Novel compounds

Abstract

The present invention provides novel compounds that are peptide hormone analogs and can be used to treat conditions such as diabetes and obesity. With respect to efficacy properties at glucagon and GLP-1 receptors, compounds of the general sequence listed in the specification have a customized profile. With respect to in vivo properties, it has been demonstrated in animal models that administration of the exemplary peptides of the present invention results in increased weight loss. 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 can be used to treat conditions such as diabetes and obesity. Background Art

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

[0003] The causes of obesity are complex and multifactorial. There is increasing evidence that obesity is not a simple matter of self - control but a complex disorder involving appetite regulation and energy metabolism. Although the etiology of obesity has not been clearly determined, genetic, metabolic, biochemical, cultural, and psychosocial factors are thought to contribute to obesity. Generally, obesity has been described as a condition in which excessive body fat places an individual at health risk.

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

[0005] Diabetes is a chronic syndrome characterized by impaired metabolism of carbohydrates, proteins, and fats due to insufficient insulin secretion or insulin resistance in target tissues. Diabetes occurs in two main forms: insulin - dependent diabetes (type 1 diabetes) and non - insulin - dependent diabetes (type 2 diabetes). Type 1 diabetes or insulin - dependent diabetes mellitus (IDDM) is caused by β - cell destruction, which results in insufficient endogenous insulin levels. Type 2 diabetes or non - insulin - dependent diabetes is due to a defect in the body's sensitivity to insulin and a relative insufficiency in insulin production. According to the 《National Diabetes Statistics Report》, approximately 28.9 million adults 20 years and older in the United States had diabetes in 2014 (estimates from the 2009 - 2012 National Health and Nutrition Examination Survey were applied to 2012 U.S. Census data). Among adults, 90% to 95% of diabetes is type 2 diabetes.

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

[0007] Although diet and exercise provide simple means of reducing weight gain, overweight and obese individuals typically cannot adequately control these factors to effectively lose weight. Pharmacological therapies can be used; several weight loss drugs have been approved by the US Food and Drug Administration and can be used as part of a comprehensive weight loss program. However, many such drugs have been shown to have serious adverse side effects and must therefore be discontinued. When less invasive methods fail and the patient is at high risk of morbidity or mortality associated with obesity, weight loss surgery may be an option for carefully selected patients with clinically severe obesity. However, these treatments are high risk and are suitable for only a limited number of patients. It is not only obese subjects who wish to lose weight. Individuals with weights within the recommended range (such as at the upper end of the recommended range) may wish to lose weight to bring their weight closer to the ideal weight. Thus, there remains a need for agents that can be used to achieve weight loss in overweight and obese subjects as well as in subjects of normal weight.

[0008] Many approaches to developing agents that can be used to achieve weight loss involve gut peptide hormones and their analogs. For example, derivatives of peptides from the preproglucagon molecule have been proposed for the treatment of obesity and / or diabetes. Preproglucagon is a precursor peptide for glucagon as well as other hormones and contains glucagon-like peptide 1 (GLP-1). Glucagon is released in the body when blood glucose levels are low and has the activity of causing the liver to convert stored glycogen into glucose, which is released into the blood, thereby raising the blood glucose level. The presence of nutrients in the intestinal lumen causes GLP-1 to be produced in vivo in intestinal L cells. GLP-1 has many physiological functions, including increasing pancreatic insulin secretion in a glucose-dependent manner, reducing pancreatic glucagon secretion, inhibiting gastric emptying, and reducing food intake by increasing satiety. The increased insulin secretion results in a decrease in the circulating glucose concentration.

[0009] Examples of analogues of such peptides are described, for example, in WO2013 / 004983, which describes peptide molecules containing sequences from GLP-1 and glucagon peptides. WO2015 / 132599 also discloses peptide hormone analogues, which are derived from proglucagon and can be used to treat conditions such as obesity and diabetes. WO2017 / 178829 discloses compounds that are analogues of exendin-4, GLP-1, and oxyntomodulin, which have modified ligand bias and therapeutically useful properties. Another example is the peptide liraglutide, a GLP-1 agonist, whose sequence is GLP-1 (7-37) , in which an arginine residue replaces the native lysine at position 34, and the side chain of the lysine residue at position 26 is hexanoyl acylated via a glutamate spacer linked to lysine. Liraglutide has been developed as an injectable drug for the treatment of type II diabetes.

[0010] However, despite significant progress, the process of identifying substances for use as drugs remains a complex and, in many cases, unpredictable area. To be used as a therapeutic agent, a compound must have a suitable range of properties. In addition to having good efficacy against the biological target of interest, a compound must also have good in vivo pharmacokinetic properties, low toxicity, and an acceptable side effect profile. For example, even with commercial agents such as liraglutide, side effects can include nausea and vomiting, and there are also concerns about thyroid cancer and pancreatitis.

[0011] Accordingly, there is still a need for additional compounds that can be used to treat conditions and diseases such as diabetes and obesity. For example, it would be desirable to identify peptides that have beneficial properties such as an improved activity profile and / or have reduced side effects. For example, it would be desirable to identify peptides that increase a subject's energy expenditure without significantly reducing 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 additionally, it would be desirable to identify peptides that have these and other biological effects over a duration. Compounds with a longer duration of activity can be administered at lower frequencies and lower doses, which results in improved convenience for the subject, fewer side effects, and lower costs. SUMMARY OF THE INVENTION

[0012] In a first aspect, there is provided a compound of formula (I):

[0013] X-W-Y1-Y2

[0014] Formula (I)

[0015] wherein

[0016] X is an amino acid sequence:

[0017] His1-Xaa2-Xaa3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Xaa10-Ser11-Xaa12-Xaa13-Leu14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe22-Xaa23-Xaa24-Trp25-Leu26-Xaa27-Xaa28-Xaa29-[SEQ ID NO:742]

[0018] wherein

[0019] Xaa2 is AIB or Ser;

[0020] Xaa3 is His, Glu, Gln, Asp or Phe;

[0021] Xaa10 is Leu, Tyr or Val;

[0022] Xaa12 is Arg, Lys or His;

[0023] Xaa13 is Tyr, Gln or His;

[0024] Xaa15 is Asp or Glu;

[0025] Xaa16 is Ala, Gln, Glu, Ser, His or Thr;

[0026] Xaa17 is Arg, Glu, His or Lys;

[0027] Xaa18 is Ala, Arg or Lys;

[0028] Xaa19 is Ala or Val;

[0029] Xaa20 is Arg, Gln or His;

[0030] Xaa21 is Asp, Leu, His or Glu;

[0031] Xaa23 is Ile or Val;

[0032] Xaa24 is Gln or Glu;

[0033] Xaa27 is Asn, Leu or Lys;

[0034] Xaa28 is Ala, Asn, Gln, Gly, His, Thr, Leu, Ser or Ile; and

[0035] Xaa29 is Gly, His, Ser or Thr;

[0036] W is an amino acid sequence:

[0037] -His30-His31-His32-His33-His34-[SEQ ID NO:743];

[0038] wherein optionally up to four of the five His residues can each independently be replaced by an amino acid selected from Gly, Ala, Glu, Gln, Pro and Ser, and at least three of the five residues in W are selected from His and Gln.

[0039] Y1 is an amino acid sequence:

[0040] -Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Lys42-Xaa43-Xaa44[SEQ IDNO:744]

[0041] wherein

[0042] Xaa35 is Pro, His, Glu, Ser or Ala;

[0043] Xaa36 is Ser, Gly, Pro or Thr;

[0044] Xaa37 is Pro, Ala, Ser, Glu, Gly or absent;

[0045] Xaa38 is Pro, Ala, Gly, Ser or absent;

[0046] Xaa39 is Pro, Gly, Ala, Ser or absent;

[0047] Xaa40 is Pro, Gly, Ser or absent;

[0048] Xaa41 is Gly, Ser or absent

[0049] Xaa43 is Ser or absent;

[0050] Xaa44 is Trp or absent;

[0051] and the lysine residue at position 42 is substituted at its ε-amino group by a Y2 group and Y2 is:

[0052] Z-Xaa45-Xaa46-Xaa47-Xaa48-[SEQ ID NO:745]

[0053] wherein:

[0054] Xaa45 is Ser, Gly, Thr or absent

[0055] Xaa46 is Ser, Gly, Thr or absent

[0056] Xaa47 is Gly, Asn, Ser, Gln, Thr, His, Tyr, Ala or absent;

[0057] Xaa48 is Ser, Thr, His, Gln, Gly, Asn or absent;

[0058] and Z is a group of the formula:

[0059]

[0060] wherein R is C 8 -C 28 alkylene or alkenylene, and

[0061] R 1 is CO 2 H.

[0062] The compound may optionally be a derivative, salt or solvate as defined herein.

[0063] Surprisingly, the compounds of the present invention have excellent biological properties. For example, with respect to the potency properties against glucagon and GLP-1 receptors, the compounds have a tailored profile. With respect to in vivo properties, it has been demonstrated that administration of exemplary peptides of the present invention to rats results in weight loss. It has also been demonstrated that the exemplary compounds achieve these effects without reducing food intake or only minimally reducing food intake, indicating that the compounds are particularly effective in improving metabolism. Rodents cannot vomit, but rodents experiencing nausea are likely to delay eating. The lack of reduction in food intake levels indicates that the rodents did not experience nausea after receiving the compounds of the present invention. Thus, the lack of reduction (or at least a reduction in food intake levels lower than the level of weight loss) in food intake levels in in vivo experiments further supports that the compounds of the present invention have an improved side effect profile. In addition, the compounds of the present invention enhance insulin release.

[0064] Compared to previous GLP-1 and analogs and derivatives of GLP-1, the compounds of the present invention have a specific residue extension at the C-terminus, including a lysine residue at position 42, and including functionalization of the lysine residue in a specific manner to incorporate the group RR 1 wherein R 1 is CO 2H. These are functionalizations that have not been studied before and the beneficial properties discovered by the present inventors have not been found before.

[0065] The present invention also provides a composition comprising a compound, derivative or salt as defined herein, a pharmaceutically acceptable carrier and optionally an additional therapeutic agent.

[0066] The present invention also provides a compound, derivative or salt as defined herein, or a composition comprising such a compound, derivative or salt and a pharmaceutically acceptable carrier, for use as a medicament for, for example, preventing or treating diabetes, obesity, heart disease, stroke or non-alcoholic fatty liver disease, so as to increase the energy consumption of a subject, improve the insulin release of the subject, improve the carbohydrate metabolism of the subject, improve the lipid profile of the subject, improve the glucose tolerance of the subject, reduce appetite, reduce food intake, reduce calorie intake, and / or act as a cytoprotectant.

[0067] The present invention also provides a method for treating or preventing a disease, disorder or other undesirable physiological condition in a subject, the method comprising, for example, administering a therapeutically effective amount of a compound, derivative or salt as defined herein, or a composition comprising such a compound, derivative or salt and a pharmaceutically acceptable carrier, in a method for treating or preventing diabetes, obesity, heart disease, stroke or non-alcoholic fatty liver disease in a subject, so as to increase the energy consumption of the subject, improve the insulin release of the subject, improve the carbohydrate metabolism of the subject, improve the lipid profile of the subject, improve the glucose tolerance of the subject, reduce appetite, reduce food intake, reduce calorie intake and / or provide cytoprotection for the subject.

[0068] The present invention also provides the use of a compound, derivative or salt as defined herein for the preparation of a medicament for preventing or treating diabetes, obesity, heart disease, stroke or non-alcoholic fatty liver disease, thereby increasing the energy consumption of a subject, improving the insulin release of the subject, improving the carbohydrate metabolism of the subject, improving the lipid profile of the subject, improving the glucose tolerance of the subject, reducing appetite, reducing food intake, reducing calorie intake, and / or acting as a cytoprotectant.

[0069] The present invention also provides a method for reducing the weight of a subject or preventing weight gain for cosmetic purposes, the method comprising administering an effective amount of a compound, derivative, salt or composition as defined herein. Description of the Drawings

[0070] Figure 1The amino acid sequences of exemplary compounds of the present invention are shown. The N-terminal residues of these compounds are presented on the left side of the table (represented by the column titled "1"). The amino acid sequence of each compound is listed on two pages. The results of feeding and receptor binding experiments are shown in the rightmost column.

[0071] Figure 2 The amino acid sequences of other exemplary compounds of the present invention are shown. The N-terminal residues of these compounds are presented on the left side of the table (represented by the column titled "1"). The amino acid sequence of each compound is listed on two pages. The results of feeding experiments are shown in the rightmost column.

[0072] Sequence Listing

[0073] This application is accompanied by a machine-readable sequence listing. In certain embodiments, the present invention includes the sequences of the sequence listing, peptides comprising or consisting of these sequences, and all related uses, methods, and products described therein.

[0074] The N-terminus of the amino acid sequences herein is shown on the left, and in the case where the sequence is shown across multiple lines, the N-terminus is at the upper left. Unless otherwise specified, the amino acid residues in the sequences are L-amino acids.

[0075] The amino acid sequences listed in this application are shown using the standard letter abbreviations for amino acids. The unnatural amino acid 2-aminoisobutyric acid is commonly abbreviated as "AIB".

[0076] The specific sequences given herein are related to specific embodiments of the present invention. Detailed Description

[0077] Definitions

[0078] For ease of review of the various embodiments of the present disclosure, the following explanations of specific terms are provided:

[0079] Animal: A living multicellular vertebrate organism, the classes of which include, for example, mammals and birds. The term mammal includes both human mammals and non-human mammals. Similarly, the term "subject" includes both human subjects and veterinary subjects. In a preferred embodiment of the present invention, the subject is a human subject.

[0080] Appetite: An innate desire or craving for food. In one embodiment, appetite is measured by a survey to assess the need for food. An increase in appetite generally leads to an increase in feeding behavior.

[0081] Appetite inhibitor: A compound that reduces the need for food. Commercially available appetite inhibitors include, but are not limited to, amfepramone (diethylpropion), phentermine, mazindol, and phenylpropanolamine, fenfluramine, dexfenfluramine, and fluoxetine.

