults, is associated with reductions in risk factors such as hypertension, hyperlipidemia, and hyperglycemia. Significant weight loss has been shown to effectively treat type 2 diabetes (Lim et al, Diabetologia June 2011).

[0007] Although dietary restriction and exercise provide simple methods for reducing weight gain, overweight and obese individuals often fail to adequately control these factors to effectively lose weight. Pharmacological treatments are available, and several weight-loss drugs that can be used as part of a comprehensive weight-loss program have been approved by the Food and Drug Administration. However, many of these drugs have serious adverse side effects. When less invasive methods are unsuccessful and patients are at high risk for obesity-related morbidity or mortality, weight-loss surgery is an option for carefully selected patients with severe clinical obesity. However, these treatments are risky and suitable for use in only a limited number of patients. Obese subjects are not the only ones who desire weight loss. For example, individuals at the upper end of the recommended weight range or within the recommended range may wish to lose weight to approach their ideal weight. Therefore, there remains a need for agents that can be used to induce weight loss in overweight and obese subjects, as well as in subjects with a normal weight.

[0008] Many approaches to developing drugs useful for inducing weight loss have involved gastrointestinal peptide hormones and their analogs. Glucose-dependent insulinotropic polypeptide (GIP), also known as gastric inhibitory polypeptide or gastric inhibitory peptide, is a gastrointestinal hormone that belongs to a class of molecules called incretins. GIP is produced in vivo by K cells in the upper small intestine in response to food. The primary function of GIP is to induce the release of insulin from pancreatic beta cells after a meal. Increased insulin secretion leads to a decrease in circulating glucose levels.

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

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

[0011] Despite significant advances, however, the process of identifying substances useful as drugs remains complex and often unpredictable. To be useful as a therapeutic agent, a compound must possess an appropriate range of properties. In addition to having good efficacy at the intended biological target, a compound must also have good in vivo pharmacokinetic properties, low toxicity, and an acceptable side effect profile. For example, even with commercially available drugs such as liraglutide, side effects can include nausea and vomiting, and there are growing concerns about thyroid cancer and pancreatitis.

[0012] Therefore, there is still a need for additional compounds that are useful for treating disorders and diseases such as diabetes and obesity.For example, it would be desirable to identify peptides that have beneficial properties, such as improved activity profiles, and / or reduced side effects.For example, it would be desirable to identify peptides that increase energy expenditure in subjects but do not significantly reduce food intake.If a compound reduces food intake less, it is expected that the compound will have fewer side effects, such as nausea.Alternatively, or in addition, it would be desirable to identify peptides that have these and other biological effects over a sustained period.Compounds with a longer duration of activity can be administered less frequently and at lower doses, which contributes to improved convenience for subjects, fewer side effects, and lower costs. Summary of the Invention

[0013] In a first aspect of the present invention, a compound of the formula: provided is the compound 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-Thr41-Gln42-Xaa43 [SEQ ID NO: 1]; During the ceremony, Xaa1 is D-Tyr, His, Phe, or Tyr, or is absent; Xaa2 is AIB or Ala or is absent; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is Tyr or His, Xaa12 is 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 Gln or Ile, Xaa18 is Ala, Arg, or His; Xaa19 is 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 Ile or Leu, Xaa28 is Ala or Asn, Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, Lys*, or absent; Xaa31 is Arg, Gly, or Pro, or is absent; Xaa32 is Asn, Lys, Lys* or absent; Xaa33 is Lys or Lys* or is absent; Xaa34 is Asn or Lys*; Xaa35 is Asp or absent, Xaa36 is Trp or Lys* or is absent; Xaa37 is Lys or Lys* or is absent; Xaa38 is His or absent, Xaa39 is Asn or Lys* or is absent; Xaa40 is Ile, Leu, or Lys* or is absent; Xaa43 is Lys* or absent, wherein Lys* is Lys substituted at its ε-amino group with a group of the formula: Z-Xaa44-Xaa45-Xaa46-Xaa47- During the ceremony, Xaa44 is Gly, Ser, Thr, or absent; Xaa45 is Gly, Ser, or absent; Xaa46 is Asn, Gln, Gly, Ser, Thr, or absent; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr, or absent; Z is a group of the formula: [ka] (Wherein R is C8-C 28 an alkylene or alkenylene chain, and R1 is -CO2H The compound of formula (I) or formula (II) contains one Lys* residue, or a derivative of said compound, or a salt or solvate of said compound or derivative.

[0014] Also provided herein are compositions comprising a compound, derivative, salt or solvate as defined herein, together with a pharmaceutically acceptable carrier and optionally a further therapeutic agent.

[0015] Also provided herein are compounds, derivatives, salts or solvates of the invention, or compositions comprising such compounds, derivatives, salts or solvates and a pharmaceutically acceptable carrier, for use as a medicament, e.g., for the prevention or treatment of diabetes, obesity, heart disease, stroke or non-alcoholic fatty liver disease, improving insulin release in a subject, improving carbohydrate metabolism in a subject, improving lipid profile in a subject, reducing appetite, reducing food intake, reducing caloric intake, improving carbohydrate tolerance in a subject, and / or as a cytoprotective agent, e.g., for the prevention or treatment of Parkinsonism, Alzheimer's disease and other types of neurodegeneration and cellular degeneration.

[0016] Also provided herein are methods of treating or preventing a disease or disorder or other undesirable physiological condition in a subject comprising administering a therapeutically effective amount of a compound, derivative, or salt or solvate as defined herein, or administering a composition comprising a therapeutically effective amount of the compound, derivative, salt, or solvate and a pharmaceutically acceptable carrier, for example in methods of treating or preventing diabetes, obesity, heart disease, stroke, or non-alcoholic fatty liver disease in a subject, for improving insulin release in a subject, for improving carbohydrate metabolism in a subject, for improving the lipid profile in a subject, for improving carbohydrate tolerance in a subject, for reducing appetite, for reducing food intake, for reducing calorie intake, and / or for providing cytoprotection in a subject.

[0017] Also provided herein is the use of a compound, derivative, salt or solvate as defined herein for the manufacture of a medicament for improving insulin release in a subject, improving carbohydrate metabolism in a subject, improving the lipid profile of a subject, improving carbohydrate tolerance in a subject, reducing appetite, reducing food intake, reducing calorie intake, preventing or treating diabetes, obesity, heart disease, stroke or non-alcoholic fatty liver disease, and / or for use as a cytoprotective agent, for example in the prevention or treatment of Parkinson's disease, Alzheimer's disease and other types of neurodegeneration and cellular degeneration.

[0018] Also provided herein are methods for causing weight loss or preventing weight gain in a subject for cosmetic purposes, comprising administering an effective amount of a compound, derivative, salt, or solvate defined herein. [Brief explanation of the drawings]

[0019] [Figure 1-1] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-2] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-3] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-4] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-5] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-6]The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-7] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-8] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-9] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-10] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-11] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-12] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-13] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-14] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1"). [Figure 1-15] The amino acid sequences of exemplary compounds of the invention are shown below: Compounds are listed with the N-terminal residue on the left side of the table (indicated by the column titled "1").

[0020] The results of the receptor activation assay (reporter assay), feeding and pharmacokinetic experiments are shown in the rightmost column of FIG.

[0021] array Amino acid sequences herein are presented with the N-terminus at the left, and when sequences are arranged across multiple lines, the N-terminus is at the top left. Unless otherwise specified, amino acid residues in a sequence are L-amino acids.

[0022] The amino acid sequences listed in this application are shown using standard abbreviations for amino acids. The unnatural amino acid 2-aminoisobutyric acid uses its conventional abbreviation "AIB." Norleucine is given the abbreviation "NLeu."

[0023] The specific sequences shown herein relate to particular embodiments of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] definition In order to facilitate review of the various embodiments of the disclosure, the following explanations of specific terms are provided:

[0025] Animal: Living multi-cellular vertebrate organisms, a classification that includes, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term "subject" includes both human and animal subjects. In preferred embodiments of the invention, the subject is a human subject.

[0026] Appetite: A natural desire or craving for food. In one embodiment, appetite is measured by a survey to assess desire for food. Increased appetite generally leads to increased feeding behavior.

[0027] Appetite suppressant: A compound that reduces the desire for food. Over-the-counter appetite suppressants include, but are not limited to, amfepramone (diethylpropion), phentermine, mazindol and phenylpropanolamine, fenfluramine, dexfenfluramine, and fluoxetine.

[0028] Body Mass Index (BMI): A mathematical formula for measuring obesity, sometimes called the Quetelet index. BMI is calculated by multiplying weight (kg) by height. 2 (m 2 The current standard accepted as "normal" for men and women is a BMI of 20-24.9 kg / m 2 In one embodiment, 25 kg / m 2 A BMI above 25 kg / m can be used to identify obese subjects. Grade 1 obesity (sometimes referred to as "overweight" rather than obesity) is defined as a BMI between 25 and 29.9 kg / m 2 Grade II obesity is 30-40 kg / m 2 and grade III obesity corresponds to a BMI of 40 kg / m 2 (Jequier, Am. J Clin. Nutr. 45:1035-47, 1987). Ideal body weight varies among species and individuals based on height, build, bone structure, and sex.

[0029] Cardioprotection refers to the protection of cardiac cells (and especially cardiomyocytes) from apoptosis, necrotic cell death, or degeneration (loss of function). Cardioprotection is most often required after myocardial infarction. However, it can also be used in subjects suffering from ischemic heart disease (e.g., angina pectoris).

[0030] Cytoprotection refers to the protection of cells from apoptosis, necrotic cell death or degeneration (loss of function).

[0031] Diabetes: The failure of cells to transport endogenous glucose across their membranes due to either endogenous insulin deficiency and / or defective insulin sensitivity. Diabetes is a chronic syndrome in which carbohydrate, protein, and fat metabolism are impaired due to insufficient insulin secretion or insulin resistance in target tissues. Diabetes occurs in two major forms: insulin-dependent diabetes mellitus (IDDM, type I) and non-insulin-dependent diabetes mellitus (NIDDM, type II), which differ in etiology, pathogenesis, genetics, age of onset, and treatment.

[0032] The two major forms of diabetes are characterized by an inability to deliver insulin in the amounts and at the precise times needed to control glucose homeostasis. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is caused by the destruction of beta cells, resulting in insufficient levels of endogenous insulin. Type II diabetes, or non-insulin-dependent diabetes, results from defects in both the body's sensitivity to insulin and a relative deficiency in insulin production.

[0033] Energy Metabolism: The body needs to consume a certain amount of energy to maintain normal metabolism. In civilized humans, this is often set at approximately 2,800 calories per day. If food consumption does not provide this, weight loss occurs. However, energy metabolism is also regulated; for example, administration of glucagon increases metabolic rate, leading to the belief that greater food intake is required to achieve energy balance and maintain body weight. Thus, if food intake is maintained at a normal level but energy metabolism is increased, weight loss occurs.

[0034] Food intake: The amount of food consumed by an individual. Food intake can be measured by volume or weight. For example, food intake may be the total amount of food ingested by an individual. In a feeding experiment, "food intake" is the weight of standardized chow consumed by an animal over a 24-hour period. Alternatively, food intake may be the amount of protein, fat, carbohydrates, cholesterol, vitamins, minerals, or any other dietary component of 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, carbohydrate, cholesterol, vitamin, or mineral consumed by an individual.

[0035] GIP (glucose-dependent insulinotropic polypeptide), 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 ingestion. GIP, along with GLP-1, is a member of the incretin class of hormone peptides.

[0036] 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-Asp-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].

[0037] GLP-1: Glucagon-like peptide 1 (GLP-1) is derived from the transcription product of the proglucagon gene. The biologically active form of GLP-1 is GLP-1 (7-37) and GLP-1 (7-36) It is a truncated form known as -NH2 (the -NH2 designation denotes an amino acid sequence in which the C-terminal amino acid has a -C(O)NH2 group instead of a carboxylic acid group).

[0038] 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].

[0039] 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].

[0040] Glucagon: Glucagon is a peptide derived from the proglucagon gene. In humans, it is a 29 amino acid polypeptide with the following sequence: 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].

[0041] Neuroprotection refers to protecting neurons in the nervous system (preferably in the central nervous system) from apoptosis, necrotic cell death, or degeneration (loss of function). Neuroprotective treatments, including those related to various aspects of the present invention, may be required after brain injury (e.g., brain injury after physical trauma or non-traumatic injury, such as stroke, brain tumor, infection, poisoning, hypoxia, ischemia, encephalopathy, or drug abuse). Neuroprotective treatments, including those related to various aspects of the present invention, may also be applied to subjects with chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Gehrig's disease, or Huntington's disease.