[0082] Body Mass Index (BMI): A mathematical formula used to measure body weight, sometimes also referred to as the Quetelet index. BMI is calculated by dividing body weight (in kg) by the square of height (in square meters). The currently considered "normal" standard BMI for men and women is 20 - 24.9 kg / m 2 . In one embodiment, a BMI greater than 25 kg / m 2 can be used to identify obese subjects. Class I obesity (sometimes referred to as "overweight" rather than obese) corresponds to a BMI of 25 - 29.9 kg / m 2 . Class II obesity corresponds to a BMI of 30 - 40 kg / m 2 ; and Class III obesity corresponds to a BMI greater than 40 kg / m 2 (Jequier, Am. J Clin. Nutr. 45:1035 - 47, 1987). Ideal body weight varies between species and individuals due to differences in height, body type, bone structure, and gender.

[0083] Cardioprotection refers to protecting heart cells (especially cardiomyocytes) from apoptosis, necrotic cell death, or degeneration (loss of function). Cardioprotection is most often needed after myocardial infarction, but can also be used in subjects with ischemic heart disease (such as angina).

[0084] Cytoprotection refers to protecting cells from apoptosis, necrotic cell death, or degeneration (loss of function).

[0085] Diabetes: Due to the lack of endogenous insulin and / or defects in insulin sensitivity, cells are unable to transport endogenous glucose across the membrane. Diabetes is a chronic syndrome characterized by impaired metabolism of carbohydrates, proteins, and fats due to insufficient insulin secretion or insulin resistance in target tissues. It occurs in two main forms: insulin - dependent diabetes mellitus (IDDM, type I) and non - insulin - dependent diabetes mellitus (NIDDM, type II), which differ in etiology, pathology, genetics, age of onset, and treatment methods.

[0086] Both main forms of diabetes are characterized by the inability to deliver a certain amount of insulin and have precise timing required to control glucose homeostasis. Type I diabetes or insulin - dependent diabetes mellitus (IDDM) is caused by β - cell destruction, which leads to insufficient levels of endogenous insulin. Type II diabetes or non - insulin - dependent diabetes is due to defects in the body's sensitivity to insulin and a relative deficiency in insulin production.

[0087] Energy metabolism: The human body must expend a certain amount of energy to maintain normal metabolism. In civilized people, this amount is typically set at approximately 2,800 calories per day. If food consumption does not provide this amount, weight loss will result. However, energy metabolism is also regulated, and for example, the administration of glucagon is thought to increase the metabolic rate, thus requiring a greater food intake to achieve energy balance and maintain weight. Therefore, if food intake is maintained at a normal level but energy metabolism increases, weight loss will occur.

[0088] Food intake: The amount of food consumed by an individual. The intake of food can be measured by volume or weight. For example, food intake can be the total amount of food consumed by an individual. Alternatively, food intake can be the amount of protein, fat, carbohydrates, cholesterol, vitamins, minerals, or any other food 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, carbohydrates, cholesterol, vitamins, or minerals consumed by an individual.

[0089] GLP-1: Glucagon-like peptide 1 (GLP-1) is a transcript from the proglucagon gene. The bioactive form of GLP-1 is known as GLP-1 (7-37) and GLP-1 (7-36) -NH 2 is a truncated form (the name -NH 2 represents an amino acid sequence in which the C-terminal amino acid has a –C(O)NH 2 group in place of the carboxylic acid group).

[0090] The sequence of human GLP-1 (7-37) 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:746]

[0091] The sequence of human GLP-1 (7-36) -NH 2 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:747]

[0092] Glucagon: Glucagon is a peptide from the proglucagon gene. Glucagon is a 29 - amino acid polypeptide in the human body, and its 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. [SEQ ID NO:748]

[0093] Neuroprotection refers to protecting neurons within the nervous system (preferably within the central nervous system) from apoptosis, necrotic cell death, or degeneration (loss of function). Neuroprotective treatment 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), including treatments involving various aspects of the present invention. Neuroprotective treatment may also be required for subjects suffering from chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Gaucher's disease, or Huntington's disease, including treatments involving various aspects of the present invention.

[0094] Normal daily diet: The average food intake of an individual of a given species. The normal daily diet can be expressed in terms of calorie, protein, carbohydrate, and / or fat intake. The normal daily diet for humans typically includes the following: from about 2,000, about 2,400, or about 2,800 to significantly more calories. Additionally, the normal daily diet for humans typically contains from about 12 g to about 45 g of protein, from about 120 g to about 610 g of carbohydrate, and from about 11 g to about 90 g of fat. A low - calorie diet will not exceed about 85%, and preferably not exceed about 70%, of the normal calorie intake of a human individual.

[0095] In animals, calorie and nutrient requirements vary depending on the species and size of the animal. For example, in cats, the total calorie intake per pound and the percentage distribution of protein, carbohydrate, and fat vary with the age and reproductive status of the cat. However, a general guideline for cats is 40 calories / pound / day (18.2 calories / kg / day). From about 30% to about 40% should be protein, from about 7% to about 10% should come from carbohydrates, and from about 50% to about 62.5% should be derived from fat intake. A person skilled in the art can readily identify the normal daily diet of an individual of any species.

[0096] Obesity: A medical condition in which excess body fat may place a person at health risks (see Barlow and Dietz, Pediatrics 102:E29, 1998; 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, body mass index (BMI) can be used to assess obesity. In a common convention, a BMI of 25.0 kg / m 2 to 29.9 kg / m 2 is overweight, and a BMI of 30 kg / m 2 or higher is obese.

[0097] In another convention, waist circumference is used to assess obesity. In this convention, in men, a waist circumference of 102 cm or more is considered obese, and in women, a waist circumference of 89 cm or more is considered obese. There is strong evidence that obesity affects an individual's morbidity and mortality. For example, obese individuals have an increased risk of developing 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, etc. (see Lyznicki et al., Am. Fam. Phys. 63:2185, 2001).

[0098] Overweight: An individual whose weight exceeds the ideal weight. An overweight individual may be obese, but is not necessarily obese. For example, an overweight individual is any individual who wishes to lose weight. By convention, an overweight individual is one with a BMI of 25.0 kg / m 2 to 29.9 kg / m 2 of an individual.

[0099] Oxyntomodulin (OXM): Oxyntomodulin is the 37-amino acid peptide member of the glucagon superfamily, which includes the entire 29-amino acid sequence of glucagon, with an eight-amino acid carboxy-terminal extension, and is produced by the tissue-specific processing of preproglucagon precursors in the brain and intestine. The human OXM sequence is as follows:

[0100] 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-Asn-Ile-Ala. [SEQ ID NO:749]

[0101] PEGylation and PEGylated: PEGylation is the process of reacting poly(alkylene glycol), preferably an activated poly(alkylene glycol), to form a covalent bond. Promoters such as amino acids, such as lysine, can be used. Although poly(ethylene glycol) or its derivatives, such as methoxypoly(ethylene glycol), are commonly used for "PEGylation", the term is not limited to the use of methoxypoly(ethylene glycol) herein and also encompasses 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).

[0102] pI: pI is an abbreviation for isoelectric point. An alternative abbreviation sometimes used is IEP. It is the pH value at which a particular molecule carries no net charge. When the pH is below its pI, a protein or peptide carries a net positive charge. When the pH is above its pI, the protein or peptide carries a net negative charge. Proteins and peptides can be separated according to their isoelectric points using a technique called isoelectric focusing, which is an electrophoretic method utilizing a pH gradient contained in a polyacrylamide gel.

[0103] 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.

[0104] Polypeptide: A polymer in which the monomers are amino acid residues linked together by amide bonds. Unless the context indicates otherwise, the terms "polypeptide", "peptide", or "protein" as used herein encompass any amino acid sequence and include modified sequences such as glycoproteins. The term "polypeptide" encompasses naturally occurring proteins as well as recombinantly or synthetically produced proteins. The term "polypeptide fragment" refers to a portion of a polypeptide, such as a fragment that exhibits at least one sequence useful 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 has been fused to another peptide that does not reduce its desired activity.

[0105] Subcutaneous administration: Subcutaneous administration is the administration of a substance into the subcutaneous layer of fat between the dermis of the skin and the underlying tissue. Subcutaneous administration can be carried out by injection using, for example, a subcutaneous injection needle mounted on a syringe or a "pen"-type injection device. Other administration methods can be used, such as microneedles. Injection with a subcutaneous injection needle generally involves a certain degree of pain on behalf of the recipient. This pain can be masked by using a local anesthetic or an analgesic. However, the common method for reducing the perceived injection pain is to distract the subject only immediately before and during the injection. By using a relatively small gauge subcutaneous injection needle, by injecting a relatively small volume of the substance, and by avoiding the use of overly acidic or alkaline compositions (which may cause a "stinging" sensation in the subject at the injection site), the pain can be minimized. Compositions with a pH generally between pH 4 and pH 10 are considered tolerable and comfortable.

[0106] Therapeutically effective amount: A dose sufficient to prevent the progression of a disease or cause the regression of a disease, or a dose capable of alleviating the signs or symptoms of a disease, or a dose capable of achieving a desired result. In some embodiments, a therapeutically effective amount of the compounds of the present invention is an amount sufficient to inhibit or prevent weight gain, or an amount sufficient to reduce appetite, or an amount sufficient to increase energy expenditure.

[0107] The compounds of the present invention

[0108] The inventors have found that the exemplary compounds of the present invention have properties including increasing weight loss in the body without reducing food intake (or reducing food intake less than the level of weight loss).

[0109] Compared with previous GLP-1 and derivatives of GLP-1, the compounds of the present invention have a specific residue extension at the C-terminus, including a lysine residue at position 42, and including the lysine residue functionalized in a specific manner to contain the group RR 1 , where R 1 is CO 2 H. These are functionalizations that have not been studied before, and the beneficial properties discovered by the inventors have not been found before.

[0110] As described above, the compounds of the present invention have the formula (I): X-W-Y1-Y2.

[0111] Within the X part of the molecule, preferably:

[0112] Xaa2 is AIB;

[0113] Xaa3 is His, Gln or Glu;

[0114] Xaa10 is Leu or Tyr;

[0115] Xaa12 is Arg or Lys;

[0116] Xaa13 is Tyr or Gln;

[0117] Xaa15 is Asp or Glu;

[0118] Xaa16 is Ala, Gln, Glu or Ser;

[0119] Xaa17 is Arg, Glu or Lys;

[0120] Xaa18 is Ala, Arg or Lys;

[0121] Xaa19 is Ala or Val;

[0122] Xaa20 is Arg, Gln or His;

[0123] Xaa21 is Asp, Glu or Leu;

[0124] Xaa23 is Ile or Val;

[0125] Xaa24 is Gln or Glu;

[0126] Xaa27 is Leu or Lys;

[0127] Xaa28 is Ala, Asn, Gln or His; and

[0128] Xaa29 is Gly, Ser or Thr;

[0129] In one embodiment within part X of the molecule, preferably:

[0130] Xaa2 is AIB

[0131] Xaa3 is His, Gln or Glu;

[0132] Xaa10 is Tyr;

[0133] Xaa12 is Arg or Lys;

[0134] Xaa13 is Tyr;

[0135] Xaa15 is Asp;

[0136] Xaa16 is Ala, Gln, Glu or Ser;

[0137] Xaa17 is Arg or Lys;

[0138] Xaa18 is Arg or Lys;

[0139] Xaa19 is Ala;

[0140] Xaa20 is Gln or His;

[0141] Xaa21 is Glu or Asp;

[0142] Xaa23 is Ile or Val;

[0143] Xaa24 is Glu or Gln;

[0144] Xaa27 is Leu;

[0145] Xaa28 is Ala, Asn, Gln, His, Thr; and

[0146] Xaa29 is Gly, Ser or Thr.

[0147] In particular, preferably:

[0148] Xaa2 is AIB

[0149] Xaa3 is His, Gln or Glu;

[0150] Xaa10 is Tyr;

[0151] Xaa12 is Arg or Lys;

[0152] Xaa13 is Tyr;

[0153] Xaa15 is Asp;

[0154] Xaa16 is Ala, Gln or Ser;

[0155] Xaa17 is Arg or Lys;

[0156] Xaa18 is Arg or Lys;

[0157] Xaa19 is Ala;

[0158] Xaa20 is Gln or His;

[0159] Xaa21 is Glu or Asp;

[0160] Xaa23 is Ile or Val;

[0161] Xaa24 is Glu or Gln;

[0162] Xaa27 is Leu;

[0163] Xaa28 is Ala, Asn, Gln or His; and

[0164] Xaa29 is Gly, Ser or Thr.

[0165] Considering the residues in turn, Xaa2 is selected from AIB and Ser. Preferably, Xaa2 is AIB.

[0166] Xaa3 is selected from His, Glu, Gln, Asp and Phe. Preferably, Xaa3 is His, Gln or Glu, for example Xaa3 is His. Alternatively, Xaa3 can be Glu.

[0167] Xaa10 is selected from Leu, Tyr and Val. Preferably, Xaa10 is Tyr.

[0168] Xaa12 is selected from Arg, Lys and His. Preferably, Xaa12 is Arg or Lys, for example Xaa12 is Arg. For example Xaa12 is Lys.

[0169] Xaa13 is selected from Tyr, Gln and His. Preferably, Xaa13 is Tyr.

[0170] Xaa15 is selected from Asp and Glu. Preferably, Xaa15 is Asp.

[0171] Xaa16 is selected from Ala, Gln, Glu, Ser, His and Thr. Preferably, Xaa16 is Ala, Gln, Glu or Ser. Xaa16 can be Ala, Gln or Glu. For example Xaa16 is Ala, Gln or Ser; for example Xaa16 is Ala or Gln, especially Ala.

[0172] Xaa17 is selected from Arg, Glu, His and Lys. Preferably, Xaa17 is Arg or Lys, for example Xaa17 is Arg. For example Xaa17 is Lys.

[0173] Xaa18 is selected from Ala, Arg and Lys. Preferably, Xaa18 is Arg or Lys, for example Xaa18 is Arg.

[0174] Xaa19 is selected from Ala and Val. Preferably, Xaa19 is Ala.

[0175] Xaa20 is selected from Arg, Gln and His. Preferably, Xaa20 is Gln or His; in one embodiment, Xaa20 is Arg; in another embodiment, Xaa20 is Gln; in another embodiment, Xaa20 is His.

[0176] Xaa21 is selected from Asp, Leu, His and Glu. Preferably, Xaa21 is Glu or Asp, for example Xaa21 is Glu.

[0177] Xaa23 is selected from Ile and Val. Preferably, Xaa23 is Ile.

[0178] Xaa24 is selected from Gln and Glu. Preferably, Xaa24 is Glu or Gln, especially Glu.

[0179] Xaa27 is selected from Asn, Leu and Lys. Preferably, Xaa27 is Leu.

[0180] Xaa28 is selected from Ala, Asn, Gln, Gly, His, Thr, Leu Ser and Ile. Preferably, Xaa28 is Ala, Asn, Gln, His or Thr. For example, Xaa28 is Ala, Asn, Gln or His, especially Gln.

[0181] Xaa29 is selected from Gly, His, Ser and Thr. Preferably, Xaa29 is Gly, Ser or Thr, especially Ser.

[0182] In a preferred embodiment, X is the amino acid sequence:

[0183] His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Xaa12-Tyr13-Leu14-Asp15-Xaa16-Xaa17-Arg18-Ala19-Xaa20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Xaa28-Xaa29-[SEQ ID NO:750]

[0184] where

[0185] Xaa12 is Arg or Lys;

[0186] Xaa16 is Ala, Gln or Glu;

[0187] Xaa17 is Arg or Lys;

[0188] Xaa20 is Arg, Gln or His; for example Gln or His;

[0189] Xaa28 is Ala, Asn, Gln or His; and

[0190] Xaa29 is Gly, Ser or Thr.

[0191] In a particularly preferred embodiment, X is the amino acid sequence:

[0192] His1 - AIB2 - His3 - Gly4 - Thr5 - Phe6 - Thr7 - Ser8 - Asp9 - Tyr10 - Ser11 - Lys12 - Tyr13 - Leu14 - Asp15 - Ala16 - Lys17 - Arg18 - Ala19 - Xaa20 - Glu21 - Phe22 - Ile23 - Glu24 - Trp25 - Leu26 - Leu27 - Gln28 - Ser29 - [SEQ ID NO:751]

[0193] wherein

[0194] Xaa20 is Arg, Gln or His.

[0195] In such a compound, Xaa20 is preferably Gln.

[0196] In the W part of the molecule, in one embodiment, W has an amino acid sequence selected from the following:

[0197] -Gly30 - His31 - His32 - His33 - His34 - [SEQ ID NO:752]

[0198] -His30 - His31 - His32 - His33 - His34 - [SEQ ID NO:753]

[0199] -His30 - His31 - Gln32 - His33 - His34 - [SEQ ID NO:754]

[0200] -His30 - Gln31 - Gln32 - Gln33 - His34 - [SEQ ID NO:755]

[0201] -His30 - Gln31 - His32 - Pro33 - Ser34 - [SEQ ID NO:756]

[0202] -His30 - Gln31 - His32 - Glu33 - Ser34 - [SEQ ID NO:757]

[0203] -His30 - His31 - Gln32 - Glu33 - Ser34 - [SEQ ID NO:758]

[0204] -His30 - His31 - Gln32 - Ser33 - Pro34 - [SEQ ID NO:759]

[0205] -His30-Glu31-Pro32-Ser33-Pro34-[SEQ ID NO:760]

[0206] -His30-Glu31-Glu32-Ser33-Pro34-[SEQ ID NO:761]

[0207] -His30-Gln31-Gln32-Glu33-Ser34-[SEQ ID NO:762]

[0208] -Gln30-His31-Gln32-His33-Gln34-[SEQ ID NO:763]

[0209] -His30-Gln31-Gln32-His33-His34-[SEQ ID NO:764]

[0210] -His30-His31-Gln32-His33-Gln34-[SEQ ID NO:765]

[0211] -His30-His31-Gln32-Gln33-His34-[SEQ ID NO:766]

[0212] -His30-Gln31-Glu32-Ser33-Pro34-[SEQ ID NO:767]

[0213] -His30-Gln31-Gln32-Pro33-Ser34-[SEQ ID NO:768]

[0214] -Gln30-Gln31-His32-Pro33-Ser34-[SEQ ID NO:769]

[0215] -Gln30-Gln31-His32-Glu33-Ser34-[SEQ ID NO:770]

[0216] -His30-Gln31-Gln32-Ser33-Pro34-[SEQ ID NO:771]

[0217] -His30-Gln31-Gln32-His33-Ser34-[SEQ ID NO:772]

[0218] -His30-Gln31-Gly32-Ala33-Pro34-[SEQ ID NO:773]

[0219] -Gly30-His31-Gly32-Ala33-Pro34-[SEQ ID NO:774]

[0220] -His30-Gly31-Gln32-Gly33-Ala34-[SEQ ID NO:775]

[0221] -His30-Gln31-Gln32-His33-Glu34-[SEQ ID NO:776]

[0222] -His30-Pro31-Ser32-Ser33-Gly34-[SEQ ID NO:777]

[0223] -Gln30-His31-Gln32-His33-Pro34-[SEQ ID NO:778]

[0224] -Gln30-His31-Gln32-His33-His34-[SEQ ID NO:779]

[0225] -His30-Gln31-His32-Gln33-His34-[SEQ ID NO:780]

[0226] -Gly30-Pro31-His32-Ser33-Gly34-[SEQ ID NO:781]

[0227] -His30-Pro31-His32-Ser33-Gly34-[SEQ ID NO:782]

[0228] -Gly30-Pro31-His32-His33-Gly34-[SEQ ID NO:783]

[0229] -His30-His31-Gln32-Gln33-Gln34-[SEQ ID NO:784]

[0230] -Gly30-Pro31-Ser32-His33-Gly34-[SEQ ID NO:785]

[0231] -Gly30-His31-Ser32-Ser33-Gly34-[SEQ ID NO:786]

[0232] -His30-Gln31-His32-Ser33-Gly34-[SEQ ID NO:787]

[0233] -His30-His31-Glu32-Ser33-Pro34-[SEQ ID NO:788]

[0234] -His30-His31-Ser32-Ser33-Gly34-[SEQ ID NO:789]

[0235] -His30-Gln31-Gln32-His33-Gly34-[SEQ ID NO:790]

[0236] -His30-His31-Gln32-His33-Glu34-[SEQ ID NO:791]

[0237] -His30-Gln31-Gln32-His33-Pro34-[SEQ ID NO:792]

[0238] -Gly30-Pro31-His32-Gln33-His34-[SEQ ID NO:793] and

[0239] -Gly30-Pro31-Gln32-His33-Pro34-[SEQ ID NO:794].

[0240] In particular, in the compounds of the present invention, W has the amino acid sequence:

[0241] -Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-[SEQ ID NO:795];

[0242] wherein:

[0243] Xaa30 is His or Gln;

[0244] Xaa31 is His or Gln;

[0245] Xaa32 is His or Gln;

[0246] Xaa33 is His, Gln, Glu or Pro; or

[0247] Xaa34 is His, Glu, Pro or Ser.

[0248] In the preferred compounds of the present invention, W has the amino acid sequence:

[0249] -His30-Gln31-His32-Pro33-Ser34-[SEQ ID NO:756]

[0250] -His30-Gln31-Gln32-His33-Glu34-[SEQ ID NO:776]

[0251] -His30-Gln31-His32-Gln33-His34-[SEQ ID NO:780]

[0252] -His30-His31-Gln32-Gln33-His34-[SEQ ID NO:766]

[0253] -Gln30-Gln31-His32-Glu33-Ser34-[SEQ ID NO:770]

[0254] -His30-Gln31-Gln32-His33-Pro34-[SEQ ID NO:792]

[0255] In one embodiment, within the W portion of the molecule, preferably, W is the amino acid sequence:

[0256] -His30-His31-His32-His33-His34-[SEQ ID NO:796];

[0257] wherein any one of the five His residues can each independently be replaced by an amino acid selected from Gly, Ala, Glu, Gln, and Ser, for example, replaced by Gln. In a preferred embodiment, the residue to be replaced is the third of the five residues. For example, where W has the amino acid sequence:

[0258] -His30-His31-His32-His33-His34-[SEQ ID NO:753]; or

[0259] -His30-His31-Gln32-His33-His34-[SEQ ID NO:754].

[0260] Within the Y1 portion of the molecule, preferably, Y1 is the amino acid sequence, wherein:

[0261] Xaa35 is Pro, His, Glu, Ser, or Ala;

[0262] Xaa36 is Ser, Gly, Pro, or Thr;

[0263] Xaa37 is Pro, Ala, Ser, Glu, Gly, or absent;

[0264] Xaa38 is Pro, Gly, Ala, Ser or absent;

[0265] Xaa39 is Pro, Gly, Ala, Ser or absent;

[0266] Xaa40 is Pro, Gly, Ser or absent;

[0267] Xaa41 is Gly, Ser or absent

[0268] Xaa43 is Ser or absent; and

[0269] Xaa44 is Trp or absent.

[0270] Within the Y1 portion of the molecule, in one embodiment, preferably, Y1 is an amino acid sequence in which:

[0271] Xaa35 is Pro, Glu, Ser or Ala;

[0272] Xaa36 is Ser or Gly;

[0273] Xaa37 is Pro, Glu, Gly or absent;

[0274] Xaa38 is Pro, Gly or absent;

[0275] Xaa39 is Pro, Gly, Ser or absent;

[0276] Xaa40 is Gly, Ser or absent;

[0277] Xaa41 is Gly, Ser or absent

[0278] Xaa43 is Ser or absent; and

[0279] Xaa44 is Trp or absent.

[0280] For example, in a preferred embodiment, Y1 is an amino acid sequence in which:

[0281] Xaa35 is Pro, Glu or Ser;

[0282] Xaa36 is Ser, Gly or Pro;

[0283] Xaa37 is Pro, Ala or Ser;

[0284] Xaa38 is Pro, Ala, Ser or absent;

[0285] Xaa39 is Pro, Gly, Ala or absent;

[0286] Xaa40 is Gly or absent;

[0287] Xaa41 is absent

[0288] Xaa43 is absent; and

[0289] Xaa44 is absent.

[0290] In particular, it is preferred that:

[0291] Xaa35 is Pro or Glu;

[0292] Xaa36 is Ser;

[0293] Xaa37 is Pro or absent;

[0294] Xaa38 is Pro or absent;

[0295] Xaa39 is Pro, Gly, Ser or absent;

[0296] Xaa40 is Gly, Ser or absent;

[0297] Xaa41 is Gly, Ser or absent

[0298] Xaa43 is Ser or absent; and

[0299] Xaa44 is Trp or absent.

[0300] Considering the residues in turn, Xaa35 is selected from Pro, His, Glu, Ser and Ala. Preferably, Xaa35 is Pro, Glu, Ser or Ala, such as Xaa35 is Pro, Glu or Ser; such as Xaa35 is Pro or Glu.

[0301] Xaa36 is selected from Ser, Gly, Pro and Thr, such as Ser, Gly and Thr. Preferably, Xaa36 is Ser, Gly or Pro, such as Ser or Gly, such as Xaa36 is Ser.

[0302] Xaa37 is selected from Pro, Ala, Ser, Glu, Gly or absent, such as Pro, Glu, Gly or absent. Preferably, Xaa37 is Pro, Ala, Ser or absent, such as Xaa37 is Pro, Ala or Ser, such as Xaa37 is Pro.

[0303] Xaa38 is selected from Pro, Gly, Ala, Ser or absent, e.g., Pro, Gly, Ser or absent. Preferably, Xaa38 is Pro, Ala, Ser or absent, e.g., Xaa38 is Pro.

[0304] Xaa39 is selected from Pro, Gly, Ala, Ser or absent, e.g., Pro, Gly, Ser or absent. Preferably, Xaa39 is Pro, Gly, Ala or absent, e.g., Xaa39 is Pro.

[0305] Xaa40 is selected from Pro, Gly, Ser or absent. Preferably, Xaa40 is Gly or Ser; e.g., Xaa40 is Gly or absent, e.g., Gly.

[0306] Xaa41 is selected from Gly, Ser or absent. Preferably, Xaa41 is Gly or absent, e.g., absent.

[0307] Xaa43 is selected from Ser or absent. Preferably, Xaa43 is absent.

[0308] Xaa44 is selected from Trp or absent. Preferably, Xaa44 is absent.

[0309] In a preferred embodiment, Y1 is the amino acid sequence:

[0310] -Pro35-Pro36-Pro37-Lys42 [SEQ ID NO:797];

[0311] -Ser35-Pro36-Pro37-Pro38-Lys42 [SEQ ID NO:798];

[0312] -Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42 [SEQ ID NO:799];

[0313] -Glu35-Ser36-Pro37-Pro38-Pro39-Lys42 [SEQ ID NO:800];

[0314] -Ser35-Gly36-Ala37-Lys42 [SEQ ID NO:801];

[0315] -Ser35-Pro36-Pro37-Pro38-Gly39-Lys42 [SEQ ID NO:802];

[0316] -Ser35-Ser36-Ser37-Ser38-Ala39-Lys42 [SEQ ID NO:803]; or

[0317] -Ser35-Ser36-Ser37-Ala38-Lys42 [SEQ ID NO:804].

[0318] In a preferred embodiment, Y1 is the amino acid sequence:

[0319] -Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42 [SEQ ID NO:805];

[0320] -Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42 [SEQ ID NO:799]; or

[0321] -Glu35-Ser36-Pro37-Pro38-Pro39-Ser40-Gly41-Lys42 [SEQ ID NO:806].

[0322] For example, Y1 is the amino acid sequence:

[0323] -Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42 [SEQ ID NO:799].

[0324] In the compounds of the present invention, the ε-amino group on Lys42 is linked to the acid group of the Xaa48 residue of the Y2 moiety of the molecule such that the bond is an amide bond. If Xaa48 of the sequence Z-Xaa45-Xaa46-Xaa47-Xaa48 [SEQ ID NO:745] or one or more other amino acids are absent, the ε-amino group on Lys42 is linked to the acid group of the next residue present, which may be the acid group of the Z group (if Xaa45, Xaa46, Xaa47, and Xaa48 are all absent).

[0325] In a lysine residue, the ε-amino group is the amino group attached to the 6-carbon. According to standard IUPAC nomenclature, the atoms in lysine are numbered as follows, indicating carbon atom numbering and α to ε positions:

[0326]

[0327] The ε-amino group on Lys42 herein refers to the amino group on the indicated C-6 carbon atom.