[0042] Standard daily diet: The average food intake of an individual of a given species. A standard daily diet can be expressed in terms of calorie intake, protein intake, carbohydrate intake, and / or fat intake. A human standard daily diet generally includes: about 2,000, about 2,400, or about 2,800 calories or significantly more. Furthermore, a human standard daily diet generally includes about 12 g to about 45 g of protein, about 120 g to about 610 g of carbohydrates, and about 11 g to about 90 g of fat. A low-calorie diet is no more than about 85%, preferably no more than about 70%, of a human individual's standard calorie intake.

[0043] In animals, calorie and nutritional requirements vary depending on the species and size of the animal. For example, in cats, the total calorie intake per pound and the distribution rate of protein, carbohydrates, and fat vary depending on the age and breeding status of the cat. However, a general guideline for cats is 40 cal / lb / day (18.2 cal / kg / day). Approximately 30% to 40% should be protein, about 7% to 10% should be carbohydrate, and about 50% to 62.5% should come from fat intake. Those skilled in the art can easily identify the standard daily diet of an individual of any species.

[0044] Obesity: A condition in which excess body fat can put a person at risk for health issues (Barlow and Dietz, Pediatrics 102:E29, 1998; see also National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), Obes. Res. 6(Suppl 2):51S-209S, 1998). Excess body fat is the result of an imbalance between energy intake and energy expenditure. For example, the body mass index (BMI) may be used to assess obesity. In one commonly used convention, a BMI of 25.0 kg / m 2 ~29.9kg / m 2 is overweight with a BMI of 30 kg / m 2 The above BMI indicates obesity.

[0045] Another convention uses waist circumference to assess obesity. In this convention, a waist circumference of 102 cm or greater is considered obese in men, and a waist circumference of 89 cm or greater is considered obese in women. Compelling evidence indicates that obesity affects both an individual's morbidity and mortality. For example, obese individuals are at increased risk of, among other things, heart disease, non-insulin-dependent (type 2) diabetes, hypertension, stroke, cancer (e.g., endometrial, breast, prostate, and colon cancer), dyslipidemia, gallbladder disease, sleep apnea, reduced fertility, and osteoarthritis (see Lyznicki et al., Am. Fam. Phys. 63-2185 (2001)).

[0046] Overweight: An individual who is heavier than their ideal body weight. An overweight individual may be obese, but is not necessarily obese. For example, an overweight individual is any individual who desires to lose weight. In one convention, an overweight individual is one who weighs less than 25.0 kg / m 2 ~29.9kg / m 2 The individual has a BMI of

[0047] Oxyntomodulin (OXM): Oxyntomodulin is a 37-amino acid peptide member of the glucagon superfamily that contains the entire 29-amino acid sequence of glucagon, plus an 8-amino acid carboxy-terminal extension that results from tissue-specific processing of the preproglucagon precursor in the brain and intestine. The human OXM sequence is: 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-Lys-Arg-Asn-Arg-Asn-Ile-Ala [SEQ ID NO: 6].

[0048] PEGylation and PEGylated: PEGylation refers to the process of reacting poly(alkylene glycol), preferably activated poly(alkylene glycol), to form a covalent bond. A promoter, such as an amino acid, for example, lysine, may be used. Although "PEGylation" is often performed using poly(ethylene glycol) or its derivatives, such as methoxypoly(ethylene glycol), the term is not limited to the use of methoxypoly(ethylene glycol) herein, but also includes the use of any other useful poly(alkylene glycol), such as poly(propylene glycol). The term PEGylated refers to a compound containing such a poly(alkylene glycol) group.

[0049] pI: pI is an abbreviation for isoelectric point. An alternative abbreviation sometimes used is IEP. IEP is the pH at which a particular molecule has no net charge. At a pH below its pI, a protein or peptide has a net positive charge. At a pH above its pI, a protein or peptide has a net negative charge. Proteins and peptides can be separated according to their isoelectric points using a technique called isoelectric focusing, an electrophoretic method that utilizes a pH gradient contained within a polyacrylamide gel.

[0050] Peripheral administration: Administration outside the central nervous system. Peripheral administration does not include direct administration to the brain. Peripheral administration includes, but is not limited to, intravascular, intramuscular, subcutaneous, inhalation, oral, rectal, transdermal, or intranasal administration.

[0051] Polypeptide: A polymer in which the monomers are amino acid residues linked together through amide bonds. Unless otherwise specified by context, the terms "polypeptide," "peptide," or "protein" as used herein encompass any amino acid sequence, including modified sequences such as glycoproteins. The term "polypeptide" includes naturally occurring proteins as well as recombinantly or synthetically produced proteins. The term "polypeptide fragment" refers to a portion of a polypeptide, e.g., a fragment that exhibits at least one useful sequence in binding to a receptor. The term "functional fragment of a polypeptide" refers to all fragments of a polypeptide that retain the activity of the polypeptide. Biologically functional peptides can also include fusion proteins in which the peptide of interest is fused to another peptide that does not reduce its desired activity.

[0052] Subcutaneous administration: Subcutaneous administration is the administration of a substance into the subcutaneous layer of fat found between the dermis and deeper tissues of the skin. Subcutaneous administration may be by injection, for example, using a hypodermic needle attached to a syringe or a "pen"-type injection device. Other administration methods, such as microneedles, may also be used. Injections using a hypodermic needle typically cause some degree of pain to the recipient. Such pain can be suppressed by the use of local anesthetics or analgesics. However, the most commonly used method to reduce the perceived pain of injection is simply to distract the subject immediately before and during the injection. Pain can be minimized by using a relatively small gauge hypodermic needle, by injecting a relatively small amount of substance, and by avoiding overly acidic or alkaline compositions, which can cause the subject to experience a "stinging" sensation at the injection site. Compositions with a pH between 4 and 10 are generally considered to be acceptably less painful.

[0053] Therapeutically effective amount: A dose sufficient to prevent progression or cause regression of a disorder, or capable of alleviating the signs or symptoms of a disorder, or capable of achieving a desired result. In some embodiments, a therapeutically effective amount of a compound of the invention is an amount sufficient to inhibit or stop weight gain, or an amount sufficient to reduce appetite.

[0054] Compounds of the Invention The inventors have found that exemplary compounds of the invention have properties that include causing weight loss in vivo. The compounds also have long half-lives in the blood, which means that they can be administered at a conveniently infrequent rate.

[0055] In comparison with GIP and previous derivatives of GIP, the compounds of the present invention have a substitution at a lysine residue at one of multiple positions in the peptide sequence, the substituted lysine is functionalized at its ε-amino group, and the substitution comprises a peptide sequence of up to four residues terminating in a group R-R1, where R1 is COH.

[0056] These are functionalizations that have not been previously investigated, and the beneficial properties discovered by the current inventors have not been seen before.

[0057] As noted above, the compounds of the present invention have the formula (I): 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-Thr41-Gln42-Xaa43 [SEQ ID NO: 1]. During the ceremony, Xaa1 is D-Tyr, His, Phe, or Tyr, or is absent; Xaa2 is AIB or Ala or is absent; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is Tyr or His, Xaa12 is 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 Gln or Ile, Xaa18 is Ala, Arg, or His; Xaa19 is 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 Ile or Leu, Xaa28 is Ala or Asn, Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, Lys*, or absent; Xaa31 is Arg, Gly, or Pro, or is absent; Xaa32 is Asn, Lys, Lys* or absent; Xaa33 is Lys or Lys* or is absent; Xaa34 is Asn or Lys*; Xaa35 is Asp or absent, Xaa36 is Trp or Lys* or is absent; Xaa37 is Lys or Lys* or is absent; Xaa38 is His or absent, Xaa39 is Asn or Lys* or is absent; Xaa40 is Ile, Leu, or Lys* or is absent; Xaa43 is Lys* or absent, wherein Lys* is Lys substituted at its ε-amino group with a group of the formula: Z-Xaa44-Xaa45-Xaa46-Xaa47- During the ceremony, Xaa44 is Gly, Ser, Thr, or absent; Xaa45 is Gly, Ser, or absent; Xaa46 is Asn, Gln, Gly, Ser, Thr, or absent; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr, or absent; Z is a group of the formula: [ka] (Wherein R is C8-C 28 an alkylene or alkenylene chain, and R1 is -CO2H The compounds of formula (I) or formula (II) contain one Lys* residue.

[0058] Next, considering the residues Xaa1 is selected from D-Tyr, His, Phe, or Tyr, or Xaa1 is absent.Preferably, Xaa1 is selected from His, Phe, and Tyr.For example, Xaa1 is selected from His and Tyr, or Xaa1 is selected from Phe and Tyr.For example, Xaa1 is Tyr.In a particularly preferred embodiment, Xaa1 is Tyr.

[0059] Xaa2 is selected from AIB or Ala, or is absent. Preferably, Xaa2 is AIB.

[0060] 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.

[0061] 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.

[0062] Xaa10 is selected from Tyr or His. Preferably, Xaa10 is Tyr.

[0063] Xaa12 is selected from Ile or Lys. Preferably, Xaa12 is Ile.

[0064] 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 Xaa13 is selected from Ala and Val. In a particularly preferred embodiment, Xaa13 is Ala.

[0065] In another embodiment, Xaa13 is selected from Ala, Asp, Asn, Ser. In a particularly preferred embodiment, Xaa13 is Ala.

[0066] According to particular embodiments, 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.

[0067] Xaa14 is selected from Leu, Met or NLeu. Preferably, Xaa14 is Leu.

[0068] Xaa17 is selected from Gln or Ile. Preferably, Xaa17 is Ile.

[0069] 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.

[0070] Xaa19 is selected from Ala or Gln. Preferably, Xaa19 is Gln.

[0071] 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 Xaa20 is selected from Gln and His. In a particularly preferred embodiment, Xaa20 is Gln.

[0072] 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.

[0073] 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.

[0074] Xaa25 is selected from Arg, His, Trp or Tyr. Preferably, Xaa25 is Trp.

[0075] Xaa27 is selected from Ile or Leu. Preferably, Xaa27 is Leu.

[0076] Xaa28 is selected from Ala or Asn. Preferably, Xaa28 is Ala.

[0077] 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.

[0078] Xaa30 is selected from Gly, Lys or Lys*, or Xaa30 is absent. 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.

[0079] Xaa31 is selected from Arg, Gly or Pro, or Xaa31 is absent.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.

[0080] Xaa32 is selected from Asn, Lys, or Lys*, or Xaa32 is absent.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*.

[0081] Xaa33 is Lys or Lys*, or Xaa33 is absent. Preferably, Xaa33 is selected from Lys and Lys*. Alternatively, Xaa33 is Lys or absent. In a particularly preferred embodiment, Xaa33 is Lys.

[0082] Xaa34 is Asn or Lys*, or Xaa34 is absent.Preferably, Xaa34 is selected from Asn and Lys*, or Xaa34 is absent.For example, Xaa34 is selected from Asn and Lys*.Alternatively, Xaa34 is Asn or absent.In a particularly preferred embodiment, Xaa34 is Asn.

[0083] Xaa35 is Asp, or Xaa35 is absent. For example, Xaa35 is Asp. Alternatively, Xaa35 is absent. In a preferred embodiment, Xaa35 is Asp.

[0084] Xaa36 is Trp or Lys*, or Xaa36 is absent. Preferably, Xaa36 is Trp or absent. For example, Xaa36 is Trp. Alternatively, Xaa36 is absent. In a particularly preferred embodiment, Xaa35 is Trp.

[0085] Xaa37 is Lys or Lys*, or Xaa37 is absent. Preferably, Xaa37 is Lys or absent. For example, Xaa37 is Lys. Alternatively, Xaa37 is absent. In a particularly preferred embodiment, Xaa37 is Lys.

[0086] Xaa38 is His, or Xaa38 is absent. For example, Xaa38 is His. Alternatively, Xaa38 is absent. In a particularly preferred embodiment, Xaa38 is His.

[0087] Xaa39 is Asn or Lys*, or Xaa39 is absent. Preferably, Xaa39 is Asn or absent. For example, Xaa39 is Asn. Alternatively, Xaa39 is absent. In a particularly preferred embodiment, Xaa39 is Asn.

[0088] Xaa40 is Ile, Leu or Lys*, or Xaa40 is absent. Preferably, Xaa40 is Ile or absent. For example, Xaa40 is Ile. Alternatively, Xaa40 is absent. In a particularly preferred embodiment, Xaa40 is Ile.

[0089] Xaa41 is Thr or Xaa41 is absent. Preferably, Xaa41 is Thr.

[0090] Xaa42 is Gln or Xaa42 is absent. Preferably, Xaa42 is Gln.

[0091] Xaa43 is Lys* or Xaa43 is absent. Preferably, Xaa43 is absent.

[0092] Lys* substituent binding In the compounds of the present 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 residue present, or to the α-acid group of the Z group if that residue is absent.

[0093] In lysine residues, the ε-amino group is the amino group attached to carbon 6. According to standard IUPAC nomenclature, the atoms in lysine are numbered as follows, indicating the carbon atom numbering and also the α to ε position: [ka]

[0094] The ε-amino group on Lys* referred to herein is the amino group on the C-6 carbon atom as shown.

[0095] According to the present invention, the substituent may be attached to the Lys residue at any position in the peptide sequence represented by Lys* in formula (I). That is, the substituent may be attached to the 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 the Lys residue at position Xaa32.

[0096] The substituents in the compounds of the present invention are of the formula: Z-Xaa44-Xaa45-Xaa46-Xaa47-

[0097] Each residue is considered in turn. Xaa44 is selected from Gly, Ser and Thr; or Xaa44 is absent.Preferably, Xaa44 is Thr, or Xaa44 is absent.For example, Xaa44 is Thr, or alternatively, Xaa44 is absent.In a particularly preferred embodiment, Xaa44 is absent.

[0098] Xaa45 is selected from Gly and Ser; or Xaa45 is absent. For example, Xaa45 is Gly or absent. Alternatively, Xaa45 is Ser or absent. Preferably, Xaa45 is Gly or absent. In a particularly preferred embodiment, Xaa45 is absent.

[0099] Xaa46 is selected from Asn, Gln, Gly, Ser and Thr; or Xaa46 is absent. Preferably, Xaa46 is selected from Asn, Gly, Ser and Thr; or Xaa46 is absent. More preferably, Xaa46 is selected from Asn, Gly and Ser; or Xaa46 is absent. For example, Xaa46 is selected from Asn and Ser; or Xaa46 is absent. Alternatively, Xaa46 is selected from Gly and Ser; or Xaa46 is absent. In a more preferred embodiment, Xaa46 is Ser or absent. In a particularly preferred embodiment, Xaa46 is absent.

[0100] 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 absent. In a particularly preferred embodiment, Xaa47 is Lys.

[0101] Group Z The Z portion of the compound is a group of the formula: [ka] where R is C8-C 28 It is an alkylene or alkenylene chain and R1 is -CO2H.

[0102] Within the Z portion of the molecule, the group R is an alkylene or alkenylene chain linked at one end to residue Xaa44 (or Xaa45 if Xaa44 is absent, or Xaa46 if both Xaa44 and Xaa45 are absent, etc.), and if all of Xaa44-Xaa47 are absent, R is linked at one end to Lys* by a Glu residue via an amide bond. At the other end, the R alkylene or alkenylene chain is attached to the R acid group (COH).

[0103] Option (i) above describes the situation where the Glu residue in the Z group is linked to the Lys* residue via the γ-carboxylic acid group of Glu. Option (ii) above describes the situation where the Glu residue in the Z group is linked to the Lys* residue via the α-carboxylic acid group of Glu. In a preferred embodiment of the invention, the Z moiety of the compound is of formula (i), i.e., the Glu residue in the Z group is linked to the Lys* residue via the γ-carboxylic acid group of Glu.

[0104] Generally, 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 root fatty acid has a chain length that is two greater than the number of carbon atoms in the R alkylene or alkenylene chain.

[0105] In a preferred embodiment, R is C 16 -C 18 R is an alkylene or alkenylene group. For example, R is a straight chain alkylene or alkenylene group. For example, R is C 16 or C 18 It is a straight chain alkylene group. For example, R is C 16 When R is a C group, it can be provided by an octadecanedioic acid moiety. For example, 18 If it is a group, it may be provided by an eicosanedioic acid moiety.

[0106] In a more preferred embodiment, R is C 18 It is an alkylene group.

[0107] In one embodiment of the present invention, the following are preferred: Xaa1 is D-Tyr, His, Phe, or Tyr, or is absent; Xaa2 is AIB or Ala or is absent; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile or Thr, Xaa10 is Tyr, Xaa12 is Ile, Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, or Val; Xaa14 is Leu, Met, or NLeu; Xaa17 is Gln or Ile, Xaa18 is Ala, Arg, or His; Xaa19 is 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 Ile or Leu, Xaa28 is Ala or Asn, Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, Lys*, or absent; Xaa31 is Arg, Gly, or Pro, or is absent; Xaa32 is Asn, Lys, Lys* or absent; Xaa33 is Lys or Lys* or is absent; Xaa34 is Asn or Lys*; Xaa35 is Asp or absent, Xaa36 is Trp or Lys* or is absent; Xaa37 is Lys or Lys* or is absent; Xaa38 is His or absent, Xaa39 is Asn or Lys* or is absent; Xaa40 is Ile, Leu, or Lys* or is absent; Xaa43 is Lys* or absent, wherein Lys* is Lys substituted at its ε-amino group with a group of the formula: Z-Xaa44-Xaa45-Xaa46-Xaa47- During the ceremony, Xaa44 is Gly, Ser, Thr, or absent; Xaa45 is Gly, Ser, or absent; Xaa46 is Asn, Gln, Gly, Ser, Thr, or absent; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr, or absent; Z is a group of the formula: [ka] (Wherein R is C8-C 28 an alkylene or alkenylene chain, and R1 is -CO2H The compounds of formula (I) or formula (II) contain one Lys* residue.

[0108] In one embodiment of the present invention, the following are preferred: Xaa1 is His, Phe, or Tyr; Xaa2 is AIB, Xaa3 is Glu, Gln, or His; Xaa7 is Ile, Xaa10 is Tyr, Xaa12 is Ile, Xaa13 is Ala, Gln, Thr, or Val; Xaa14 is Leu or Met, Xaa17 is Gln or Ile, Xaa18 is Ala or His, Xaa19 is Ala or Gln, Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Asp or Glu, Xaa24 is Asn, Gln, or Glu; Xaa25 is Trp, Xaa27 is Leu, Xaa28 is Ala or Asn, Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, or Lys*; Xaa31 is Arg, Gly or Pro, Xaa32 is Asn, Lys, or Lys*; Xaa33 is Lys or Lys*, or Xaa33 is absent; Xaa34 is Asn or Lys*, or Xaa34 is absent; Xaa35 is Asp or Xaa35 is absent; Xaa36 is Trp or Xaa36 is absent, Xaa37 is Lys, or Xaa37 is absent. Xaa38 is His or Xaa38 is absent, Xaa39 is Asn or Xaa39 is absent, Xaa40 is He or Xaa40 is absent, Xaa41 is Thr or Xaa41 is absent; Xaa42 is Gln or Xaa42 is absent, Xaa43 is Lys* or Xaa43 is absent; Z is (i): [ka] (Wherein R is C 16 or C 18 an alkylene chain, and R1 is -CO2H); Xaa44 is Thr or Xaa44 is absent; Xaa45 is Gly or Xaa45 is absent, Xaa46 is Asn, Gly, or Ser, or Xaa46 is absent, and Xaa47 is Gly or Lys, or Xaa47 is absent.

[0109] In a more preferred embodiment Xaa1 is Tyr, Xaa2 is AIB, Xaa3 is Glu or Gln, Xaa7 is Ile, Xaa10 is Tyr, Xaa12 is Ile, Xaa13 is Ala, Xaa14 is Leu, Xaa17 is Ile, Xaa18 is His, Xaa19 is Gln, Xaa20 is Gln or Lys, Xaa21 is Asp, Xaa24 is Asn or Gln, Xaa27 is Leu, Xaa28 is Ala, Xaa29 is Gln or Gly, Xaa30 is Gly or Lys, Xaa31 is Gly or Pro, Xaa32 is Lys or Lys*, Xaa33 is Lys or Lys*, Xaa34 is Asn or Xaa34 is absent, Xaa35 is Asp or Xaa35 is absent; Xaa36 is Trp or Xaa36 is absent, Xaa37 is Lys, or Xaa37 is absent. Xaa38 is His or Xaa38 is absent; Xaa39 is Asn or Xaa39 is absent, Xaa40 is He or Xaa40 is absent, Xaa41 is Thr or Xaa41 is absent; Xaa42 is Gln or Xaa42 is absent, Xaa43 is Lys* or Xaa43 is absent; Z is (i): [ka] (Wherein R is C 18 an alkylene chain, and R1 is -CO2H); Xaa44 is absent Xaa45 is absent Xaa46 is Ser or Xaa46 is absent; Xaa47 is Lys or Xaa47 is absent.

[0110] For example, in such an embodiment Xaa3 is Glu, Xaa20 is Gln, Xaa24 is Asn, Xaa29 is Gln, Xaa30 is Lys, Xaa31 is Gly, Xaa32 is Lys*, Xaa33 is Lys, Xaa34 is Asn, Xaa35 is Asp, Xaa36 is Trp, Xaa37 is Lys, Xaa38 is His, Xaa39 is Asn, Xaa40 is Ile, Xaa41 is Thr, Xaa42 is Gln, Xaa43 is absent Xaa46 is absent, Xaa47 is Lys or absent.

[0111] In such embodiments, it is even more preferred that Xaa47 is Lys.

[0112] In another embodiment of the present invention, the following are preferred: Xaa1 is His, Phe, or Tyr; Xaa2 is AIB, Xaa3 is Glu, Gln, or His; Xaa7 is Ile or Ser, Xaa10 is Tyr or His, Xaa12 is Ile or Lys, Xaa13 is Ala, Asp, Asn, Gln, Ser, Thr, or Val; Xaa14 is Leu or Met, Xaa17 is Gln or Ile, Xaa18 is Ala or His, Xaa19 is Ala or Gln, Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Asp or Glu, Xaa24 is Asn, Gln, or Glu; Xaa25 is Trp, Xaa27 is Leu, Xaa28 is Ala or Asn, Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, or Lys*; Xaa31 is Arg, Gly or Pro, Xaa32 is Asn, Lys, or Lys*; Xaa33 is Lys or Lys*, or Xaa33 is absent; Xaa34 is Asn or Lys*, or Xaa34 is absent; Xaa35 is Asp or Xaa35 is absent; Xaa36 is Trp or Xaa36 is absent, Xaa37 is Lys, or Xaa37 is absent; Xaa38 is His or Xaa38 is absent, Xaa39 is Asn or Xaa39 is absent, Xaa40 is He or Xaa40 is absent, Xaa41 is Thr or Xaa41 is absent; Xaa42 is Gln or Xaa42 is absent, Xaa43 is Lys* or Xaa43 is absent; Z is (i): [ka] (Wherein R is C 16 or C 18 an alkylene chain, and R1 is -CO2H); Xaa44 is Thr or Xaa44 is absent; Xaa45 is Gly or Xaa45 is absent, Xaa46 is Asn, Gly, or Ser, or Xaa46 is absent, and Xaa47 is Gly or Lys, or Xaa47 is absent.

[0113] For example, in such an embodiment Xaa1 is Tyr, Xaa2 is AlB, Xaa3 is Glu, Xaa7 is Ile or Ser, Xaa10 is Tyr or His, Xaa12 is Ile or Lys, Xaa13 is Asp, Asn, Ala, or Ser; Xaa14 is Leu, Xaa17 is Ile, Xaa18 is His, Xaa19 is Gln, Xaa20 is Gln, Xaa21 is Asp, Xaa24 is Asn, Xaa25 is Trp, Xaa27 is Leu, Xaa28 is Ala, Xaa29 is Gln, Xaa30 is Lys, Xaa31 is Gly, Xaa32 is Lys, Xaa33 is Lys* or absent, Xaa34 is Lys* or absent, Xaa35 is absent Xaa36 is absent Xaa37 is absent Xaa38 is absent Xaa39 is absent Xaa40 is absent Xaa41 is absent Xaa42 is absent Xaa43 is absent Z is (i): [ka] (Wherein R is C 18 an alkylene chain, and R1 is -CO2H); Xaa44 is absent Xaa45 is absent Xaa46 is Asn or absent, Xaa47 is Lys or His, or is absent, for example, Xaa47 is Lys or His.

[0114] As a further example: Xaa7 is Ile, Xaa10 is Tyr, Xaa12 is Ile or Lys, Xaa13 is Ala or Asp, Xaa33 is Lys*, Xaa34 is absent Xaa46 is absent, Xaa47 is Lys or absent, for example, Xaa47 is Lys.