[0328] Within the Y2 moiety of the molecule, preferably, Y2 is:

[0329] Z-Xaa45-Xaa46-Xaa47-Xaa48-[SEQ ID NO:807]

[0330] wherein:

[0331] Xaa45 is Gly, Thr or absent

[0332] Xaa46 is Ser, Gly, Thr or absent

[0333] Xaa47 is Gly, Asn, Ser, Gln, Thr, His, Tyr, Ala or absent; and

[0334] Xaa48 is Ser, Thr, His, Gln, Gly, Asn or absent.

[0335] Within the Y2 portion of the molecule, for example Y2 is:

[0336] Z-Xaa45-Xaa46-Xaa47-Xaa48-[SEQ ID NO:808]

[0337] wherein:

[0338] Xaa45 is Gly, Thr or absent

[0339] Xaa46 is Ser, Gly or absent

[0340] Xaa47 is Gly, Asn, Ser, Gln, Thr, His, Tyr or absent; and

[0341] Xaa48 is Ser, Thr, His, Gln, Gly, Asn or absent.

[0342] In particular, preferably, Xaa47 is Gly, Asn, Ser or absent.

[0343] In an alternative embodiment, Y2 is an amino acid sequence, wherein:

[0344] Xaa45 is absent

[0345] Xaa46 is absent

[0346] Xaa47 is Gly, Asn or absent;

[0347] Xaa48 is Ser, His, Asn or absent.

[0348] Considering the residues in turn, Xaa45 is selected from Gly, Thr or absent. Preferably, Xaa45 is absent.

[0349] Xaa46 is selected from Ser, Gly, Thr or is absent. Preferably, Xaa46 is Ser, Gly or is absent; for example, Xaa46 is absent.

[0350] Xaa47 is selected from Gly, Asn, Ser, Gln, Thr, His, Tyr, Ala or is absent. Preferably, Xaa47 is Gly, Asn, Ser, Gln, Thr, His, Tyr or is absent. For example, Xaa47 is Gly, Asn, Ser or is absent, such as Gly, Asn or is absent; for example, it is Asn.

[0351] Xaa48 is selected from Ser, Thr, His, Gln, Gly, Asn or is absent; for example, Xaa48 is Ser, Thr, His, Gln, Gly, Asn or is absent, such as it is Ser, His or is absent. Preferably, Xaa48 is present and is selected from Ser, Thr, His, Gln, Gly and Asn, such as selected from Ser or His, for example, His.

[0352] In a preferred embodiment, Y2 is:

[0353] Z-Gly47-Ser48-;

[0354] Z-Ser46-Gly47-Thr48-;

[0355] Z-Asn47-His48-;

[0356] Z-Gln48-;

[0357] Z-;

[0358] Z-Gly45-Ser46-Gly47-Ser48-[SEQ ID NO:809];

[0359] Z-Asn48-; or

[0360] Z-Thr45-Gly46-Ser47-Gly48-[SEQ ID NO:810].

[0361] For example, Y2 is:

[0362] Z-Gly47-Ser48-;

[0363] Z-Ser46-Gly47-Thr48-;

[0364] Z-Asn47-His48-;

[0365] Z-Gln48-;

[0366] Z-Gly45-Ser46-Gly47-Ser48-[SEQ ID NO:809];

[0367] Z-Asn48-; or

[0368] Z-Thr45-Gly46-Ser47-Gly48-[SEQ ID NO:810].

[0369] In a preferred embodiment, Y2 is:

[0370] Z-Gly47-Ser48-;

[0371] Z-Asn47-His48-;

[0372] Z-; or

[0373] Z-Asn48-.

[0374] For example, Y2 is Z-Asn47-His48-.

[0375] Within the Z portion of the molecule, Z is a group selected from:

[0376]

[0377] wherein R is C 8 -C 28 alkylene or alkenylene, and

[0378] R 1 is CO 2 H.

[0379] Preferably, Z is group (i).

[0380] Group R is an alkylene or alkenylene chain that is linked at one end via an amide bond to residue Xaa48 (or, if Xaa48 and one or more additional residues of Xaa45 to Xaa47 are absent, the next residue). At its other end, the R alkylene or alkenylene chain is bonded to the R 1 acid group (CO 2 H).

[0381] Typically, R has an even number of carbon atoms. For example, R can be an alkylene or alkenylene chain found in a naturally occurring fatty acid. The chain length of the root fatty acid is two times higher than the number of carbon atoms in the R alkylene or alkenylene chain.

[0382] Preferably, R is C 14 C 16 C 18 C20 or C 22 group. For example, R is a straight-chain alkylene or alkenylene group. For example, R is C 16 or C 18 straight-chain alkylene group. For example, when R is C 14 group, it can be provided by the hexadecanedioic acid moiety. For example, when R is C 16 group, it can be provided by the octadecanedioic acid moiety. For example, when R is C 18 group, it can be provided by the eicosanedioic acid moiety. For example, when R is C 20 group, it can be provided by the docosanedioic acid moiety. For example, when R is C 22 group, it can be provided by the tetracosanedioic acid moiety.

[0383] In a preferred embodiment, the compound of the present invention is a compound of formula (I):

[0384] X-W-Y1-Y2

[0385] Formula (I)

[0386] wherein X is an amino acid sequence:

[0387] His1-Xaa2-Xaa3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Xaa10-Ser11-Xaa12-Xaa13-Leu14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe22-Xaa23-Xaa24-Trp25-Leu26-Xaa27-Xaa28-Xaa29-[SEQ ID NO:811]

[0388] wherein

[0389] Xaa2 is AIB;

[0390] Xaa3 is His, Gln or Glu;

[0391] Xaa10 is Leu or Tyr;

[0392] Xaa12 is Arg or Lys;

[0393] Xaa13 is Tyr or Gln;

[0394] Xaa15 is Asp or Glu;

[0395] Xaa16 is Ala, Gln, Glu or Ser;

[0396] Xaa17 is Arg, Glu or Lys;

[0397] Xaa18 is Ala, Arg or Lys;

[0398] Xaa19 is Ala or Val;

[0399] Xaa20 is Arg, Gln or His;

[0400] Xaa21 is Asp, Glu or Leu;

[0401] Xaa23 is Ile or Val;

[0402] Xaa24 is Gln or Glu;

[0403] Xaa27 is Leu or Lys;

[0404] Xaa28 is Ala, Asn, Gln or His; and

[0405] Xaa29 is Gly, Ser or Thr;

[0406] W is an amino acid sequence selected from the following:

[0407] -Gly30-His31-His32-His33-His34-[SEQ ID NO:752]

[0408] -His30-His31-His32-His33-His34-[SEQ ID NO:753]

[0409] -His30-His31-Gln32-His33-His34-[SEQ ID NO:754]

[0410] -His30-Gln31-Gln32-Gln33-His34-[SEQ ID NO:755]

[0411] -His30-Gln31-His32-Pro33-Ser34-[SEQ ID NO:756]

[0412] -His30-Gln31-His32-Glu33-Ser34-[SEQ ID NO:757]

[0413] -His30-His31-Gln32-Glu33-Ser34-[SEQ ID NO:758]

[0414] -His30-His31-Gln32-Ser33-Pro34-[SEQ ID NO:759]

[0415] -His30-Glu31-Pro32-Ser33-Pro34-[SEQ ID NO:760]

[0416] -His30-Glu31-Glu32-Ser33-Pro34-[SEQ ID NO:761]

[0417] -His30-Gln31-Gln32-Glu33-Ser34-[SEQ ID NO:762]

[0418] -Gln30-His31-Gln32-His33-Gln34-[SEQ ID NO:763]

[0419] -His30-Gln31-Gln32-His33-His34-[SEQ ID NO:764]

[0420] -His30-His31-Gln32-His33-Gln34-[SEQ ID NO:765]

[0421] -His30-His31-Gln32-Gln33-His34-[SEQ ID NO:766]

[0422] -His30-Gln31-Glu32-Ser33-Pro34-[SEQ ID NO:767]

[0423] -His30-Gln31-Gln32-Pro33-Ser34-[SEQ ID NO:768]

[0424] -Gln30-Gln31-His32-Pro33-Ser34-[SEQ ID NO:769]

[0425] -Gln30-Gln31-His32-Glu33-Ser34-[SEQ ID NO:770]

[0426] -His30-Gln31-Gln32-Ser33-Pro34-[SEQ ID NO:771]

[0427] -His30-Gln31-Gln32-His33-Ser34-[SEQ ID NO:772]

[0428] -His30-Gln31-Gly32-Ala33-Pro34-[SEQ ID NO:773]

[0429] -Gly30-His31-Gly32-Ala33-Pro34-[SEQ ID NO:774]

[0430] -His30-Gly31-Gln32-Gly33-Ala34-[SEQ ID NO:775]

[0431] -His30-Gln31-Gln32-His33-Glu34-[SEQ ID NO:776]

[0432] -His30-Pro31-Ser32-Ser33-Gly34-[SEQ ID NO:777]

[0433] -Gln30-His31-Gln32-His33-Pro34-[SEQ ID NO:778]

[0434] -Gln30-His31-Gln32-His33-His34-[SEQ ID NO:779]

[0435] -His30-Gln31-His32-Gln33-His34-[SEQ ID NO:780]

[0436] -Gly30-Pro31-His32-Ser33-Gly34-[SEQ ID NO:781]

[0437] -His30-Pro31-His32-Ser33-Gly34-[SEQ ID NO:782]

[0438] -Gly30-Pro31-His32-His33-Gly34-[SEQ ID NO:783]

[0439] -His30-His31-Gln32-Gln33-Gln34-[SEQ ID NO:784]

[0440] -Gly30-Pro31-Ser32-His33-Gly34-[SEQ ID NO:785]

[0441] -Gly30-His31-Ser32-Ser33-Gly34-[SEQ ID NO:786]

[0442] -His30-Gln31-His32-Ser33-Gly34-[SEQ ID NO:787]

[0443] -His30-His31-Glu32-Ser33-Pro34-[SEQ ID NO:788]

[0444] -His30-His31-Ser32-Ser33-Gly34-[SEQ ID NO:789]

[0445] -His30-Gln31-Gln32-His33-Gly34-[SEQ ID NO:790]

[0446] -His30-His31-Gln32-His33-Glu34-[SEQ ID NO:791]

[0447] -His30-Gln31-Gln32-His33-Pro34-[SEQ ID NO:792]

[0448] -Gly30-Pro31-His32-Gln33-His34-[SEQ ID NO:793] and

[0449] -Gly30-Pro31-Gln32-His33-Pro34-[SEQ ID NO:794];

[0450] Y1 is an amino acid sequence, wherein:

[0451] Xaa35 is Pro, His, Glu, Ser or Ala;

[0452] Xaa36 is Ser, Gly, Pro or Thr;

[0453] Xaa37 is Pro, Ala, Ser, Glu, Gly or absent;

[0454] Xaa38 is Pro, Gly, Ala, Ser or absent;

[0455] Xaa39 is Pro, Gly, Ala, Ser or absent;

[0456] Xaa40 is Pro, Gly, Ser or absent;

[0457] Xaa41 is Gly, Ser or absent

[0458] Xaa43 is Ser or absent;

[0459] Xaa44 is Trp or absent;

[0460] Y2 is selected from:

[0461] Z-Gly47-Ser48-;

[0462] Z-Ser46-Gly47-Thr48-;

[0463] Z-Asn47-His48-;

[0464] Z-Gln48-;

[0465] Z-;

[0466] Z-Gly45-Ser46-Gly47-Ser48-[SEQ ID NO:809];

[0467] Z-Asn48-; and

[0468] Z-Thr45-Gly46-Ser47-Gly48-[SEQ ID NO:810];

[0469] and Z is a group of the formula:

[0470]

[0471] wherein R is C 14 、C 16 、C 18 、C 20 or C 22 linear alkylene, and

[0472] R 1 is CO 2 H.

[0473] For example, the compounds of the present invention are compounds of formula (I):

[0474] X-W-Y1-Y2

[0475] Formula (I)

[0476] wherein:

[0477] X is an amino acid sequence:

[0478] His1-Xaa2-Xaa3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Xaa10-Ser11-Xaa12-Xaa13-Leu14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe22-Xaa23-Xaa24-Trp25-Leu26-Xaa27-Xaa28-Xaa29-[SEQ ID NO:742]

[0479] wherein

[0480] Xaa2 is AIB or Ser;

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

[0482] Xaa10 is Leu, Tyr or Val;

[0483] Xaa12 is Arg, Lys or His;

[0484] Xaa13 is Tyr, Gln or His

[0485] Xaa15 is Asp or Glu;

[0486] Xaa16 is Ala, Gln, Glu, Ser, His or Thr;

[0487] Xaa17 is Arg, Glu, His or Lys;

[0488] Xaa18 is Ala, Arg or Lys;

[0489] Xaa19 is Ala or Val;

[0490] Xaa20 is Arg, Gln or His;

[0491] Xaa21 is Asp, Leu, His or Glu;

[0492] Xaa23 is Ile or Val;

[0493] Xaa24 is Gln or Glu;

[0494] Xaa27 is Asn, Leu or Lys;

[0495] Xaa28 is Ala, Asn, Gln, Gly, His, Thr, Leu, Ser or Ile; and

[0496] Xaa29 is Gly, His, Ser or Thr;

[0497] W is the amino acid sequence:

[0498] -His30-His31-His32-His33-His34-[SEQ ID NO:797];

[0499] wherein at most two of the five His residues, optionally, may each independently be replaced by an amino acid selected from Gly, Ala, Glu, Gln, and Ser;

[0500] Y1 is the amino acid sequence:

[0501] -Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Lys42-Xaa43-Xaa44[SEQ IDNO:812]

[0502] wherein

[0503] Xaa35 is Pro, His, Glu, Ser, or Ala;

[0504] Xaa36 is Ser, Gly, or Thr;

[0505] Xaa37 is Pro, Glu, Gly, or absent;

[0506] Xaa38 is Pro, Gly, Ser, or absent;

[0507] Xaa39 is Pro, Gly, Ser, or absent;

[0508] Xaa40 is Pro, Gly, Ser, or absent;

[0509] Xaa41 is Gly, Ser, or absent

[0510] Xaa43 is Ser or absent;

[0511] Xaa44 is Trp or absent;

[0512] and the lysine residue at position 42 is substituted at its ε-amino group by the group Y2

[0513] and Y2 is:

[0514] Z-Xaa45-Xaa46-Xaa47-Xaa48-[SEQ ID NO:745]

[0515] wherein:

[0516] Xaa45 is Ser, Gly, Thr, or absent

[0517] Xaa46 is Ser, Gly, Thr or absent

[0518] Xaa47 is Gly, Asn, Ser, Gln, Thr, His, Tyr, Ala or absent; and

[0519] Xaa48 is Ser, Thr, His, Gln, Gly, Asn or absent;

[0520] and Z is a group of the formula:

[0521]

[0522] wherein R is C 8 -C 28 alkylene or alkenylene, and

[0523] R 1 is CO 2 H.