[0115] In one embodiment of the first aspect of the present invention, there is provided a compound of formula (I) or formula (II): WX(I) or WY(II) During the ceremony, 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] During the ceremony, Xaa1 is D-Tyr, His, Phe, or Tyr, or is absent; Xaa2 is AIB or Ala or is absent; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is Tyr or His, Xaa12 is 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 Gln or Ile, Xaa18 is Ala, Arg, or His; Xaa19 is 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 Ile or Leu, Xaa28 is Ala or Asn, and Xaa29 is Gln, Gly, or Thr; X, if present, is the amino acid sequence -Xaa30-Xaa31-Xaa32-Xaa33-Asn34-Asp35-Xaa36-Xaa37-His38-Xaa39-Xaa40-Thr41-Gln42-Xaa43 [SEQ ID NO: 8] During the ceremony, Xaa30 is Gly, Lys, or Lys*; Xaa31 is Gly or Pro, Xaa32 is Lys or Lys*, Xaa33 is Lys or Lys*, Xaa36 is Trp or Lys*, Xaa37 is Lys or Lys*, Xaa39 is Asn or Lys*, Xaa40 is Ile, Leu, or Lys*, and Xaa43 is Lys* or absent, Y, if present, is the amino acid sequence -Xaa30-Xaa31-Xaa32-Xaa33-Xaa34 During the ceremony, Xaa30 is Gly or Lys or is absent; Xaa31 is Arg, Gly, or Pro, or is absent; Xaa32 is Asn or Lys or is absent; Xaa33 is Lys, Lys* or absent; Xaa34 is Lys* or absent, wherein Lys* is Lys substituted at its ε-amino group with a group of the formula: Z-Xaa44-Xaa45-Xaa46-Xaa47- During the ceremony, Xaa44 is Gly, Ser, or Thr, or is absent; Xaa45 is Gly or Ser or is absent; Xaa46 is Asn, Gln, Gly, Ser, or Thr, or is absent; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, or Thr, or is absent; Z is a group of the formula: [ka] (Wherein R is C8-C 28 an alkylene or alkenylene chain, and R1 is -CO2H The compound of formula (I) or formula (II) contains one Lys* residue, or a derivative of said compound, or a salt or solvate of said compound or derivative.

[0116] In certain embodiments of the invention, the compound has formula (I): WX(I) compound, W is the amino acid sequence Xaa1-Xaa2-Xaa3-Gly4-Thr5-Phe6-Xaa7-Ser8-Asp9-Tyr10-Ser11-Ile12-Xaa13-Xaa14-Asp15-Lys16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe22-Val23-Xaa24-Xaa25-Leu26-Xaa27-Xaa28-Xaa29-[SEQ ID NO: 9] During the ceremony, Xaa1 is D-Tyr, His, Phe, or Tyr, or is absent; Xaa2 is AIB or Ala or is absent; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile or Thr, Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, or Val; Xaa14 is Leu, Met, or NLeu; Xaa17 is Gln or Ile, Xaa18 is Ala, Arg, or His; Xaa19 is 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 Ile or Leu, Xaa28 is Ala or Asn, and Xaa29 is Gln, Gly, or Thr; X is the amino acid sequence: -Xaa30-Xaa31-Xaa32-Xaa33-Asn34-Asp35-Xaa36-Xaa37-His38-Xaa39-Xaa40-Thr41-Gln42-Xaa43 [SEQ ID NO: 8] During the ceremony, Xaa30 is Gly, Lys, or Lys*; Xaa31 is Gly or Pro, Xaa32 is Lys or Lys*, Xaa33 is Lys or Lys*, Xaa36 is Trp or Lys*, Xaa37 is Lys or Lys*, Xaa39 is Asn or Lys*, Xaa40 is Ile, Leu, or Lys*, and Xaa43 is Lys* or absent.

[0117] In a preferred embodiment, when the compound of the present invention is a compound of formula (I), Xaa1 is His, Phe, or Tyr; Xaa2 is AIB, Xaa3 is Gln, Glu, or His; Xaa7 is Ile, Xaa13 is Ala, Gln, Thr, or Val; Xaa14 is Leu or Met, Xaa17 is Gln or Ile, Xaa18 is Ala or His, Xaa19 is Ala or Gln, Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Asp or Glu, Xaa24 is Asn, Gln, or Glu; Xaa25 is Trp, Xaa27 is Leu, Xaa28 is Ala or Asn, and Xaa29 is Gln, Gly or Thr.

[0118] In such an embodiment, it is even more preferred that: Xaa1 is Tyr, Xaa2 is AIB, Xaa3 is Glu or Gln, preferably Glu; Xaa7 is Ile, Xaa13 is Ala, Xaa14 is Leu, Xaa17 is Ile, Xaa18 is His, Xaa19 is Gln, Xaa20 is Gln or Lys, preferably Gln; Xaa21 is Asp, Xaa24 is Asn or Gln, preferably Asn; Xaa25 is Trp, Xaa27 is Leu, Xaa28 is Ala, and Xaa29 is Gln or Gly, preferably Gln.

[0119] In a preferred embodiment, when the compound of the present invention is a compound of formula (I), Xaa30 is Lys or Lys*, Xaa31 is Gly, Xaa32 is Lys or Lys*, Xaa33 is Lys or Lys*, Xaa36 is Trp or Lys*, Xaa37 is Lys or Lys*, Xaa39 is Asn or Lys*, Xaa40 is Ile or Lys*, and Xaa43 is Lys* or is absent.

[0120] In such an embodiment, it is even more preferred that: Xaa30 is Lys, Xaa32 is Lys*, Xaa33 is Lys, Xaa36 is Trp, Xaa37 is Lys, Xaa39 is Asn, Xaa40 is He, and Xaa43 is absent.

[0121] In some embodiments, the compound is a compound of formula (II): WY (II) and W is the amino acid sequence: Xaa1-Xaa2-Xaa3-Gly4-Thr5-Phe6-Xaa7-Ser8-Asp9-Tyr10-Ser11-Ile12-Xaa13-Xaa14-Asp15-Lys16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe22-Val23-Xaa24-Xaa25-Leu26-Xaa27-Xaa28-Xaa29-[SEQ ID NO: 9] During the ceremony, Xaa1 is D-Tyr, His, Phe, or Tyr, or is absent; Xaa2 is AIB or Ala or is absent; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile or Thr, Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, or Val; Xaa14 is Leu, Met, or NLeu; Xaa17 is Gln or Ile, Xaa18 is Ala, Arg, or His; Xaa19 is 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 Ile or Leu, Xaa28 is Ala or Asn, and Xaa29 is Gln, Gly, or Thr; Y is the amino acid sequence -Xaa30-Xaa31-Xaa32-Xaa33-Xaa34, During the ceremony, Xaa30 is Gly or Lys or is absent; Xaa31 is Arg, Gly, or Pro, or is absent; Xaa32 is Asn or Lys or is absent; Xaa33 is Lys or absent, Xaa34 is Lys*.

[0122] In another embodiment, when the compound of the present invention is a compound of formula (II): Xaa1 is Tyr, Xaa2 is AlB, Xaa3 is Glu, Xaa7 is Ile, Ser, or Thr; Xaa10 is Tyr or His, Xaa12 is Ile or Lys, Xaa13 is AIB, Ala, Asn, Asp, Ser, or Tyr; Xaa14 is Leu, Xaa17 is Gln or Ile, Xaa18 is Ala or His, Xaa19 is Ala or Gln, Xaa20 is AIB, Gln, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is Ile or Leu, Xaa28 is Ala or Asn, Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly or Lys or is absent; Xaa31 is Arg, Gly, or Pro, or is absent; Xaa32 is Asn or Lys or is absent; Xaa33 is Lys or absent, Xaa34 is Lys*.

[0123] In a preferred embodiment, when the compound of the present invention is a compound of formula (I), Xaa1 is His, Phe, or Tyr; Xaa2 is AIB, Xaa3 is Gln, Glu, or His; Xaa7 is Ile, Xaa13 is Ala, Gln, Thr, or Val; Xaa14 is Leu or Met, Xaa17 is Gln or Ile, Xaa18 is Ala or His, Xaa19 is Ala or Gln, Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Asp or Glu, Xaa24 is Asn, Gln, or Glu; Xaa25 is Trp, Xaa27 is Leu, Xaa28 is Ala or Asn, and Xaa29 is Gln, Gly or Thr.

[0124] In such an embodiment, it is even more preferred that: Xaa1 is Tyr, Xaa2 is AIB, Xaa3 is Glu or Gln, preferably Glu; Xaa7 is Ile, Xaa13 is Ala, Xaa14 is Leu, Xaa17 is Ile, Xaa18 is His, Xaa19 is Gln, Xaa20 is Gln or Lys, preferably Gln; Xaa21 is Asp, Xaa24 is Asn or Gln, preferably Asn; Xaa25 is Trp, Xaa27 is Leu, Xaa28 is Ala, and Xaa29 is Gln or Gly, preferably Gln.

[0125] In a preferred embodiment, when the compound of the present invention is a compound of formula (II), Xaa30 is Lys or Gly, Xaa31 is Gly or Pro, Xaa32 is Lys or absent, Xaa33 is absent, Xaa34 is Lys*.

[0126] In such an embodiment, it is even more preferred that: Xaa30 is Lys, Xaa31 is Gly, Xaa32 is absent Xaa33 is absent, Xaa34 is Lys*.

[0127] In a preferred embodiment, when the compound of the present invention is a compound of formula (II), Xaa1 is Tyr, Xaa2 is AlB, Xaa3 is Glu, Xaa7 is Ile or Ser, Xaa10 is Tyr or His, Xaa12 is Ile or Lys, Xaa13 is Asp, Asn, Ala, or Ser; Xaa14 is Leu, Xaa17 is Ile, Xaa18 is His, Xaa19 is Gln, Xaa20 is Gln, Xaa21 is Asp, Xaa24 is Asn, Xaa25 is Trp, Xaa27 is Leu, Xaa28 is Ala, Xaa29 is Gln, Xaa30 is Lys, Xaa31 is Gly, Xaa32 is Lys, Xaa33 is Lys or absent, Xaa34 is Lys*, wherein Lys* is Lys substituted at its ε-amino group with a group of the formula: Z-Xaa44-Xaa45-Xaa46-Xaa47- During the ceremony, Xaa44 is absent Xaa45 is absent Xaa46 is Asn or absent, Xaa47 is Lys or His, Z is (i): [ka] where R is C 18 an alkylene chain, and R1 is -CO2H); for example, Xaa10 is Tyr, Xaa12 is Ile or Lys, Xaa13 is Ala or Asp, Xaa33 is absent Xaa34 is Lys*, Xaa46 is absent, Xaa47 is Lys.

[0128] In a particularly preferred embodiment, the compound is one of the compounds of the invention set forth in the table of FIG.

[0129] Derivatives and Salts The present invention provides compounds of formula (I), derivatives of such compounds, and salts or solvates of such compounds and derivatives.

[0130] The compounds, derivatives and salts may be produced by recombinant methods well known in the art, or alternatively, by synthetic methods also well known in the art.

[0131] derivative In some embodiments, the present invention relates to compounds of Formula (I) but not derivatives, while in other embodiments, the present invention relates to derivatives of compounds of Formula (I). Derivatives may include, for example, one or more derivatizations selected from amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidation, pegylation, and fusion to another peptide or protein to form a fusion protein; for example, derivatives may include one or more derivatizations selected from amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidation, and pegylation. The structure may be modified at unspecified positions within the molecule or at predetermined positions within the molecule and may include one, two, three, or more attached chemical moieties.

[0132] In certain embodiments, the primary peptide chain of the compounds of the present invention can preferably be amidated at their C-terminus.Such modification is very common in nature, and about half of naturally occurring peptides, including certain gastrointestinal peptide hormones, are susceptible to C-terminus amidation.The present invention encompasses all of the general and specific sequences disclosed herein, including those in the sequence listing and figures, both in amidated and non-amidated form, and where present, particularly preferred on the C-terminus of the primary peptide sequence.

[0133] The derivative may be, for example, a fusion protein, in which the structure of formula (I) is fused to another protein or polypeptide (fusion partner) using recombinant methods known in the art. Alternatively, such a fusion protein may be synthetically synthesized by any known method. Such a fusion protein comprises the structure of formula (I). Any suitable peptide or protein can be used as the fusion partner (e.g., serum albumin, carbonic anhydrase, glutathione-S-transferase, or thioredoxin). Such a fusion protein can be produced by linking the carboxy terminus of the fusion partner to the amino terminus of the structure of formula (I), or vice versa. Optionally, a cleavable linker can be used to link the structure of formula (I) to the fusion partner. The resulting cleavable fusion protein can be cleaved in the body to release the active form of the compound of the present 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 cleavage enzyme, and renin, respectively. For details, see, for example, U.S. Patent No. 6,410,707, the contents of which are incorporated herein by reference.

[0134] The derivatives of the present invention may be, for example, physiologically functional derivatives of the structure of formula (I). The term "physiologically functional derivative" is used herein to refer to chemical derivatives of the compound of formula (I) that have the same physiological function as the corresponding unmodified compound. For example, physiologically functional derivatives may be convertible to the compound of formula (I) in the body. According to the present invention, examples of physiologically functional derivatives include esters, amides, and carbamates, preferably esters and amides. Esters and amides are preferred.

[0135] In addition to derivatization at Lys42, the compounds of the present invention can be further derivatized at additional positions. For example, pharmaceutically acceptable esters and amides of the compounds of the present invention can be prepared by reacting an alkyl, alkenyl, aryl, aralkyl, or aminoalkyl group containing an alcohol or amino moiety with an acid moiety present in the compound of formula (I), or by reacting an alkyl, alkenyl, aryl, aralkyl, or aminoalkyl group containing an activated acyl group with an alcohol or amine group present in the compound of formula (I), with an appropriately attached C 1-20 Alkyl-, C 2-20 Alkenyl-, C 5-10 Aryl-, C 5-10 ar-C 1-20 It may contain an alkyl-, or amino acid-ester or amide group. 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 ), Oleil (C 15 H 29 ) or stearyl (C 17 H 35 )) and bile acids (e.g., cholic acid or deoxycholic acid).

[0136] Methods for lipidating sulfhydryl-containing compounds with fatty acid derivatives are disclosed in U.S. Patent No. 5,936,092; U.S. Patent No. 6,093,692; and U.S. Patent No. 6,225,445 (the contents of which are incorporated herein by reference). Fatty acid derivatives of the compounds of the present invention, including compounds of the present invention linked to a fatty acid via a disulfide bond, can be used to deliver the compounds of the present invention to nerve cells and tissues. Lipidation significantly increases the absorption of the compounds and extends the retention time of the compounds in blood and tissues compared to the absorption rate of the corresponding unlipidated compounds. Furthermore, the disulfide bonds of lipidated derivatives are relatively unstable intracellularly, thus facilitating the intracellular release of the molecules from the fatty acid moiety. Suitable lipid-containing 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 ), Oleil (C 15 H 29 ) or stearyl (C 17 H 35 )) and bile acids (e.g., cholic acid or deoxycholic acid). While the lipid-functionalized compounds of the present invention may have benefits in certain circumstances, it is expected that in most cases it will be simplest and preferable if the compounds of the present invention are not further derivatized so that no additional lipid groups are present.

[0137] Cyclization methods include cyclization via disulfide bridge formation and head-to-tail cyclization using a cyclization resin. Cyclized peptides may have enhanced stability, such as increased resistance to enzymatic degradation, as a result of their conformational constraints. Cyclization may be advantageous, particularly when the non-cyclized peptide contains an N-terminal cysteine ​​group. Suitable cyclized peptides include monomeric and dimeric head-to-tail cyclized structures. Cyclized peptides may contain one or more additional residues, particularly additional cysteines incorporated for the purpose of disulfide bond formation or side chains incorporated for the purpose of resin-based cyclization.

[0138] The derivative may be, for example, a pegylated structure of formula (I). The pegylated compound derivative of the present invention may provide additional advantages, such as increased solubility, stability, and circulation time of the polypeptide, or reduced immunogenicity (see U.S. Pat. No. 4,179,337, the contents of which are incorporated herein by reference).

[0139] Chemical moieties for 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, carboxymethylcellulose, dextran, and polyvinyl alcohol. The polymer moieties for derivatization of the compounds of the present invention may be of any molecular weight, branched or unbranched. For ease of handling and manufacturing, the preferred molecular weight of polyethylene glycol for derivatization of the compounds of the present invention is about 1 kDa to about 100 kDa, the term "about" indicating that in the synthesis of polyethylene glycol, some molecules will be larger and some will be smaller than the stated molecular weight. Polymers of other molecular weights can be used depending on the desired therapeutic profile, e.g., the desired duration of sustained release, the effect on biological activity, if any, the ease of handling, the degree or lack of antigenicity, and other known effects of polyethylene glycol on therapeutic proteins or analogs. For example, polyethylene glycol may be used in the following ranges: about 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, 15, The antibody may have an average molecular weight of 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.

[0140] salt Salt forms of the compounds of formula (I) and derivatives of the compounds also form part of the present invention. In some embodiments, the salts are salts of the compounds of formula (I). In other embodiments, the salts are salts of derivatives of the compounds of formula (I).

[0141] Salts of the compounds of the present invention include those that are pharmaceutically acceptable, i.e., suitable for use in medicines. However, salts having pharmaceutically unacceptable counterions are also within the scope of the invention, for example, for use as intermediates in the preparation of the compounds.

[0142] Suitable salts according to the present invention include salts formed with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed with 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 isethionic acid. Other acids, such as oxalic acid, may be useful as intermediates in obtaining the compounds of the present invention in their final form.

[0143] Pharmaceutically acceptable salts with bases include ammonium salts, alkali metal salts such as potassium salts and sodium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.

[0144] solvate Those skilled in the art of organic chemistry and / or medicinal chemistry will recognize that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. Such complexes are known as "solvates." For example, a complex with water is known as a "hydrate." The present invention also encompasses solvates of the compound of formula (I), solvates of derivatives of the compound, and solvates of salts of the derivatives.

[0145] Those skilled in the art of organic chemistry and / or medicinal chemistry will also understand that many organic compounds can exist in different forms, including as amorphous material and / or in one or more crystalline forms. The various physical forms of an organic compound are known as polymorphs. The present invention also encompasses all such different physical forms of the compound of formula (I), as well as the different physical forms of their derivatives and salts.

[0146] biological activity The compound of the present invention also has activity at human GIP receptor, and can be considered as GIP receptor agonist.This can be evaluated for example by in vitro or cell binding assay or by reporter assay.Preferred compound of the present invention, for example, when tested according to the assay described in the following example section, shows the activity at human GIP receptor that is at least 1 / 50 of the activity of human GIP, preferably at least 1 / 30, 1 / 20, 1 / 10, 1 / 5, 1 / 3 or 1 / 2 of the activity of human GIP.

[0147] Methods for assessing GIP receptor activity are well known. For example, homogeneous time-resolved fluorescence (HRTF) assays (RJ Samms et al., GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice, J. Invest., 2021, 131(12):e146353) detect changes in cAMP accumulation in response to G-coupled G protein-coupled receptor (GPCR) activation. Specific methods are described herein below.

[0148] The preferred compounds of the present invention are effective in promoting insulin release / secretion. This can be assessed, for example, by in vitro or in vivo assays. Methods for assessing insulin release are well known.

[0149] The compounds of the present invention meet some, or more preferably all, of the following criteria. 1) sustained biological activity at the human GIP receptor resulting in appetite inhibition; 2) insulin-releasing activity; 3) High solubility in aqueous solutions with a pH of 3.0 to 8.0, which allows for effective doses to be administered via low-volume injections (thereby reducing the pain of injections). Solubility can be easily assessed by simple in vitro tests. 4) long-term activity in vivo (as assessed in humans or animal models) that allows injections no more than once per day, preferably no more than twice per week, and more preferably no more than once per week, while maintaining acceptable therapeutic or cosmetic benefit; 5) Good weight loss (assessed in human subjects or animal models, evaluation can be completed with co-administration of a GLP1r agonist).

[0150] According to certain embodiments of the invention, particularly those relating to weight loss, obesity, carbohydrate metabolism and diabetes, the compounds, derivatives and salts of the invention have one, some or all of the following characteristics: A. Sufficient solubility between pH 3.0 and pH 8.0 to allow an effective dose to be administered in a volume of less than 1 mL, less than 0.5 mL, or less than 0.3 mL; B. Activation of cAMP signaling in cells overexpressing the human GIP receptor; C. One, some, or all of an additional 1 to 5 characteristics listed above.

[0151] Pharmacokinetics, duration of action and solubility The compounds of the present invention exhibit potent and extended duration of action in vivo after subcutaneous administration. To achieve this, the compounds must possess both good activity at the biological target and excellent pharmacokinetic properties.

[0152] The compounds of the present invention have a therapeutically useful duration of action, which is reflected in the beneficial effects observed in the experiments described herein over several days. The half-life of the compounds of the present invention was evaluated in a pig PK model. It was found that the preferred compounds of the present invention have a half-life equivalent to or longer than that of semaglutide. In addition to exhibiting a long in vivo half-life, the compounds of the present invention have good storage stability and can be used for 4 o C, no significant degradation was observed after 4 weeks of storage in solution.

[0153] Poor water solubility is a known problem for lipid-containing molecules. In contrast, the compounds of the present invention have very good solubility.

[0154] conditions The present invention also provides a compound, derivative or salt of the invention, or a composition comprising said compound, derivative or salt together with a pharmaceutically acceptable carrier and, optionally, a further therapeutic agent, for use as a pharmaceutical.

[0155] The present invention also provides a method for treating or preventing a disease or disorder or other undesirable physiological condition in a subject, comprising administering a therapeutically effective amount of a compound, derivative, or salt of the present invention, or a composition containing said compound, derivative, or salt and a pharmaceutically acceptable carrier, optionally together with an additional therapeutic agent. Preferably, the compound, derivative, salt, or composition is administered subcutaneously.

[0156] According to certain embodiments, the disease or disorder or other undesirable physiological condition is diabetes or obesity, particularly diabetes (eg, type II diabetes).

[0157] According to certain embodiments, the disease or disorder or other undesirable physiological condition may be the physiological condition of being overweight.

[0158] The subject to be administered the compound can be overweight, for example, obese.Alternatively or additionally, the subject can be, for example, a diabetic patient with insulin resistance or impaired glucose tolerance, or both.The subject can have diabetes mellitus, for example, the subject can have type II diabetes.The subject can be overweight, for example, obese, and can have diabetes mellitus, for example, type II diabetes.

[0159] In addition, or alternatively, subject may have or be at risk of the disorder that obesity or overweight is a risk factor.Such disorder includes but is not limited to heart disease, cardiovascular disease, such as hypertension, atherosclerosis, congestive heart failure and dyslipidemia.Stroke; gallbladder disease; osteoarthritis; sleep apnea; reproductive disorder, such as polycystic ovarian syndrome; cancer, such as breast cancer, prostate cancer, colon cancer, endometrial cancer, kidney cancer and esophageal cancer; varicose veins; acanthosis nigricans; eczema; exercise intolerance; insulin resistance; hypertension, high cholesterol; cholelithiasis; osteoarthritis; orthopedic injury; insulin resistance, such as type 2 diabetes and syndrome X; and thromboembolic disease (referring to Kopelman, Nature 404:635-43,2000; Rissanen et al., British Med.J.301,835,1990).

[0160] Other disorders associated with obesity include depression, anxiety, panic attacks, migraine, premenstrual syndrome, chronic pain conditions, fibromyalgia, insomnia, impulsivity, obsessive-compulsive disorder, and myoclonus. Certain neurological disorders and certain neurodegenerations are also associated with obesity. Furthermore, obesity is a recognized risk factor for the increased incidence of complications of general anesthesia (see, for example, Kopelman, Nature 404:635-43, 2000). In general, obesity shortens lifespan and carries a significant risk of the comorbidities listed above.

[0161] Other diseases or disorders associated with obesity are birth defects, maternal obesity associated with an increased incidence of neural tube defects, carpal tunnel syndrome (CTS), chronic venous insufficiency (CVI); daytime sleepiness; deep vein thrombosis (DVT); end-stage renal disease (ESRD); gout; heat disorders; impaired immune response; respiratory dysfunction; infertility; liver disease; back pain; obstetric and gynecological complications; pancreatitis; abdominal hernia; acanthosis nigricans; endocrine disorders; chronic hypoxia and hypercapnia; dermatological effects; elephantiasis; gastroesophageal reflux; heel protrusion; lower extremity edema; breast enlargement causing significant problems such as bra strap pain, skin breakdown, neck pain, chronic odor, and infections in the skin folds under the breasts; large anterior abdominal wall masses, e.g., abdominal panniculitis with frequent panniculitis, causing interference with walking, frequent infections, odor, difficulty dressing, and back pain. musculoskeletal disorders; pseudotumor cerebri (or benign intracranial hypertension), and sliding hiatal hernia.

[0162] In some embodiments, the disease or disorder can be non-alcoholic fatty liver disease.

[0163] According to certain embodiments, the disease or disorder or other undesirable physiological condition may be an undesirable weight, even if the subject is not obese or overweight. The subject may be of normal weight (including, but not limited to, a subject who was previously overweight or obese and wants to prevent returning to an unhealthy weight). The subject may also be a subject who desires weight loss, for example, a female and / or male subject who desires a change in appearance. In some cases where the subject is of normal weight, aspects of the present invention may relate to cosmetic treatments rather than therapeutic treatments.

[0164] The present invention also provides a method for reducing appetite in a subject, reducing food intake in a subject, reducing calorie intake in a subject, improving insulin release in a subject, improving carbohydrate metabolism in a subject, and / or improving carbohydrate tolerance in a subject, comprising administering a therapeutically effective amount of the compound, derivative, salt or composition of the present invention.Such a method can be related to the treatment of a subject with prediabetic conditions, such as insulin insensitivity or prediabetes.

[0165] The present invention also provides a method for improving the lipid profile in a subject, comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention.The present invention also provides a method for alleviating a condition or disorder that can be alleviated by reducing nutrient availability, comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention.