[0524] Such compounds may have the preferred features described above.

[0525] For example, the compounds of the present invention are compounds of formula (I):

[0526] X-W-Y1-Y2

[0527] Formula (I)

[0528] wherein X is the amino acid sequence:

[0529] His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Xaa12-Tyr13-Leu14-Asp15-Xaa16-Xaa17-Arg18-Ala19-Xaa20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Xaa28-Xaa29-[SEQ ID NO:813]

[0530] wherein

[0531] Xaa12 is Arg or Lys;

[0532] Xaa16 is Ala, Gln or Glu;

[0533] Xaa17 is Arg or Lys;

[0534] Xaa20 is Gln or His;

[0535] Xaa28 is Ala, Asn, Gln or His; and

[0536] Xaa29 is Gly, Ser or Thr.

[0537] W is the amino acid sequence:

[0538] -His30-His31-His32-His33-His34-[SEQ ID NO:753]; or

[0539] -His30-His31-Gln32-His33-His34-[SEQ ID NO:754].

[0540] Y1 is the amino acid sequence:

[0541] -Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42[SEQ ID NO:805];

[0542] -Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42[SEQ ID NO:799]; or

[0543] -Glu35-Ser36-Pro37-Pro38-Pro39-Ser40-Gly41-Lys42[SEQ ID NO:806].

[0544] Y2 is selected from:

[0545] Z-Gly47-Ser48-;

[0546] Z-Ser46-Gly47-Thr48-;

[0547] Z-Asn47-His48-;

[0548] Z-Gln48-;

[0549] Z-;

[0550] Z-Gly45-Ser46-Gly47-Ser48-[SEQ ID NO:809];

[0551] Z-Asn48-; and

[0552] Z-Thr45-Gly46-Ser47-Gly48-[SEQ ID NO:810];

[0553] and Z is a group of the formula:

[0554]

[0555] wherein R is C 16 or C 18 a straight-chain alkylene group, and

[0556] R 1 is CO 2 H.

[0557] For example, the compound of the present invention is a compound of formula (I):

[0558] X-W-Y1-Y2

[0559] Formula (I)

[0560] wherein X is an amino acid sequence:

[0561] His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-Asp15-Ala16-Lys17-Arg18-Ala19-Xaa20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-[SEQ ID NO:751]

[0562] wherein Xaa20 is Arg, Gln or His;

[0563] W is an amino acid sequence:

[0564] -His30-Gln31-His32-Pro33-Ser34-[SEQ ID NO:756]

[0565] -His30-Gln31-Gln32-His33-Glu34-[SEQ ID NO:776]

[0566] -His30-Gln31-His32-Gln33-His34-[SEQ ID NO:780]

[0567] -His30-His31-Gln32-Gln33-His34-[SEQ ID NO:766]

[0568] -Gln30-Gln31-His32-Glu33-Ser34-[SEQ ID NO:770]

[0569] -His30-Gln31-Gln32-His33-Pro34-[SEQ ID NO:792]

[0570] Y1 is the amino acid sequence:

[0571] -Pro35-Pro36-Pro37-Lys42[SEQ ID NO:797];

[0572] -Ser35-Pro36-Pro37-Pro38-Lys42[SEQ ID NO:798];

[0573] -Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42[SEQ ID NO:799];

[0574] -Glu35-Ser36-Pro37-Pro38-Pro39-Lys42[SEQ ID NO:800];

[0575] -Ser35-Gly36-Ala37-Lys42[SEQ ID NO:801];

[0576] -Ser35-Pro36-Pro37-Pro38-Gly39-Lys42[SEQ ID NO:802];

[0577] -Ser35-Ser36-Ser37-Ser38-Ala39-Lys42[SEQ ID NO:803]; or

[0578] -Ser35-Ser36-Ser37-Ala38-Lys42[SEQ ID NO:804];

[0579] Y2 is selected from:

[0580] Z-Gly47-Ser48-;

[0581] Z-Asn47-His48-;

[0582] Z-; or

[0583] Z-Asn48-;

[0584] and Z is a group of the formula:

[0585]

[0586] wherein R is C 16 or C 18 a straight-chain alkylene group, and

[0587] R 1 is CO 2 H.

[0588] This group of compounds is hereinafter referred to as Group I.

[0589] In a particularly preferred embodiment, the compound is Figure 1 a table of or Figure 2 one of the compounds of the present invention listed in the table of.

[0590] Derivatives and salts

[0591] The present invention provides compounds of formula (I), derivatives of such compounds, and salts or solvates of such compounds and derivatives.

[0592] The compounds, derivatives, and salts can be produced by recombinant methods known in the art. Alternatively, the compounds, derivatives, and salts can be produced by synthetic methods, which are also known in the art.

[0593] Derivatives

[0594] Although in some embodiments the present invention relates to compounds of formula (I) rather than derivatives, in other embodiments the present invention relates to derivatives of compounds of formula (I). Derivatives can include, for example, one or more derivatizations selected from the following: amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidation, polyethylene glycolylation, and fusion with another peptide or protein to form a fusion protein. The structure can be modified at random positions within the molecule or at predetermined positions within the molecule, and can contain one, two, three, or more linked chemical moieties.

[0595] In certain embodiments, it is preferred that the primary peptide chains of the compounds of the present invention can be amidated at their C-terminus. This modification is very common in nature, where approximately half of the naturally occurring peptides (including certain gastrointestinal peptide hormones) are prone to amidation at their C-terminus. The present invention includes all general and specific sequences disclosed herein, including amidated and non-amidated forms in the sequence listing and drawings, where amidation, when present, is particularly preferably present at the C-terminus of the primary peptide sequence.

[0596] The derivatives can be, for example, fusion proteins, whereby the structure of formula (I) is fused to another protein or polypeptide (fusion partner) using recombinant methods known in the art. Alternatively, such fusion proteins can be synthesized synthetically by any known method. Such fusion proteins comprise 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, etc.). Such fusion proteins can be made by linking the carboxyl terminus of the fusion partner to the amino terminus of the structure of formula (I) or vice versa. Optionally, the structure of formula (I) can be linked to the fusion partner using a cleavable linker. The resulting cleavable fusion protein can be cleaved in vivo such that the active form of the compound of the present invention is released. Examples of such cleavable linkers include, but are not limited to, the linkers Asp-Asp-Asp-Asp-Tyr [SEQ ID NO:814], Gly-Pro-Arg, Ala-Gly-Gly and His-Pro-Phe-His-Leu [SEQ ID NO:815], which can be cleaved by enterokinase, thrombin, ubiquitinase and renin, respectively. For details, see, for example, U.S. Patent No. 6,410,707, the content of which is incorporated herein by reference.

[0597] The derivatives of the present invention can be, for example, physiologically functional derivatives having the structure of formula (I). The term "physiologically functional derivative" is used herein to denote a chemical derivative of a compound of formula (I) that has the same physiological function as the corresponding unmodified compound. For example, the physiologically functional derivative can be converted in vivo to the compound of formula (I). According to the present invention, examples of physiologically functional derivatives include esters, amides and carbamates; preferably esters and amides.

[0598] In addition to the 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 include C 1-20 alkyl-, C 2-20 alkenyl-, C 5-10 aryl, C 5-10 aryl-C 1-20 alkyl or amino-acid-ester or amide groups, said ester or amide groups being formed, for example, by reaction of an alkyl, alkenyl aryl, aralkyl or aminoalkyl containing an alcohol or amine moiety with the acid moiety present in the compound of formula (I), or by reaction of an alkyl, alkenyl aryl, aralkyl or aminoalkyl containing an activated acyl group with the alcohol or amine moiety present in the compound of formula (I). Examples of suitable moieties are hydrophobic substituents having 4 to 26 carbon atoms, preferably 5 to 19 carbon atoms. Suitable lipid groups include fatty acids (e.g., lauroyl (C12 H 23 )), palm-based (C 15 H 31 ))), oil-based (C 15 H 29 ))), or stearyl-based (C 17 H 35 ))) and bile acids (e.g., cholate or deoxycholate).

[0599] U.S. Patent No. 5,936,092; U.S. Patent No. 6,093,692 and U.S. Patent No. 6,225,445 disclose methods for esterifying thiol-containing compounds with fatty acid derivatives, 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 fatty acids through disulfide bonds, can be used to deliver the compounds of the present invention to neuronal cells and tissues. Lipidation significantly increases the absorption of the compound and prolongs the blood and tissue retention of the compound relative to the absorption rate of the corresponding unlipidated compound. In addition, the disulfide bond in the lipidated derivative is relatively unstable in cells and thus promotes the intracellular release of the molecule from the fatty acid moiety. Suitable lipid moieties are hydrophobic substituents having 4 to 26 carbon atoms (preferably 5 to 19 carbon atoms). Suitable lipid groups include fatty acids (e.g., lauroyl (C 12 H 23 ))), palm-based (C 15 H 31 ))), oil-based (C 15 H 29 ))), or stearyl-based (C 17 H 35 ))) and bile acids (e.g., cholate or deoxycholate). Although the lipid-functionalized compounds of the present invention may be beneficial in some cases, it is expected that in most cases, it will be simplest and preferred if the compounds of the present invention are not further derivatized and thus do not have additional lipid groups.

[0600] The cyclization method includes cyclization by forming a disulfide bond and cyclization from end to end using a cyclization resin. Cyclized peptides may have enhanced stability due to their conformational constraints, including increased resistance to enzymatic degradation. Cyclization can be particularly advantageous when the uncyclized peptide contains an N-terminal cysteine group. Suitable cyclized peptides include monomeric and dimeric head-to-tail cyclized structures. The cyclized peptide may contain one or more additional residues, particularly additional cysteines bound to form a disulfide bond or side chains bound for resin-based cyclization.

[0601] The derivative can be, for example, a polyethylene glycolated structure of formula (I). Derivatives of the compounds of the invention as polyethylene glycolated can provide additional advantages such as increased polypeptide solubility, stability, and circulation time, or reduced immunogenicity (see U.S. Patent No. 4,179,337, the content of which is incorporated herein by reference).

[0602] The chemical moieties for derivatizing the compounds of the invention can also be selected from water-soluble polymers such as polyethylene glycol, ethylene glycol / propanediol copolymer, carboxymethyl cellulose, dextran, polyvinyl alcohol, and the like. The polymeric moiety for derivatizing the compounds of the invention can have any molecular weight and can be branched or linear. For ease of handling and manufacture, the preferred molecular weight of the polyethylene glycol for derivatizing the compounds of the invention is from about 1 kDa to about 100 kDa, the term "about" indicating that in the preparation of polyethylene glycol, the weight of some molecules will be more or less than the specified molecular weight. Polymers of other molecular weights can be used, depending on the desired treatment regimen, such as the duration of the desired sustained release, the effect on biological activity (if any), ease of handling, degree or lack of antigenicity, and other known effects of polyethylene glycol on the therapeutic protein or analog. For example, the average molecular weight of polyethylene glycol can be 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, 15,500, 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.

[0603] Salt

[0604] The salt forms of the compounds of formula (I) and the salt forms of the derivatives of such compounds also form part of the invention. In some embodiments, the salt is a salt of the compound of formula (I). In other embodiments, the salt is a salt of a derivative of the compound of formula (I).

[0605] The salts of the compounds of the present invention include pharmaceutically acceptable salts, i.e., salts suitable for use in pharmaceuticals. However, salts with non-pharmaceutically acceptable counterions are also within the scope of the present invention, for example, as intermediates for preparing the compounds.

[0606] Suitable salts according to the present invention include salts formed from organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts include salts 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 2-hydroxyethanesulfonic acid. Other acids (such as oxalic acid) can also be used as intermediates to obtain analogs of the present invention in their final form.

[0607] Pharmaceutically acceptable salts formed from 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 formed from organic bases, such as dicyclohexylamine and N-methyl-D-glucosamine.

[0608] Solvates

[0609] Those skilled in the fields of organic chemistry and / or medicinal chemistry will understand that many organic compounds can form complexes with solvents, where the organic compounds react in the solvent or precipitate or crystallize from the solvent. Such complexes are called "solvates". For example, the complex with water is called a "hydrate". The present invention also encompasses solvates of the compounds of formula (I), solvates of derivatives of the compounds, and solvates of salts of the derivatives.

[0610] Those skilled in the fields of organic chemistry and / or medicinal chemistry will also realize that many organic compounds can exist in different forms, including in the form of amorphous materials and / or in one or more crystalline forms. Different physical forms of organic compounds are called polymorphs. The present invention also encompasses all such different physical forms of the compounds of formula (I), as well as different physical forms of derivatives and salts of the compounds.

[0611] Biological activity

[0612] The compounds of the present invention have agonist activity against the human glucagon receptor and can thus be regarded as glucagon receptor agonists. This can be evaluated, for example, by in vitro or cell binding assays or reporter gene assays. For example, when tested according to the assays described in the following Examples section, the preferred compounds of the present invention exhibit activity against the human glucagon receptor that is at least 1 / 10 of the activity of human glucagon th , preferably, the activity is at least 1 / 5 of the activity of human glucagonth 、 1 / 3 rd or 1 / 2. Certain preferred compounds of the present invention exhibit activity against the human glucagon receptor that is at least equivalent to the activity of human glucagon.

[0613] Methods for assessing activity against the glucagon receptor are well known. For example, Thermo Scientific (Lafayette, Colorado, USA) sells an in vitro glucagon receptor assay.