[0166] The compounds, derivatives, salts, or compositions of the invention can be used for weight management and treatment, for example, reducing or preventing obesity, particularly for any one or more of the following: inducing and promoting weight loss; and reducing obesity as measured by body mass index. The compounds, derivatives, salts, or compositions of the invention can be used to maintain any one or more of a desired weight, a desired body mass index, a desired appearance, and good health.

[0167] The present invention may also be used to treat, prevent, ameliorate, or alleviate conditions or disorders caused by, complicated by, or exacerbated by relatively high nutrient availability. The term "condition or disorder that can be alleviated by reducing calorie (or nutrient) availability" is used herein to refer to any condition or disorder in a subject that is caused by, complicated by, or exacerbated by relatively high nutrient availability, or that can be alleviated by reducing nutrient availability, for example, by reducing food intake. Subjects who are insulin resistant, glucose intolerant, or have any type of diabetes mellitus, such as type I, type II, or gestational diabetes, can also benefit from the methods according to the present invention.

[0168] Conditions or disorders associated with increased caloric intake include, but are not limited to, insulin resistance, impaired glucose tolerance, obesity, diabetes, including type 2 diabetes, eating disorders, insulin resistance syndrome, and Alzheimer's disease.

[0169] J. Cereb. Blood Flow Metab. 2011 Apr 13 (Teramoto S et al.) reviewed the use of both GLP-1 and exendin-4 to confer cardioprotection after myocardial infarction and demonstrated that exendin-4 can be used to provide neuroprotection against cerebral ischemia-reperfusion injury. This study showed that mice receiving intravenous exendin-4 after 60 minutes of focal cerebral ischemia significantly reduced infarct volume, improved functional impairment, and suppressed oxidative stress, inflammatory responses, and cell death after reperfusion. This study provided evidence that the protective effects of exendin-4 are mediated through an increase in intracellular cAMP levels, suggesting that exendin-4 may be useful in the treatment of acute ischemic stroke.

[0170] Accordingly, the present invention also provides a method of providing cytoprotection in a subject, such as providing cardioprotection, providing neuroprotection, and / or treating or preventing neurodegeneration, comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention.

[0171] In certain embodiments, the disease or disorder or other undesirable physiological condition that can be treated or prevented by using the compound, derivative, salt or composition of the present invention is neurodegeneration.Such neurodegeneration can be caused by the apoptosis, necrosis or loss of function of nerve cells, preferably in CNS.The neurodegeneration that can be treated or prevented can be the neurodegeneration after brain injury (for example, after physical trauma or after non-traumatic injury such as stroke, tumor, hypoxia, poisoning, infection, ischemia, encephalopathy or drug abuse). Alternatively, or in addition, neurodegeneration may be prevented or treated in a subject with (or diagnosed as predisposed to) a neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, other demyelination-related disorders, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Guillain-Barré syndrome, Wilson's disease, Pick's disease, neuroinflammatory disorders, encephalitis, encephalomyelitis, meningitis, other central nervous system infections, prion diseases, cerebellar ataxia, cerebellar degeneration syndromes, spinocerebellar degeneration, Friedreich's ataxia, ataxia-telangiectasia, spinal dysmyopathy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis, etc. Preferably, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis) and Huntington's disease.In this situation, the treatment is considered to be neuroprotective.According to a particular preferred embodiment, the treatment is neuroprotection after cerebral ischemia or neuroprotection in subjects diagnosed with or predisposed to neurodegenerative diseases.

[0172] According to other embodiments, the disease or disorder or other undesirable physiological condition is cardiac degeneration (particularly myocardial degeneration due to apoptosis, necrosis, or loss of function of cardiomyocytes), in which case the compounds, derivatives, salts, or compositions of the invention provide cardioprotection. According to particularly preferred embodiments, the treatment is the protection of myocardial function after myocardial infarction.

[0173] The present invention also provides a compound, derivative, salt, or composition of the invention for use in the treatment of obesity or diabetes.

[0174] The present invention also provides the compound, derivative, salt or composition of the present invention for use in increasing the energy expenditure of a subject, improving insulin release in a subject, improving carbohydrate tolerance in a subject and / or improving carbohydrate metabolism in a subject.Such use may be related to the treatment of a subject with a pre-diabetic condition, such as insulin insensitivity or pre-diabetes.

[0175] The present invention also provides the compound, derivative, salt or composition of the present invention for use in reducing the appetite of an object, for use in reducing the food intake of an object, for use in reducing the calorie intake of an object, for use in improving the insulin release of an object, and / or for use in improving carbohydrate tolerance of an object.This use can be related to the treatment of the object with pre-diabetic condition, such as insulin insensitivity or pre-diabetes.

[0176] The present invention also provides the compound, derivative, salt or composition of the present invention for use as a cytoprotective agent (for example, in treating or preventing neurodegeneration, in neuroprotection and / or in providing cardioprotection).For example, the compound, derivative, salt or composition may be used for myocardial protection in a subject after myocardial infarction, or for neuroprotection in a subject after cerebral ischemia or stroke, or for neuroprotection in a subject with chronic neurodegenerative disease.The use of the compound, derivative, salt or composition with various neuroprotective or cardioprotective characteristics can be as outlined above in connection with the method of the present invention.

[0177] In the case of neuroprotection, the subject may have previously experienced brain injury, stroke, or other events that cause cerebral ischemia. Alternatively, the subject may have a predisposition to a chronic neurodegenerative disease or may have been diagnosed as having a predisposition to developing a chronic neurodegenerative disease. In the case of cardioprotection, the subject may have previously experienced an event that causes myocardial ischemia, such as myocardial infarction and angina pectoris. According to some embodiments, the compound, derivative, salt, or composition of the present invention can be administered as soon as possible after the subject experiences a suspected myocardial infarction. According to certain embodiments, the compound, derivative, salt, or composition of the present invention can be administered as soon as possible after the subject experiences a suspected stroke.

[0178] The invention also provides the use of a compound, derivative, salt, or composition of the invention for the manufacture of a medicament for the treatment of obesity or diabetes in a subject, which may be as described above in relation to other aspects of the invention.

[0179] The present invention also provides the use of a compound, derivative or salt of the present invention for the manufacture of a medicament for improving insulin release in a subject, improving carbohydrate tolerance in a subject, and / or improving carbohydrate metabolism in a subject. Such uses may be relevant to the treatment of a subject with a pre-diabetic state, such as insulin insensitivity or pre-diabetes.

[0180] The invention also provides the use of a compound, derivative or salt of the invention for the manufacture of a medicament for use in reducing appetite in a subject, reducing food intake in a subject, reducing calorie intake in a subject, improving insulin release in a subject, and / or improving carbohydrate tolerance in a subject.

[0181] The present invention also provides the use of a compound, derivative or salt of the invention for the manufacture of a medicament for providing cytoprotection (e.g., preventing or treating neurodegeneration, providing neuroprotection and / or providing cardioprotection) in a subject as described above with reference to other aspects of the invention.

[0182] According to certain 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.

[0183] The compound, derivative, salt or composition of the present invention is preferably used for treatment in human subjects.However, although the compound, derivative, salt or composition of the present invention is typically used for treating human subjects, they can also be used for treating similar or identical conditions in other vertebrates, such as other primates.Land animals, such as pigs, cattle and poultry;Sport animals, such as horses;Or companion animals, such as dogs and cats.

[0184] composition The compound of formula (I), or its derivatives and / or salts, is preferably included in a pharmaceutical formulation or composition. Accordingly, the present invention provides compositions comprising the compound, derivative, or salt of the present invention, together with a pharmaceutically acceptable excipient and, optionally, another therapeutic ingredient. Compositions comprising the compound, derivative, or salt are suitable for pharmaceutical 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 to 8.0. The compositions of the present invention may take the form of pharmaceutical formulations, as described below.

[0185] Pharmaceutical formulations according to the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intraarticular), inhalation (including fine particle dusts or mists which may be generated by various types of metered-dose pressurized aerosols, nebulizers, or insufflators), rectal, and topical (including dermal, transdermal, transmucosal, buccal, sublingual, and ocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient.

[0186] Preparation can be conveniently presented in unit dosage form, and can be prepared by any method well known in the field of pharmacy.All methods include the step of associating active ingredient with carrier that constitutes one or more auxiliary ingredients.Generally, preparation is prepared by uniformly and intimately associating active ingredient with liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping product into desired preparation.

[0187] The formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary, or paste. Various pharmaceutically acceptable carriers and their formulations are described in standard formulation treatises, such as Remington's Pharmaceutical Sciences by EW Martin. See also Wang, YJ, and Hanson, MA, Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S, 1988, the contents of which are incorporated herein by reference.

[0188] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, glidant, inert diluent, lubricant, surfactant, or dispersant in a suitable machine. Molded tablets may be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored, and may be formulated to provide slow or controlled release of the active ingredient. The compound may be administered in a form suitable for immediate or extended release, for example. Immediate release or extended release can be achieved by using a suitable pharmaceutical composition containing the compound, or, particularly in the case of sustained release, by using a device such as a subcutaneous implant or an osmotic pump. The compound may also be administered in liposomes.

[0189] Preferably, the composition according to the present invention is suitable for subcutaneous administration, for example, by injection. According to certain embodiments, the composition 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 into the circulatory system from the site of subcutaneous administration.

[0190] Exemplary compositions for oral administration include suspensions (such as those known in the art) that may contain, for example, microcrystalline cellulose for bulking, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents; and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose, and / or other excipients, binders, fillers, disintegrants, diluents, and lubricants (such as those known in the art). Such compositions may also contain permeation enhancers. The compounds of the present invention may also be delivered through the oral cavity by sublingual and / or buccal administration. Molded, compressed, or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include those in which the compounds of the present invention are formulated with fast-dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations may also include high-molecular-weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). Such formulations may also include excipients to aid adhesion to the mucosa, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and agents to control release, such as polyacrylic copolymers (Carbopol 934). Lubricants, glidants, flavors, colorants, and stabilizers may also be added for ease of manufacture and use.

[0191] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, a suitable non-toxic, parenterally acceptable diluent or solvent, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agent, and suspending agents including synthetic mono- or diglycerides, and fatty acids, including oleic acid or Cremaphor. The aqueous carrier may be, for example, an isotonic buffer solution having 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, and sodium acetate / acetic acid buffers. The composition preferably does not contain any compounds known to be harmful to peptide compounds.

[0192] 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 minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0193] Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, and / or other solubilizing or dispersing agents (such as those known in the art). Conveniently, in compositions for nasal aerosol or inhalation administration, the compounds of the present invention are delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as 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 to deliver a metered amount. Capsules and cartridges, for example, of gelatin, for use in inhalers or insufflators can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch. In one specific, non-limiting example, the compounds of the present invention are administered as an aerosol from a metered-dose valve through an aerosol adapter, also known as an actuator. Optionally, stabilizers are also included, and / or porous particles are included for deep lung delivery (see, eg, US Pat. No. 6,447,743).

[0194] Formulations for rectal administration may be prepared as retention enemas or suppositories with conventional carriers such as cocoa butter, synthetic glyceride esters, or polyethylene glycols. Such carriers are typically solid at ordinary temperatures but liquefy and / or melt in the rectal cavity to release the drug.

[0195] Formulations for topical administration in the mouth, e.g., buccal or sublingual, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. An exemplary composition for topical administration comprises a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0196] Preferred unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0197] It will be understood that in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents commonly used in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0198] The compounds, derivatives, and salts of the present invention may also be suitably administered as sustained-release systems.Suitable examples of sustained-release systems of the present invention include semipermeable polymer matrices, such as shaped articles, for example, films, or microcapsules.Suitable hydrophobic materials, for example, emulsions in acceptable oils.Or ion exchange resins; and sparingly soluble derivatives of the compounds of the present invention, for example, sparingly soluble salts.Sustained-release systems can be administered orally; rectally; parenterally; intracisternally; intravaginally; intraperitoneally; topically, for example, as powders, ointments, gels, drops, or transdermal patches; bucally; or as oral or nasal sprays.

[0199] The preparation for administration can be suitably formulated to provide controlled release of the compound, derivative and salt of the present invention.For example, pharmaceutical composition can be in the form of particles, which contain one or more of biodegradable polymer, polysaccharide gelling and / or bioadhesive polymer, amphiphilic polymer, agent that can modify the interfacial properties of particles of the compound of the present invention.These compositions exhibit certain biocompatible characteristics that allow controlled release of active substance.See U.S. Patent No. 5,700,486, the contents of which are incorporated by reference.

[0200] The use of controlled-release compositions is preferred for indications such as the treatment of obesity and / or diabetes, where it is desirable to maximize the time between injections. 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 in the shortest possible time, an immediate-release formulation would be preferred. In such cases, an administration regimen including administering a dose of an immediate-release formulation of the active agent (i.e., as soon as possible after suspected myocardial infarction or stroke) followed by administering a dose of a controlled-release formulation of the active agent is preferred.

[0201] The compounds, derivatives, or salts of the present invention can be delivered by pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201, 1987; Buchwald et al., Surgery 88:507, 1980; Saudek et al., N. Engl. J. Med. 321:574, 1989) or by continuous subcutaneous infusion, for example, using a minipump. An intravenous bag solution may also be used. An important factor in selecting the appropriate dose is the results obtained, as measured by a reduction in total body weight or the ratio of body fat to lean body mass, or by other criteria for measuring the management or prevention of obesity or obesity-related conditions, as deemed appropriate by the physician. Other controlled-release systems are discussed in the review by Langer (Science 249:1527-1533, 1990), which is incorporated herein by reference. In another aspect of the disclosure, the compounds of the present invention are delivered by an implantable pump, for example, as described in U.S. Pat. No. 6,436,091, U.S. Pat. No. 5,939,380, and U.S. Pat. No. 5,993,414, the contents of which are incorporated herein by reference.

[0202] Implantable drug infusion devices are used to continuously and long-term administer or infuse drugs or other therapeutic agents into patients. Essentially, such devices can be classified as either active or passive. The compounds, derivatives or salts of the present invention can be formulated as depot preparations. Such long-acting depot preparations can be administered, for example, by subcutaneous or intramuscular implantation or by intramuscular injection. Or by intramuscular injection. Thus, for example, the active ingredient can be formulated with a suitable polymeric or hydrophobic material, for example, as an emulsion in an acceptable oil. Or ion exchange resin; Or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0203] The therapeutically effective amount of the active agent of the present invention can be administered as a single pulse dose, as a bolus dose, or as a pulse dose that is administered over a period of time.Therefore, in pulse dose, a bolus dose of active agent is provided, followed by a period in which no active agent is administered to the subject, and then a second bolus dose is administered.In a specific non-limiting example, pulse dose is administered over a period of one day, one week, or one month.

[0204] Combination treatment: In certain 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 additional agent(s).The compound, derivative, or salt may be administered simultaneously with, for example, one or more additional therapeutic agent(s), or may be administered sequentially or separately.Thus, the present invention provides a compound, derivative, or salt of the present invention for use as a drug to be used together with a therapeutically effective amount of additional therapeutic agent(s) (e.g., for simultaneous, sequential, or separate administration).In certain embodiments, the active agent of the present invention is formulated and administered together with the additional therapeutic agent(s) as a single dose.

[0205] In certain embodiments, the additional therapeutic agent(s) is an additional antidiabetic agent, appetite suppressant, food intake reducer, plasma glucose lowering agent, or plasma lipid altering agent. Specific, non-limiting examples of additional appetite suppressants include amfepramone (diethylpropion), phentermine, mazindol and phenylpropanolamine, fenfluramine, dexfenfluramine, phendimetrazine, benzphetamine, sibutramine, rimonabant, topiramate, fluoxetine, bupropion, zonisamide, naltrexone, orlistat, and cetilistat. Specific non-limiting examples of additional antidiabetic agents include metformin, phenformin, rosiglitazone, pioglitazone, troglitazone, repaglinide, nateglinide, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, fibroblast growth factor 21, miglitol, acarbose, exenatide, pramlintide, vildagliptin, and sitagliptin.

[0206] In a preferred embodiment, the additional therapeutic agent(s) is a GLP-1 receptor agonist. In another preferred embodiment, the additional therapeutic agent(s) is an amylin receptor agonist. In another preferred embodiment, the additional therapeutic agent(s) is a glucagon receptor agonist.

[0207] In an alternative embodiment, the additional therapeutic agents are a GLP-1 receptor agonist and an amylin receptor agonist. In another alternative embodiment, the additional therapeutic agents are a GLP-1 receptor agonist and a glucagon receptor agonist. In another alternative embodiment, the additional therapeutic agents are an amylin receptor agonist and a glucagon receptor agonist.

[0208] In further alternative embodiments, the additional therapeutic agents are a GLP-1 receptor agonist, an amylin receptor agonist, and a glucagon receptor agonist.

[0209] In alternative embodiments, the additional therapeutic agent(s) is an additional cardioprotective or neuroprotective agent. Specific, non-limiting examples of additional cardioprotective agents include aspirin, N-acetylcysteine, phenethylamine, 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 drugs used to treat Parkinson's disease include anticholinergics, pramipexole, bromocriptine, levodopa, carbidopa, rasagiline, amantadine, and ropinirole.

[0210] Dosage: The compounds, derivatives, salts, or compositions of the invention may be administered whenever an effect is desired, such as appetite suppression, reduced food intake, reduced calorie intake, etc., or shortly before the 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 the effect is desired.

[0211] The therapeutically effective amount of an active agent of the present invention will depend on the molecule utilized, the subject being treated, the severity and type of disease, and the method and route of administration. For example, a therapeutically effective amount of a compound of the present invention can vary from about 0.01 μg / kg body weight to about 1 g / kg body weight, e.g., from about 0.1 μg / kg body weight to about 20 mg / kg body weight, e.g., from about 1 μg / kg body weight to about 5 mg / kg body weight, or from about 5 μg / kg body weight to about 1 mg / kg body weight.

[0212] In one embodiment of the present invention, the compound, derivative, or salt of the present invention is administered to a subject at a dose of 0.5 to 1,333 nmol / kg body weight, for example, 1 to 1,333 nmol / kg body weight, for example, 2 to 1,000 nmol / kg body weight, for example, 4 to 1,333 nmol / kg body weight, for example, 5 to 1,000 nmol / kg body weight, for example, 10 to 750 nmol / kg body weight, for example, 20 to 500 nmol / kg body weight, particularly 30 to 240 nmol / kg body weight. In a preferred embodiment, the highly active compound of the present invention is administered to a subject at a dose of 0.2 to 10 nmol / kg body weight, for example, 0.5 to 5.0 nmol / kg body weight, for example, 1.0 to 2.0 nmol / kg body weight, for example, 1.5 nmol / kg body weight. For a 75 kg subject, such a dose corresponds to a dosage of 37.5 nmol to 100 μmol, e.g., 75 nmol to 100 μmol, e.g., 150 nmol to 100 μmol, e.g., 300 nmol to 100 μmol, e.g., 375 nmol to 75 μmol, e.g., 750 nmol to 56.25 μmol, e.g., 1.5 to 37.5 μmol, especially 2.25 to 18 μmol. In a preferred embodiment for a highly potent compound of the invention, for a 75 kg subject, such a dose corresponds to a dosage of 15 to 750 nmol, e.g., 37.5 to 375.0 nmol, e.g., 75 to 150 nmol, e.g., 112.5 nmol. The present invention also contemplates dosage ranges bounded by any of the specific dosage amounts referred to herein.

[0213] The exact dose will be readily determined by one of ordinary skill in the art based on the potency of the particular compound employed, the route of delivery of the compound, and the age, weight, sex, and physiological condition of the subject.

[0214] For compounds with long blood half-lives, the above doses can be administered, for example, once or twice a month, or once, twice, three or four times a week.For preferred compounds, doses can be administered less frequently than once a week.Alternatively, for compounds with short blood half-lives, the doses discussed above can be administered, for example, once, twice, three or four times a day, or once or twice a week.In some embodiments, they can also be administered once every 2, 3 or 4 days.According to certain embodiments, they can be administered once just before each meal is consumed. [Example]

[0215] The invention will now be further described with reference to the following non-limiting examples.

[0216] material and method Peptide synthesis Peptide synthesis was performed on a tricyclic amide linker resin. Amino acids were attached using the Fmoc strategy. Each amino acid was added sequentially from the C-terminus to the N-terminus for the Xaa1–Xaa43 portion of the molecule. Peptide coupling was mediated using reagents such as HBTU. Peptide cleavage from the resin was achieved using trifluoroacetic acid in the presence of a scavenger. In the second step, after deprotection of the ε-amino group, the lysine residue to be substituted was functionalized with its ε-amino group. The chains on the substituted lysine residue were then constructed sequentially using the same amino acid coupling chemistry.

[0217] Peptides were purified by reverse-phase HPLC. Quality control was performed on all purified peptides, and peptides were shown to be >90% pure in most cases by HPLC in two buffer systems. MALDI-MS showed the expected molecular ion.

[0218] Exemplary Synthesis Exemplary compound 91 (GIP Ref 117) was prepared using standard Fmoc chemistry as follows: 1. Preparation of resin: 1-Chloro-2-[chloro(diphenyl)methyl]benzene resin (0.3 mmol, 1.00 eq, Sub 1.08 mmol / g) and Fmoc-Gln(Trt)-OH (1.0 eq) in DCM (20 mL) were added to DIEA (4.0 eq) and stirred with N2 at 25 °C for 2.5 h. The mixture was then filtered to obtain the resin.

[0219] 2. Deprotection: 20% piperidine in DMF (25.00 mL) was added to the resin, and the mixture was stirred with N2 for 15 minutes at 20° C. The resin was washed with DMF (25.00 mL×5) and filtered to obtain the resin.

[0220] 3. Coupling: A solution of HBTU (2.85 eq) and Fmoc-Thr(tBu)-OH (3.00 eq) in DMF (20 mL) was added to the resin along with DIEA (6.00 eq) and stirred with N for 30 min at 20° C. The resin was then washed with DMF (20.0 mL × 5).

[0221] 4. Steps 2 and 3 were repeated using the reagents in Table 1 for the coupling of the following amino acids (3-42):

[0222] [Table 1]

[0223] 5. After coupling of tert-butoxycarbonyl tert-butyl carbonate, 3% H2N·NH2 / DMF was added and reacted for 30 minutes, the reaction was repeated, then drained and washed with DMF (20.0 mL × 5).

[0224] 6. Steps 2 and 3 were repeated for the coupling of the remaining amino acids (43-45) using the reagents in Table 2.

[0225] [Table 2]

[0226] These groups 43-45 are residues 47 and Z in the structure definition in FIG. 1 and in the claims.

[0227] * The protected glutamic acid reagent 44, with its C-1 acid group protected with tBu, reacts with lysine 43 at its C-5 acid, which is the Fmoc-Glu-OtBu reagent providing the glutamic acid residue moiety in the Z portion of the compound when Z is (i). [ka]

[0228] Peptide cleavage and purification: 7. The resin was washed with MeOH (20.0 mL × 2) and dried under vacuum to give 3 g of peptide resin. Then, 30 mL of cleavage buffer (92.5% TFA / 2.5% 3-Mpr / 2.5% TIS / 2.5% HO) was added to the flask containing the side-chain protected peptide resin 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 for 2 h). The peptide precipitate was washed two more times with isopropyl ether (300 mL). The crude peptide was dried under vacuum for 2 h, and its identity was confirmed by LCMS.

[0229] 8. The residue was purified by preparative HPLC (TFA conditions; 30 °C, A: 0.075% TFA / H2O, B: CH3CN) to afford the title compound (244.5 mg, 43.2 μmol, 14.4% yield, 98.3% purity, TFA) as a white solid, the identity of which was confirmed by LCMS.

[0230] An equivalent approach was taken for all other peptides described herein. The sequences and other structural features of the exemplified peptides are shown in Figure 1, in which the Lys* residue is substituted on its epsilon amino group with the group Z-Xaa44-Xaa45-Xaa46-Xaa47- (a blank in the row in question means the residue is absent), and Z is a group with the following structure: [ka] wherein R is C8-C 28 is an alkylene or alkenylene group, R1 is CO2H.

[0231] The number of carbon atoms in the alkylene or alkenylene group of R (n, n = 8-28) is shown in Figure 1 in the column headed "n (R = Cn)." In the examples shown, n is 14, 16, or 18.

[0232] Some of the exemplary compounds in Figure 1 are duplicate preparations of compounds listed elsewhere in the figure and are indicated as "dupl" etc. in the column headed "Notes."

[0233] Receptor potency of peptides at the human GIP receptor overexpressed in HEK cells Biological activity was assessed by the ability of the peptides to stimulate cAMP production in a human embryonic kidney (HEK) cell line overexpressing the SNAP-tagged human GIP receptor. Receptor expression was induced by adding tetracycline to the cell culture medium 24 hours prior to use. On the day of the assay, 8 × 10 cells were cultured in serum-free medium. -5 Cells were seeded in 96-well half-area plates at a density of 1000 cells / mL. After 30 minutes of peptide stimulation and an additional hour of lysis, intracellular cAMP was quantified using a commercially available cAMP kit (Cisbio) by homogeneous time-resolved fluorescence (HTRF) technology. Plates were read on a SpectraMax i3x multimode detection platform plate reader, and concentration-response curves were plotted using Graph Pad Prism 8.0 (or later). EC 50 Values ​​were generated for each peptide and compared to the control for that day.