[0614] The compounds of the present invention are also active against the human GLP-1 receptor and can therefore be considered GLP-1 receptor agonists. This can be evaluated by, for example, in vitro or cell binding assays or reporter gene assays. For example, when tested according to the assays described in the Examples section below, preferred compounds of the present invention exhibit activity against the human GLP-1 receptor that is at least 1 / 50 of the activity of human GLP-1 th , preferably, said activity is at least 1 / 30 of the activity of human GLP-1 th 、 1 / 20 th 、 1 / 10 th 、 1 / 5 th 、 1 / 3 rd or 1 / 2. Certain preferred compounds of the present invention exhibit activity against the human GLP-1 receptor that is at least equivalent to the activity of human GLP-1.

[0615] Methods for assessing activity against the GLP-1 receptor are well known. For example, Mukai et al. (2009) Biochem. Biophys. Res. Comm. 28993:523-6 discloses a method for assaying GLP-1 receptor binding. The specific method is described below.

[0616] Preferred compounds of the present invention effectively promote insulin release / secretion. This can be evaluated by, for example, in vitro assays. Methods for assessing the release of insulin from β-cells are well known.

[0617] The compounds of the present invention meet some, or more preferably, all of the following criteria:

[0618] 1) Have sustained biological activity against the human glucagon receptor, resulting in increased energy consumption;

[0619] 2) Have sustained biological activity against the human GLP-1 receptor, resulting in suppressed appetite;

[0620] 3) Promote the activity of insulin release from β-cells;

[0621] 4) The incidence of side effects such as nausea and vomiting is low, especially at therapeutically effective dose levels;

[0622] 5) It has high solubility in an aqueous solution at pH 5, so that an effective dose can be administered in a small injection volume (thereby reducing the pain during injection). Solubility can be easily evaluated by simple in vitro tests;

[0623] 6) It has a long duration of activity in vivo (evaluated in human or animal models), so that the injection frequency does not exceed once a day, and preferably does not exceed twice a week, or more preferably does not exceed once a week, while still producing acceptable therapeutic or cosmetic benefits;

[0624] 7) Good weight loss (as evaluated in human subjects or animal models), where food intake does not decrease or decreases less than the level of weight loss;

[0625] 8) Low antigenicity to humans. This can be evaluated in human or animal models (specifically, mice that have been experimentally recombined through the human immune system to simulate the human antibody repertoire), or using prediction software (such as prediction software incorporating the "antigen index" algorithm (Jameson and Wolf (1988) Comput. Appl. Biosci. 4(1):181 - 6) or the PREDITOP algorithm (Pellequer and Westhof, (1993) J. Mol. Graph. 11(3):204 - 10)) or using the method of Kolaskar and Tongankar (1990) FEBS Leu. 10:276(1 - 2):172 - 4, the content of which is incorporated herein by reference);

[0626] According to certain embodiments of the present invention (especially those related to weight loss, obesity, carbohydrate metabolism, and diabetes), the compounds, derivatives, and salts of the present invention have one, several, or all of the following characteristics:

[0627] A) It has sufficient solubility between pH 4 and pH 5, thus allowing an effective dose to be administered in a volume less than 1 ml, less than 0.5 ml, or less than 0.3 ml;

[0628] B) Activates the cAMP signal in human embryonic kidney cells overexpressing the human GLP - 1 receptor;

[0629] C) Activates the cAMP signal in cells overexpressing the human glucagon receptor;

[0630] D) One, several, or all of the additional 1 to 8 features listed above.

[0631] Pharmacokinetics, duration of action, and solubility

[0632] After subcutaneous administration, the compounds of the present invention exhibit an effective and prolonged duration of action in vivo. To achieve this, the compounds are required to have both good activity against biological targets and excellent pharmacokinetic properties.

[0633] The compounds of the present invention have a therapeutically useful duration of action, and the beneficial effects observed in the experiments described below persist for several days on their own. The half-life of the compounds of the present invention was evaluated in a porcine PK model. It was found that the half-life of the preferred compounds of the present invention is significantly longer than that of semaglutide. In addition to exhibiting a long in vivo half-life, the compounds of the present invention also have good storage stability and no significant degradation was observed when stored in solution at 25 °C for 4 weeks.

[0634] Poor water solubility is a known problem for lipid-containing molecules. In contrast, the compounds of the present invention have very good solubility.

[0635] Incorporating one or more His residues into a peptide with poor water solubility generally results in the peptide having enhanced solubility at acidic pH (e.g., pH 5) due to the presence of charged His side chain groups, but lower solubility at physiological pH (pH 7.4). The pI of the side chain group of histidine is approximately 6.0. This property enables the formulation of His-containing peptides in a weakly acidic medium. After subcutaneous administration of such formulations, the solubility decreases, leading to subcutaneous precipitation of the peptide, which redissolves over time. Zinc-containing formulations of His-containing peptides can enhance this effect because at pH 7.4 rather than pH 5, zinc ions coordinate with histidine residues and cause further reduction in solubility, which may contribute to increased precipitation at the subcutaneous injection site or may contribute to increased stability of the precipitate. However, when the precipitation of the peptide is not rapid enough after subcutaneous administration, an initial "spike" or "burst" in the blood concentration level of the peptide may still occur. This property is undesirable because it increases the likelihood that the subject will experience side effects (such as nausea) associated with high concentration levels of the peptide, even if this is only temporary. In contrast to peptides that do not have the multiple-His-containing C-terminal sequence of the present invention, the compounds of the present invention do not exhibit an initial "spike" or "burst" in plasma concentration levels after subcutaneous administration, or any such "burst" is significantly reduced. This reduces the likelihood and / or severity of possible side effects associated with high circulating levels of the compound.

[0636] Disease conditions

[0637] The present invention also provides the compounds, derivatives or salts of the present invention for use as a medicament, or a composition comprising said compound, derivative or salt and a pharmaceutically acceptable carrier and optionally an additional therapeutic agent.

[0638] The present invention also provides a method of treating or preventing a disease or disorder or other undesirable physiological condition in a subject, said method comprising administering a therapeutically effective amount of a compound, derivative or salt of the present invention, or a composition comprising said compound, derivative or salt and a pharmaceutically acceptable carrier and optionally an additional therapeutic agent. Preferably, the compound, derivative, salt or composition is administered subcutaneously.

[0639] According to certain embodiments, the disease or disorder or other undesirable physiological condition is diabetes or obesity, particularly diabetes (e.g., type II diabetes).

[0640] According to certain embodiments, the disease or disorder or other undesirable physiological condition may be an overweight physiological condition.

[0641] The subject to whom the compound is administered may be overweight, e.g., obese. Alternatively, or in addition, the subject may be a diabetic, e.g., having insulin resistance or glucose intolerance, or both. The subject may have diabetes, e.g., the subject may have type II diabetes. The subject may be overweight (e.g., obese) and have diabetes (e.g., type II diabetes).

[0642] Additionally, or alternatively, the subject may have a condition in which obesity or overweight is a risk factor, or may be at risk of developing said condition. Such conditions include but are not limited to heart disease, cardiovascular disease (e.g., hypertension, atherosclerosis, congestive heart failure and dyslipidemia); stroke; gallbladder disease; osteoarthritis; sleep apnea; reproductive system disorders (e.g., polycystic ovary syndrome); cancer (e.g., breast cancer, prostate cancer, colon cancer, endometrial cancer, kidney cancer and esophageal cancer); varicose veins; acanthosis nigricans; eczema; exercise intolerance; insulin resistance; hyperinsulinemic hypercholesterolemia; choledocholithiasis; osteoarthritis; orthopedic trauma; insulin resistance (e.g., type 2 diabetes and syndrome X); and thromboembolic disease (see Kopelman, Nature 404:635-43; Rissanen et al., British Med. J. 301, 835, 1990).

[0643] Other conditions associated with obesity include depression, anxiety, panic attacks, migraine, PMS, chronic pain conditions, fibromyalgia, insomnia, impulsivity, obsessive-compulsive disorder, and myoclonus. In addition, obesity is a recognized risk factor for increasing the incidence of complications during general anesthesia (see, e.g., Kopelman, Nature 404:635-43, 2000). In general, obesity shortens lifespan and poses a significant risk of developing comorbidities such as those listed above.

[0644] Other diseases or conditions associated with obesity are congenital defects, increased incidence of neural tube defects in pregnant women with obesity, carpal tunnel syndrome (CTS); chronic venous insufficiency (CVI); daytime sleepiness; deep vein thrombosis (DVT); end-stage renal disease (ESRD); gout; heat stroke; impaired immune response; impaired respiratory function; infertility; liver disease; lower back pain; obstetric and gynecological complications; pancreatitis; and abdominal hernias; acanthosis nigricans; endocrine abnormalities; chronic hypoxia and hypercapnia; dermatological effects; elephantiasis; gastroesophageal reflux; heel spurs; lower extremity edema; breast enlargement, which can cause many problems such as bra strap pain, skin damage, cervical pain, chronic odor, and infection of the skin folds under the breast; large masses in the anterior abdominal wall (e.g., abdominal panniculitis), which are accompanied by frequent panniculitis, interfere with walking, cause frequent infections, odor, difficulty dressing, lower back pain; musculoskeletal diseases; pseudotumor cerebri (or benign intracranial hypertension) and hiatal hernia.

[0645] In some embodiments, the disease or condition can be non-alcoholic fatty liver disease.

[0646] According to certain embodiments, the disease or condition or other undesirable physiological state can be an undesirable weight (although not obese or overweight). The subject can be a subject of normal weight (this includes but is not limited to subjects who were previously overweight or obese and subjects who wish to prevent a return to an unhealthy weight). The subject can be a subject desiring weight loss, such as female and / or male subjects desiring an appearance change. In some cases where the subject has a normal weight, aspects of the present invention can relate to cosmetic treatment rather than therapeutic treatment.

[0647] The present invention also provides a method for increasing the energy expenditure of a subject, reducing the appetite of the subject (e.g., due to the biological activity on the GLP-1 receptor, rather than related to nausea or vomiting), reducing the food intake of the subject, reducing the calorie intake of the subject, improving the insulin release of the subject, improving the carbohydrate metabolism of the subject, and / or improving the glucose tolerance of the subject, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention. Such methods can relate to treating subjects having a pre-diabetic state (such as insulin insensitivity) or pre-diabetes.

[0648] Energy is burned in all physiological processes. By modulating the efficiency of these processes or by changing the number and nature of the processes that are occurring, the body can directly alter the rate of energy expenditure. For example, during digestion, the body expends energy by moving food through the gut and digesting the food, and within cells, the efficiency of cellular metabolism can be altered to produce more or less heat.

[0649] In one aspect, the method of the invention involves manipulating an arcuate circuit that coordinately alters food intake and conversely alters energy expenditure. Energy expenditure is the result of cellular metabolism, protein synthesis, metabolic rate, and calorie utilization. Thus, in this aspect of the invention, administration of a compound, derivative, salt, or composition of the invention results in increased energy expenditure and decreased efficiency of calorie utilization.

[0650] The increased energy expenditure may manifest as a decrease in normal energy expenditure following a decrease in food intake, or it may manifest as an absolute increase in energy expenditure, such as by promoting an increased level of physical activity or by an increase in basal metabolic rate.

[0651] The invention also provides a method for improving the lipid profile of a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the invention. The invention also provides a method for alleviating a condition or disorder that can be alleviated by reducing nutrient utilization, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the invention.

[0652] The compounds, derivatives, salts, or compositions of the invention can be used for weight control and treatment (e.g., reducing or preventing obesity), specifically for any one or more of the following: preventing and reducing weight gain; inducing and promoting weight loss; and reducing obesity as measured by body mass index. The compounds, derivatives, salts, or compositions of the invention can be used to maintain any one or more of the following: desired weight, desired body mass index, desired appearance, and good health.

[0653] The invention can also be used to treat, prevent, improve, or alleviate a condition or disorder caused by, associated with, or exacerbated by relatively high nutrient utilization. The term "condition or disorder that can be alleviated by reducing calorie (or nutrient) utilization" is used herein to mean any condition or disorder in a subject that is caused by, associated with, or exacerbated by relatively high nutrient utilization, or that can be alleviated by reducing nutrient utilization (e.g., by reducing food intake). Subjects with insulin resistance, glucose intolerance, or suffering from any form of diabetes (e.g., type 1, type 2, or gestational diabetes) can also benefit from the method of the invention.

[0654] Medical conditions or disorders associated with increased caloric intake include, but are not limited to, insulin resistance, glucose intolerance, obesity, diabetes (including type 2 diabetes), eating disorders, insulin resistance syndrome, and Alzheimer's disease.

[0655] The Journal of Cerebral Blood Flow and Metabolism (J. Cereb. Blood Flow Metab.) on April 13, 2011 (Teramoto S et al.) discussed the use of both GLP-1 and exendin-4 in conferring cardioprotection after myocardial infarction and demonstrated that exendin-4 can be used to provide neuroprotection against cerebral ischemia-reperfusion injury. The study showed that after 60 minutes of focal cerebral ischemia, mice receiving intravenous injection of exendin-4 exhibited significantly reduced infarct volume and improved functional deficits, as well as suppressed oxidative stress, inflammatory response, and cell death after reperfusion. The study provided evidence that the protective effect of exendin-4 is mediated by increasing intracellular cAMP levels and suggested that exendin-4 may be useful in the treatment of acute ischemic stroke.

[0656] Accordingly, the present invention also provides a method for providing cytoprotection (such as providing cardioprotection, providing neuroprotection, and / or treating or preventing neurodegeneration) to a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention.

[0657] In certain embodiments, the diseases or disorders or other undesirable physiological states that the compounds, derivatives, salts or compositions of the present invention can be used to treat or prevent are neurodegeneration. Such neurodegeneration may be caused by apoptosis, necrosis or loss of function of neuronal cells (preferably, in the CNS). The neurodegeneration to be treated or prevented may be that after brain injury (e.g., brain injury after suffering physical trauma or non-traumatic injury such as stroke, tumor, hypoxia, poisoning, infection, ischemia, encephalopathy or drug abuse). Alternatively or additionally, it can be used to prevent or treat neurodegeneration in subjects suffering from neurodegenerative diseases (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, cerebrovascular 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 syndrome, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, myoclonus, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis). Preferably, the neurodegenerative diseases are selected from the group consisting of Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis) and Huntington's disease. In this case, the treatment will be regarded as having a neuroprotective effect. According to certain preferred embodiments, the treatment has a neuroprotective effect after cerebral ischemia, or has a neuroprotective effect in subjects suffering from or diagnosed as being predisposed to neurodegenerative diseases.