[0234] In vivo efficacy study: Single dose feeding study in male mice Male mice (Charles River Ltd, Margate, UK) were used for animal experiments. Mice were individually housed in IVC cages and randomized into treatment groups stratified by weight. Mice were fasted overnight before injection. All peptide solutions were freshly prepared immediately before administration. Control animals received 5% v / v water and 95% NaCl (0.9% w / v). Treatment groups received a single subcutaneous injection of 10-45 nmol / kg body weight of GIP analogs combined with 1-1.5 nmol / kg body weight of the GLP-1r agonist G7097 prepared in water for injection. At the time of injection (early light phase; 0900-1000), body weight was measured in grams (g), and each mouse was refed a known amount of food. Subsequent measurements of remaining food and body weight were taken up to 72 hours after administration. Animals had free access to water throughout the study.

[0235] The results for exemplary compounds 1-110 are shown in Figure 1. Mice were fasted overnight, dosed during the early light phase, and then given a known amount of food. Mice were administered a single subcutaneous injection of a subtherapeutic dose of the GLP-1r agonist G7097 (0.5-1 nmol / kg) combined with an exemplary compound (4.5-30 nmol / kg). In the table in Figure 1, column "n" indicates the number of times the compound in question was tested. Each test generally involved administering the compound to a group of five animals. Compounds were evaluated for their tendency to inhibit food intake and their ability to produce weight change. The sum of their effects is reported in Figure 1 as a single value, termed "x," representing efficacy. To assess "potency," the mean difference in food intake, measured in grams, compared to vehicle control was multiplied by the mean difference in body weight, measured in grams, compared to vehicle control, measured at at least two of the following time points: 24, 48, and 72 hours post-dose. The higher the number, the more potent the analog.

[0236] PK measurements for half-life assessment Göttingen minipigs received a single subcutaneous injection of the test compound at the start of the study (0 hours). Repeated blood samples were taken from the pigs over the course of 216 hours, and plasma was separated and stored at -20°C to -80°C. o The plasma concentrations of the test compounds were quantified using mass spectrometry. max t for half of max Calculate the half-life (t 1 / 2- ) is shown. Typically, the presented 1 / 2- is the average of two separate animals.

[0237] result 1 is a table providing amino acid sequences and other structural information for exemplary compounds of the invention. For example, the amino acid sequence of exemplary compound No. 1 is as follows [SEQ ID NO: 12]: [Table 3]

[0238] and the Lys* residue at position 43 has a group at its ε-amino group, Z-Gly-Ser-Gly- Z is a group of the formula: [ka] R is C 18 is a straight-chain alkylene group, R1 is CO2H.

[0239] The figure also summarizes the results of in vivo feeding efficacy studies with exemplary peptides of the invention, as described above.

[0240] To the right of the column showing feeding scores, a figure shows receptor potency data, e.g., for peptides of the GIP receptor overexpressed in human embryonic kidney (HEK) cells. Biological activity was assessed by the potency of the peptides to stimulate cAMP production in HEK cells, as described above.

[0241] As can be seen, mice fasted overnight and administered an example peptide of the invention in combination with the GLP-1r agonist G7097 achieved reduced weight gain or weight loss compared to mice administered G7097 alone or vehicle control animals, supporting the idea that compounds of the invention are particularly effective in improving metabolism and find use in the treatment of disorders such as obesity.

[0242] Half-life: The half-lives of selected compounds of the present invention were measured. The results are shown in hours and are shown in the t 1 / 2 are shown in the column labeled

[0243] Where the above description describes integral inventions or elements that have known, obvious, or foreseeable equivalents, such equivalents are incorporated herein as if individually set forth. The true scope of the invention should be construed to encompass any such equivalents, and reference should be made to the claims to determine this true scope. The reader will also understand that any integers or features of the invention described as preferred, advantageous, convenient, or the like are optional and do not limit the scope of the independent claims. Furthermore, it should be understood that such optional integers or features, while a possible advantage in some embodiments of the invention, may be undesirable and therefore may not be present in other embodiments.

Claims

1. formula: Xaa1-Xaa2-Xaa3-Gly4-Thr5-Phe6-Xaa7-Ser8-Asp9-Xaa10-Ser11-Xaa12-Xaa 13-Xaa14-Asp15-Lys16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe22-Val23-Xaa 24-Xaa25-Leu26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43 [SEQ ID NO: 1], During the ceremony, Xaa1 is DTyr, His, Phe, or Tyr, or is absent; Xaa2 is AIB or Ala or is absent; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is Tyr or His, Xaa12 is 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 Gln or Ile, Xaa18 is Ala, Arg, or His; Xaa19 is 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 Ile or Leu, Xaa28 is Ala or Asn, Xaa29 is Gln, Gly or Thr; Xaa30 is Gly, Lys, or Lys*, or is absent; Xaa31 is Arg, Gly, or Pro, or is absent; Xaa32 is Asn, Lys, Lys*, or absent; Xaa33 is Lys or Lys* or is absent; Xaa34 is Asn or Lys* or is absent; Xaa35 is Asp or absent, Xaa36 is Trp or Lys* or is absent; Xaa37 is Lys or Lys* or is absent; Xaa38 is His or absent, Xaa39 is Asn or Lys* or is absent; Xaa40 is Ile, Leu, or Lys* or is absent; Xaa41 is Thr or absent; Xaa42 is Gln or absent, Xaa43 is Lys* or absent, wherein Lys* is Lys substituted at its ε-amino group with a group of the formula: Z-Xaa44-Xaa45-Xaa46-Xaa47- During the ceremony, Xaa44 is Gly, Ser, Thr or absent; Xaa45 is Gly, Ser, or absent; Xaa46 is Asn, Gln, Gly, Ser, Thr, or is absent; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr, or is absent; Z is a group of the formula: 【Chemistry 1】 (Wherein R is C ８ -C ２８ is an alkylene or alkenylene chain, R １ is -CO ２ H) The compounds of formula (I) or (II) contain one Lys* residue, or a compound containing a derivative of said compound, or a salt or solvate of said derivative.

2. the compound is a compound of formula (I) or (II), W-X (I) or W-Y (II) During the ceremony, 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] During the ceremony, Xaa1 is DTyr, His, Phe, or Tyr, or is absent; Xaa2 is AIB or Ala or is absent; Xaa3 is Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is Tyr or His, Xaa12 is 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 Gln or Ile, Xaa18 is Ala, Arg, or His; Xaa19 is 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 Ile or Leu, Xaa28 is Ala or Asn, and Xaa29 is Gln, Gly or Thr; X, if present, is the amino acid sequence -Xaa30-Xaa31-Xaa32-Xaa33-Asn34-Asp35-Xaa36-Xaa37-His38-Xaa39-Xaa40-Thr41-Gln42-Xaa43 [SEQ ID NO: 8] During the ceremony, Xaa30 is Gly, Lys, or Lys*; Xaa31 is Gly or Pro, Xaa32 is Lys or Lys*, Xaa33 is Lys or Lys*, Xaa36 is Trp or Lys*; Xaa37 is Lys or Lys*, Xaa39 is Asn or Lys*; Xaa40 is Ile, Leu, or Lys*, and Xaa43 is Lys* or absent, wherein Y, if present, is the amino acid sequence -Xaa30-Xaa31-Xaa32-Xaa33-Xaa34 During the ceremony, Xaa30 is Gly or Lys or is absent; Xaa31 is Arg, Gly, or Pro, or is absent; Xaa32 is Asn or Lys or is absent; Xaa33 is Lys, Lys*, or absent, and Xaa34 is Lys* or absent, wherein Lys* is Lys substituted at its ε-amino group with a group of the formula: Z-Xaa44-Xaa45-Xaa46-Xaa47- During the ceremony, Xaa44 is Gly, Ser, or Thr, or is absent; Xaa45 is Gly or Ser or is absent; Xaa46 is Asn, Gln, Gly, Ser, or Thr, or is absent; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, or Thr, or is absent; Z is a group of the formula: 【Chemistry 2】 (Wherein R is C ８ -C ２８ is an alkylene or alkenylene chain, R １ is -CO ２ H) The compound of formula (I) or formula (II) contains one Lys* residue, or a derivative of said compound, a salt or solvate of said derivative according to claim 1.

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

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

5. Xaa3 is Glu, Xaa20 is Gln, Xaa24 is Asn, and 5. The compound, derivative, salt or solvate of claim 4, wherein 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. Xaa30 is Lys or Lys*; Xaa31 is Gly, Xaa32 is Lys or Lys*, Xaa33 is Lys or Lys*, Xaa36 is Trp or Lys*; Xaa37 is Lys or Lys*, Xaa39 is Asn or Lys*; Xaa40 is Ile or Lys*, and 7. The compound, derivative, salt or solvate of claim 6, wherein Xaa43 is Lys* or is absent.

8. Xaa30 is Lys, Xaa32 is Lys*, Xaa33 is Lys, Xaa36 is Trp, Xaa37 is Lys, Xaa39 is Asn, Xaa40 is He, and 8. The compound, derivative, salt or solvate of claim 7, wherein Xaa43 is absent.

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. Xaa30 is Lys or Gly; Xaa31 is Gly or Pro, Xaa32 is Lys or absent, Xaa33 is Lys, Lys* or absent, and 10. The compound, derivative, salt or solvate of claim 9, wherein Xaa34 is Lys* or is absent.

11. Xaa30 is Lys, Xaa31 is Gly, Xaa32 is Lys or absent, Xaa33 is Lys, Lys*, or absent, and 11. The compound, derivative, salt or solvate of claim 10, wherein Xaa34 is Lys* or absent.

12. 2. The compound, derivative, salt or solvate of claim 1 having an amino acid sequence corresponding to any one of the amino acid sequences listed in the table of FIG.

13. 13. A derivative of a compound according to any one of claims 1 to 12, or a salt or solvate of such a derivative, comprising one or more derivatisations selected from amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclisation, lipidation, pegylation and fusion to another peptide or protein to form a fusion protein.

14. A compound, derivative, salt or solvate according to any one of claims 1 to 13 in combination with a further therapeutic agent for simultaneous, sequential or separate administration.

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

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

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

18. A compound, derivative, salt or solvate according to any one of claims 1 to 15, or a composition according to claim 16 or 17, for use as a medicament.

19. A method for treating or preventing a disease or disorder or other undesirable physiological condition in a subject, 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.

20. 18. A compound, derivative, salt or solvate according to any one of claims 1 to 15 or a composition according to claim 16 or 17 for use in the prevention or treatment of diabetes, obesity, heart disease, stroke and non-alcoholic fatty liver disease, for improving insulin release in a subject, for improving carbohydrate metabolism in a subject, for improving the lipid profile of a subject, for reducing appetite, for reducing food intake, for reducing calorie intake, for improving carbohydrate tolerance in a subject, and / or for use as a cytoprotective agent.

21. 21. The compound, derivative, salt or solvate or composition for use as a cytoprotective agent according to claim 20, wherein the compound, derivative, salt or composition provides neuroprotection and / or provides cardioprotection, for use in the prevention or treatment of neurodegeneration.

22. 22. The compound, derivative, salt or solvate, or composition for use as a cytoprotective agent of claim 21, wherein the compound, derivative, salt, or composition is for providing cardioprotection in a subject following a myocardial infarction.

23. 23. The compound, derivative, salt or solvate, or composition for use as a cytoprotective agent of claim 22, wherein the compound, derivative, salt, or composition is for providing neuroprotection in a subject diagnosed with or at risk of having a chronic neurodegenerative disease.

24. 24. The compound, derivative, salt or solvate, or composition for use according to claim 23, wherein the chronic neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, other demyelination-related disorders, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Guillain-Barré syndrome, Wilson's disease, Pick's disease, neuroinflammatory disorders, encephalitis, encephalomyelitis, meningitis, other central nervous system infections, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedreich's ataxia, ataxia-telangiectasia, spinal dysmyopathy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis.

25. 19. A method of 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 the lipid profile in a subject, improving carbohydrate tolerance in a subject, reducing appetite, decreasing food intake, decreasing calorie intake, and / or providing cytoprotection in a subject, comprising administering a therapeutically effective amount of a compound, derivative, salt or solvate of any one of claims 1 to 15, or a composition of claim 16 or claim 17.

26. 16. Use of a compound, derivative, salt or solvate according to any one of claims 1 to 15 for the manufacture of a medicament for the prevention or treatment of diabetes, obesity, heart disease, stroke, and non-alcoholic fatty liver disease, for improving insulin release in a subject, for improving carbohydrate metabolism in a subject, for improving the lipid profile of a subject, for improving carbohydrate tolerance in a subject, for reducing appetite, for reducing food intake, for reducing calorie intake, and / or for use as a cytoprotective agent.

27. 18. A method for causing weight loss or preventing weight gain in a subject for cosmetic purposes, 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 claim 17.

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