[0658] According to other embodiments, the disease or disorder or other undesirable physiological state is cardiac degeneration (specifically, myocardial degeneration caused by apoptosis, necrosis or loss of function of cardiomyocytes), in which case the compounds, derivatives, salts or compositions according to the present invention provide cardioprotection. According to certain preferred embodiments, the treatment has a protective effect on myocardial function after myocardial infarction.

[0659] The present invention also provides the compounds, derivatives, salts or compositions of the present invention for treating obesity or diabetes.

[0660] The present invention also provides the compounds, derivatives, salts or compositions of the present invention for increasing the energy consumption of a subject, improving the insulin release of the subject, improving the glucose tolerance of the subject and / or improving the carbohydrate metabolism of the subject. Such uses may relate to treating subjects with a pre-diabetic state (such as insulin insensitivity) or pre-diabetes.

[0661] The present invention also provides the compounds, derivatives, salts or compositions of the present invention for reducing the appetite of a subject, for reducing the food intake of a subject, for reducing the calorie intake of a subject, for improving the insulin release of a subject and / or for improving the glucose tolerance of a subject. Such uses may relate to treating subjects having a pre-diabetic state (such as insulin insensitivity) or pre-diabetes.

[0662] The present invention also provides the compounds, derivatives, salts or compositions of the present invention for use as cytoprotective agents (e.g., for treating or preventing neurodegeneration, providing neuroprotection and / or providing cardioprotection). For example, the compounds, derivatives, salts or compositions may be used for myocardial protection of a subject after myocardial infarction, or for neuroprotection of a subject after cerebral ischemia or stroke, or for neuroprotection of a subject suffering from a chronic neurodegenerative disease. The various features of the neuroprotective or cardioprotective uses of the compounds, derivatives, salts or compositions may be as outlined above with respect to the methods of the present invention.

[0663] In the case of neuroprotection, the subject may have previously experienced a brain injury, stroke or other event causing cerebral ischemia. Alternatively, the subject may have a chronic neurodegenerative disease or have been diagnosed as predisposed to a chronic neurodegenerative disease. In the case of cardioprotection, the subject may have previously experienced an event causing myocardial ischemia, such as myocardial infarction and angina. According to some embodiments, the compounds, derivatives, salts or compositions of the present invention may be administered as soon as possible after the subject has experienced a suspected myocardial infarction. According to certain embodiments, the compounds, derivatives, salts or compositions of the present invention may be administered as soon as possible after the subject has experienced a suspected stroke.

[0664] The present invention also provides the use of the compounds, derivatives, salts or compositions of the present invention in the manufacture of a medicament for treating obesity or diabetes in a subject, which subject may be as described above with reference to other aspects of the present invention.

[0665] The present invention also provides the use of the compounds, derivatives, salts or compositions of the present invention in the manufacture of a medicament for increasing the energy expenditure of a subject, for improving the insulin release of a subject, for improving the glucose tolerance of a subject and / or for improving the carbohydrate metabolism of a subject. Such uses may relate to treating subjects having a pre-diabetic state (such as insulin insensitivity) or pre-diabetes.

[0666] The present invention also provides the use of the compounds, derivatives, salts or compositions of the present invention in the manufacture of a medicament for reducing the appetite of a subject, reducing the food intake of a subject, reducing the calorie intake of a subject, improving the insulin release of a subject and / or for improving the glucose tolerance of a subject.

[0667] The present invention also provides the use of the compounds, derivatives, salts or compositions of the present invention in the preparation of a medicament for providing cytoprotection (such as preventing or treating neurodegeneration, providing neuroprotection and / or providing cardioprotection) to a subject, which subject may be as described above with reference to other aspects of the present invention.

[0668] According to certain embodiments, the compounds, derivatives, salts or compositions of the present invention will be 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.

[0669] The compounds, derivatives, salts or compositions of the present invention are preferably used for treating human subjects. However, although the compounds, derivatives, salts or compositions of the present invention will generally be used for treating human subjects, they can also be used for treating similar or identical conditions in other vertebrates (such as other primates; domestic animals such as pigs, cows and poultry; sport animals such as horses; or pets such as dogs and cats).

[0670] Composition

[0671] The compound of formula (I) or its derivative and / or salt is preferably present in a pharmaceutical formulation or composition. Accordingly, the present invention provides a composition comprising a compound, derivative or salt of the present invention and a pharmaceutically acceptable excipient and optionally another therapeutic ingredient. The composition comprising the compound, derivative or salt is suitable for therapeutic use. According to certain preferred embodiments, the composition is present in a syringe or other administration device for subcutaneous administration to humans. According to certain preferred embodiments, the pH of the composition is less than 5 and / or the composition comprises zinc ions. The composition of the present invention may take the form of a pharmaceutical formulation described below.

[0672] The pharmaceutical formulations according to the present invention comprise pharmaceutical formulations suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intra-articular), inhalation (including fine dusts or mists that can be generated by various types of metered-dose pressurized aerosol, nebulizer or insufflator means), rectal and topical (including dermal, transdermal, transmucosal, buccal, sublingual and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient.

[0673] These formulations may be presented conveniently in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0674] Formulations of the invention suitable for oral administration may be presented in discrete unit form, such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; in the form of powders or granules; in solution or suspension in an aqueous liquid or a non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented in the form of boluses, electuaries or pastes. Various pharmaceutically acceptable carriers and their formulations are described in standard pharmaceutical treatises, for example, Remington's Pharmaceutical Sciences by E.W. Martin. See also Wang, Y.J. and Hanson, M.A., Journal of Parenteral Science and Technology, Technical Report No. 10, Supplement 42:2S, 1988, the contents of which are incorporated herein by reference.

[0675] Tablets may be made by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surfactant or dispersing agent. Molded tablets may be prepared by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated so as to provide for slow or controlled release of the active ingredient therein. The compounds of the invention may be administered, for example, in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by use of a suitable pharmaceutical composition including the compound of the invention, or specifically, in the case of extended release, by use of devices such as subcutaneous implants or osmotic pumps. The compounds of the invention may also be administered via liposomes.

[0676] Preferably, the composition according to the 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 may limit solubility and thus delay absorption from the subcutaneous administration site into the circulatory system. In a particularly preferred embodiment, the composition contains zinc ions (preferably, the molar ratio of zinc ions to the compound, derivative or salt of the invention is 1:4, 1:2, 1:1, 2:1 or 4:1, or the ratio is in the range between any two of the integer ratios just given above, for example, the molar ratio range is from 1:4 to 4:1).

[0677] Exemplary compositions for oral administration include: suspensions, which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetening or flavoring agents (as known in the art); and immediate-release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, bulking agents, disintegrants, diluents and lubricants (such as known in the art). The compounds of the invention can also be delivered orally by sublingual and / or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include compositions formulated with a rapidly dissolving diluent such as mannitol, lactose, sucrose and / or cyclodextrin for one or more compounds of the invention. Such formulations may also contain high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). Such formulations may also contain excipients that aid in mucoadhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and controlled release agents such as polypropylene copolymers (e.g., Carbopol 934). For ease of manufacture and use, lubricants, glidants, flavoring agents, coloring agents and stabilizers may also be added.

[0678] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic agents, and solutes which 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, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition which requires only the addition immediately prior to use of a sterile liquid carrier, for example, saline or water for injection. Interim injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the foregoing types. 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 agents and suspending agents including synthetic mono- or di-glycerides of fatty acids and fatty acids such as oleic acid or Cremophor. The aqueous carrier may be, for example, an isotonic buffered solution having a pH of from about 3.0 to about 8.0, preferably from about 3.5 to about 7.4 (such as from 3.5 to 6.0, such as from 3.5 to about 5.0). Useful buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid, as well as sodium acetate / acetic acid buffer. The composition preferably does not contain any compound known to be harmful to the peptide compound.

[0679] Excipients which may be included are, for example, other proteins such as human serum albumin or plasma products. If desired, the pharmaceutical composition may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents such as sodium acetate or sorbitan monolaurate.

[0680] Exemplary compositions for nasal aerosol or inhalation administration comprise a solution in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability and / or other solubilizing or dispersing agents (as known in the art). Conveniently, in compositions for nasal aerosol or inhalation administration, in the presence of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas), the compounds of the present invention can be delivered in the form of an aerosol spray from a pressurized pack or nebulizer. In the case of a pressurized aerosol, the dose unit can be determined by providing a valve for delivering a metered amount. Capsules and cartridges (e.g., of gelatin) for inhalers or insufflators can be configured to contain a powder mixture of the compound and a suitable powder matrix (e.g., lactose or starch). In a specific non-limiting example, the compounds of the present invention are administered in aerosol form from a metered dose valve through an aerosol adapter (also known as an actuator). Optionally, stabilizers are also included and / or porous particles for deep lung delivery (e.g., see U.S. Patent No. 6,447,743).

[0681] Formulations for rectal administration can be presented as a retention enema or suppository in combination with a carrier such as cocoa butter, synthetic glycerides or polyethylene glycols. Such carriers are generally solid at ordinary temperature but liquefy and / or dissolve in the rectal cavity to release the drug.

[0682] Formulations for topical administration in the mouth (e.g., buccally or sublingually) include lozenges comprising the active ingredient in a flavored matrix such as sucrose and acacia or tragacanth, and troches comprising the active ingredient in a matrix such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0683] Preferred unit dose formulations are those containing an effective dose of the above-mentioned active ingredient or an appropriate portion thereof.

[0684] It should be understood that with respect to the types of formulations discussed, in addition to the ingredients specifically mentioned above, the formulations of the present invention may also contain other agents conventional in the art, e.g., formulations suitable for oral administration may contain flavoring agents.

[0685] The compounds, derivatives, and salts of the present invention may also be suitably administered as sustained-release systems. Suitable examples of the sustained-release systems of the present invention include: suitable polymeric materials, such as semi-permeable polymer matrices in the form of shaped articles (e.g., films or microcapsules); suitable hydrophobic materials, such as emulsions in acceptable oils; or ion exchange resins; and sparingly soluble derivatives of the compounds of the present invention, such as sparingly soluble salts. The sustained-release systems may be administered orally; rectally; parenterally; intracranially; vaginally; intraperitoneally; topically, e.g., in the form of powders, ointments, gels, drops, or transdermal patches; buccally; or as an oral spray or nasal spray.

[0686] Formulations for administration may be suitably formulated to provide controlled release of the compounds, derivatives, and salts of the present invention. For example, the pharmaceutical composition may be in the form of granules that include one or more of the following: biodegradable polymers, polysaccharide gelling and / or bioadhesive polymers, amphiphilic polymers, agents capable of altering the interfacial properties of the particles of the compounds of the present invention. Certain biocompatibility characteristics exhibited by these compositions allow for the controlled release of the active substance, see U.S. Patent No. 5,700,486, the content of which is incorporated herein by reference.

[0687] Controlled release of the compounds, derivatives, and salts of the present invention may also be achieved by using a pharmaceutical composition that includes zinc ions. As described above, at pH 7.4 rather than pH 5, zinc ions coordinate with histidine residues and result in increased precipitation at the subcutaneous injection site. The zinc-containing precipitate will redissolve more slowly because solubilization depends on the outflow of zinc from the injection site into the circulatory system and / or the surrounding tissue fluid, thereby prolonging the time of release into the circulatory system. A controlled-release composition is preferably used for indications such as the treatment of obesity and / or diabetes, where it is desired to maximize the time interval between injections. However, for indications such as providing neuroprotection or cardioprotection (e.g., after a suspected myocardial infarction or stroke), i.e., where it is desired to achieve a therapeutic plasma concentration of the active agent in the shortest possible time period, a rapid-release formulation is preferred. In such cases, a dosing regimen that includes a rapid-release formulation of a dose of the active agent (i.e., administered as soon as possible after a suspected myocardial infarction or stroke) and subsequently a controlled-release formulation of a dose of the active agent may be preferred.

[0688] The compounds, derivatives or salts of the present invention can be delivered by a pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201, 1987; Buchwald et al., Surgery 88:507, 1980; Saudek et al., New England Journal of Medicine 321:574, 1989) or by continuous subcutaneous infusion (e.g., using a micropump). Intravenous infusion bags can also be used. The key factor in selecting an appropriate dose is the result obtained, which is measured by a decrease in total body weight or the ratio of fat to lean mass, or by other criteria used to measure the control or prevention of obesity or the prevention of obesity-related conditions, as deemed appropriate by the practitioner. 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 present disclosure, the compounds of the present invention are delivered by implantation of a pump, as described in, for example, U.S. Patent No. 6,436,091; U.S. Patent No. 5,939,380; U.S. Patent No. 5,993,414, the contents of which are incorporated herein by reference.

[0689] Implanted drug infusion devices are used to provide a patient with a long-term fixed dose or infusion of a drug or any other therapeutic agent. In essence, such devices can be classified as active or passive. The compounds, derivatives or salts of the present invention can be formulated into long-acting preparations. Such long-acting preparations can be administered, for example, by subcutaneous or intramuscular implantation or by intramuscular injection. Thus, for example, the active ingredient can be formulated with a suitable polymeric material or a hydrophobic material, such as as an emulsion in an acceptable oil; or an ion exchange resin; or as a sparingly soluble derivative, such as a sparingly soluble salt.

[0690] A therapeutically effective amount of the active agent of the present invention can be administered as a single pulse dose, a bolus dose, or a pulsed dose administered over time. Thus, in a pulsed dose, a bolus administration of the active agent is provided, followed by a period of time during which no active agent is administered to the subject, and then a second bolus administration. In a specific non-limiting example, the pulsed dose is administered over the course of a day, a week, or a month.

[0691] Combination therapy:

[0692] In certain embodiments, a therapeutically effective amount of a compound, derivative, salt, or composition of the invention is administered together with a therapeutically effective amount of one or more additional agents. The compound, derivative, or salt can be administered, for example, simultaneously with one or more additional therapeutic agents, or can be administered sequentially or separately. Accordingly, the invention provides a compound, derivative, or salt of the invention for use as a medicament, wherein the compound, derivative, or salt is used in combination with a therapeutically effective amount of one or more additional therapeutic agents (e.g., administered simultaneously, sequentially, or separately). In certain embodiments, the active agent of the invention is formulated with one or more additional therapeutic agents and administered in a single dosage form.

[0693] In certain embodiments, the one or more additional therapeutic agents are additional anti-diabetic, appetite suppressant, food intake reducing, plasma glucose lowering, or plasma lipid altering agents. Specific non-limiting examples of additional appetite suppressants include amfepramone (diethylpropion), phentermine, mazindol, and phenylpropanolamine, fenfluramine, dexfenfluramine, benzthiazide, amphetamine, sibutramine, rimonabant, topiramate, fluoxetine, bupropion, zonisamide, naltrexone, orlistat, and cetilistat. Specific non-limiting examples of additional anti-diabetic 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.

[0694] In alternative embodiments, the one or more additional therapeutic agents are additional cardioprotective or neuroprotective agents. 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 agents for treating Parkinson's disease include anticholinergics, pramipexole, bromocriptine, levodopa, carbidopa, rasagiline, amantadine, and ropinirole.

[0695] Dosage:

[0696] The compounds, derivatives, salts or compositions of the present invention can be administered whenever an effect such as appetite suppression, reduced food intake, increased energy expenditure or reduced caloric intake is desired, or at a time slightly earlier than the time when 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 when the effect is desired).

[0697] The therapeutically effective amount of the active agent of the present invention will depend on the molecule used, the subject being treated, the severity and type of the disease, and the mode and route of administration. For example, the therapeutically effective amount of the compounds of the present invention can range from about 0.01 μg per kilogram (kg) of body weight to about 1 g per kg of body weight, such as from about 0.1 μg per kg of body weight to about 20 mg, such as from about 1 μg per kg of body weight to about 5 mg or from about 5 μg per kg of body weight to about 1 mg.

[0698] In one embodiment of the present invention, the compounds, derivatives or salts of the present invention can be administered to a subject at 4 to 1,333 nmol per kg of body weight (such as 5 to 1,000 nmol per kg of body weight, such as 10 to 750 nmol per kg of body weight, such as 20 to 500 nmol per kg of body weight, specifically, 30 to 240 nmol per kg of body weight). For a 75 kg subject, such a dose corresponds to a dose of 300 nmol to 100 μmol (such as 375 nmol to 75 μmol, such as 750 nmol to 56.25 μmol, such as 1.5 to 37.5 μmol, specifically, 2.25 to 18 μmol). The present invention also contemplates dose ranges defined by any of the specific doses described herein.

[0699] In alternative embodiments, the compounds, derivatives or salts of the invention can be administered to a subject at a dose of 0.5 to 135 picomoles (pmol) per kg body weight (e.g., 5 to 100 pmol per kg body weight, e.g., 10 to 90 pmol per kg body weight, e.g., about 72 pmol per kg body weight). In a specific non-limiting example, the compound of the invention is administered at a dose of about 1 nmol or more, 2 nmol or more or 5 nmol or more. In this example, the dose of the compound of the invention is generally not more than 100 nmol, e.g., the dose is 90 nmol or less, 80 nmol or less, 70 nmol or less, 60 nmol or less, 50 nmol or less, 40 nmol or less, 30 nmol or less, 20 nmol or less, 10 nmol. For example, the dose range can include any combination of any specified dose lower limit and any specified dose upper limit. Thus, non-limiting examples of dose ranges for the compounds, derivatives and salts of the invention are in the range of 1 to 100 nmol, 2 to 90 nmol, 5 to 80 nmol.

[0700] In a specific non-limiting example, about 1 to about 50 nmol (e.g., about 2 to about 20 nmol, e.g., about 10 nmol) of the compound of the invention is administered by subcutaneous injection. Those skilled in the art can readily determine the exact dose based on the potency of the particular compound used, the route of delivery of the compound, and the age, weight, sex and physiological condition of the subject.

[0701] The above doses can be administered, for example, once, twice, three times or four times a day or once or twice a week. In some embodiments, the dose can be administered no more than once a week. Alternatively, the dose can be administered once every 2 days, every 3 days or every 4 days. According to certain embodiments, the dose can be administered shortly before each meal.

[0702] Examples

[0703] The invention is further described with reference to the following non-limiting examples.

[0704] Materials and Methods:

[0705] Peptide Synthesis

[0706] Peptide synthesis is carried out on a resin with a tricyclic amide linker. Amino acids are coupled using the Fmoc strategy. For the portion of the molecule from Xaa1 to Xaa45, each amino acid is added sequentially from the C-terminus to the N-terminus. Peptide coupling is mediated with a reagent such as TBTU. Cleavage of the peptide from the resin is achieved with trifluoroacetic acid in the presence of a scavenger. In the second stage, the lysine 42 residue is functionalized at its ε-amino group after ε-amino deprotection. Then the chain on the lysine 42 residue is constructed sequentially using the same amino acid coupling chemistry.

[0707] The peptides are purified by reverse-phase HPLC. Quality control is performed on all purified peptides, and in two buffer systems, HPLC confirms that the peptide purity is greater than 90% in most cases. MALDI-MS shows the expected molecular ion.

[0708] Example Synthesis

[0709] The example compound 366 is prepared using standard Fmoc chemistry as follows:

[0710] 1. Resin preparation: To 2Cl-Trt resin (0.30 mmol, 1.00 equivalent), add FMOC-LYS(DDE)-OH (159.78 mg, 300.00 μmol, 1.00 equivalent) and DIEA (232.63 mg, 1.80 mmol, 313.52 μL, 6.00 equivalents) in DCM (10.0 mL). Stir the mixture at 20 °C for 2 h with N 2 then add MeOH (0.3 mL) and stir with N 2 for an additional 30 min. Wash the resin with DMF (15.0 mL * 3). Then add 20% piperidine in DMF (5.00 mL) and stir the mixture at 20 °C with N 2 for 30 min. Then filter the mixture to obtain the resin. Wash the resin with DMF (15.0 mL * 5) and filter to obtain the resin.

[0711] FMOC-LYS(DDE)-OH has the following structure:

[0712]

[0713] The free acid is attached to the resin. Piperidine deprotection removes the FMOC group and creates a free amino terminus for the next coupling.

[0714] 2. Coupling: A solution of FMOC-PRO-OH (303.66 mg, 900.00 μmol, 3.00 equivalents), DIEA (232.63 mg, 1.80 mmol, 313.52 μL, 6.00 equivalents), and HBTU (324.25 mg, 855.00 μmol, 2.85 equivalents) in DMF (5.00 mL) was added to the resin and stirred with N at 20 °C for 30 min. Then the resin was washed with DMF (15.0 mL * 3). 2 The resin was then washed with DMF (15.0 mL * 3).

[0715] 3. Deprotection: 20% piperidine in DMF (5.00 mL) was added to the resin and the mixture was stirred with N at 20 °C for 30 min. The resin was washed with DMF (15.0 mL * 5) and filtered to obtain the resin. 2 The resin was washed with DMF (15.0 mL * 5) and filtered to obtain the resin.

[0716] 4. Repeat steps 2 - 3 using the reagents in Table 1 until the last amino acid is added (Reaction iteration #1 in Table 1 is the first added Pro residue as stated in steps 2 and 3 above).

[0717] Table 1:

[0718]

[0719]

[0720]

[0721]

[0722] 5. After the coupling of tert-butyl N-Boc-L-lysinate in iteration #39, 3% H 2 N·NH 2 / DMF was added and allowed to react for 30 min to remove Dde, and then repeated. Then the mixture was drained and washed 5 times with DMF (20.0 mL). After removing the Dde group, the compound has a free amino terminus at the ε-amino group of lysine in step 1 and it can be used for the next coupling.

[0723] 6. Then the reactions of steps 2 - 3 were carried out using the reagents in Table 2 until the last reagent was added (Reaction iteration #44 in the table).

[0724] Table 2:

[0725]

[0726] *Since the C-1 acid group of the protected glutamic acid reagent 43 is protected by TBU, it reacts with the previous residue (Gly) at its C-5 acid. When Z is (i), it is the FMOC-GLU-OTBU reagent, providing the glutamic acid residue portion in the Z part of the compound:

[0727]

[0728] 7. Peptide cleavage and purification:

[0729] The resin was washed with MeOH (30.0 mL * 2) and dried under vacuum to give 2.20 g of peptide resin. Then, 25.0 mL of cleavage buffer (92.5% TFA / 2.5% Mpr / 2.5% TIS / 2.5% H 2 O) was added to the flask containing the peptide resin with protected side chains, and the mixture was stirred for 2 h. The peptide was precipitated with cold tert-butyl methyl ether (300 mL) and centrifuged (3 min at 5000 rpm). The peptide precipitate was washed twice more with tert-butyl methyl ether (150 mL). The crude peptide was dried and its identity was confirmed by LCMS.

[0730] The residue was purified by preparative HPLC (TFA conditions; 30 °C, A: 0.075% TFA / H 2 O, B: CH 3 CN) to give the title compound as a white solid (136 mg, 24.82 μmol, 8.27% yield, 98.92% purity, TFA), whose identity was confirmed by LCMS).

[0731] An equivalent method was employed for all other peptides described herein. The sequences and other structural features of the exemplary peptides are as Figure 1 and Figure 2 shown. In the figure, the lysine residue at position 42 is replaced at its ε-amino group by Z-Xaa45-Xaa46-Xaa47-Xaa48-[SEQ ID NO:745], where Xaa45, Xaa46, Xaa47, and Xaa48 have the meanings shown (the blank in the column under discussion indicates the absence of the residue), and Z is a group having the following structure as indicated in the column "Z":

[0732]

[0733] where R is a straight-chain alkylene containing n carbon atoms; and

[0734] R 1 is CO 2 H.

[0735] The value of n is between Figure 1 and Figure 2Indicated in the column titled "n(R=Cn)". In the example shown, n is 12, 14, 16, 18, 20 or 22.

[0736] Figure 1 and Figure 2 Some of the example compounds in are chlorides or acetates, which are indicated in the column titled "Notes". Figure 1 and 2 Some of the example compounds in are duplicate preparations of the compounds listed elsewhere in the figure, and they are indicated in the column titled "Notes" as, for example, "Dupl".

[0737] Receptor potencies of peptides against human GLP-1 and glucagon receptors overexpressed in CHO cells

[0738] Bioactivity was evaluated by the potency of the peptide to stimulate cAMP production in a Chinese hamster ovary (CHO) cell line overexpressing human GLP-1 or human glucagon receptor. On the day of the assay, cells were plated at a density of 8x10 -5 cells / mL in medium (DMEM containing 0.1% v / v BSA, 0.05 IBMX) into 96-well half-area plates. After 30 min of peptide stimulation and a further 1 h of lysis, cAMP in the cells was quantified using a commercial cAMP kit (Cisbio) by HTRF (homogeneous time-resolved fluorescence) technology. The plates were read on a SpectraMax i3x multimode detection platform plate reader, and concentration-response curves were plotted using Graph Pad Prism. The EC 50 values for each peptide were generated and compared to the control on the same day to provide the EC 50 ratios of the compound compared to the GLP-1 or glucagon control, respectively. (For example, for the GLP-1 EC 50 ratio, a value of 0.5 indicates that the concentration of the example compound required to stimulate 50% of the maximum cAMP release is half the concentration of the native GLP-1 required, while a value of 2 indicates that the concentration of the example compound required to stimulate 50% of the maximum cAMP release is twice the concentration of the native GLP-1). For each peptide, the ratio of its EC 50 to glucagon was compared to its EC 50 to GLP-1 to provide the glucagon:GLP-1 receptor potency ratio. Since a lower EC 50 ratio indicates higher activity, the glucagon:GLP-1 receptor potency ratio was calculated as EC 50 (GLP-1) / EC 50 (glucagon). Thus, a value >1 indicates relatively higher activity at the glucagon receptor compared to the GLP-1 receptor (and EC 50Lower)

[0739] In vivo efficacy study: Single-dose feeding study in male Wistar rats

[0740] Male Wistar rats (Charles River Ltd, Margate, UK) were used for the animal experiments. Rats with ad libitum access to food were individually housed in IVC cages. The animals were randomly assigned to treatment groups, stratified by body weight. All peptide solutions were freshly prepared immediately before administration. Water 5% v / v water and 95% NaCl (0.9% w / v) were given to control animals, while the peptides (7.5, 15 or 30 nmol / kg body weight) were resuspended in water for injection. The peptides and vehicle were administered by subcutaneous injection during the early light phase (0900 - 1000), and the animals were provided with a known amount of food. During the study period, the animals had free access to food and water. Throughout the study, the body weight and remaining food of the animals were usually weighed at 24, 48, 72, 96 and 168 h after dosing. The results presented are graphs at 7 days (168 h) after dosing.

[0741] Results were calculated by comparing the food intake and body weight changes of individual rats with the mean changes of saline control animals and expressed as treatment group means (averages). For example, a food intake value of '-16' indicates a 16 g average decrease in food intake compared to the mean food intake of control animals at the same time interval in the study. The results for Example Compounds 1 to 405 are shown in Figure 1 the columns titled "7.5 nM single dose", "15 nM single dose" and "30 nM single dose".

[0742] The results for Example Compounds 406 to 737 are shown in Figure 2 . The rats were given a single subcutaneous injection of the peptide. The dose was generally 7.5 nmol / kg body weight, but doses of 1.5 nmol / kg, 2.0 nmol / kg, 3 nmol / kg, 5 nmol / kg or 6 nmol / kg were sometimes used. In the Figure 2 table, the 'n' column shows the number of times the compound in question was tested. Each test generally involved giving the compound to a group of 5 animals. The ability of the compound to cause a change in body weight was evaluated, called "potency" in Figure 2 and their tendency to inhibit food intake was evaluated, called Figure 2is referred to as "food" in the present context. These compounds were compared with semaglutide / Ozempic. For "efficacy", a score of 7 means that the compound has the same effect as Ozempic. A score higher than 7 indicates greater weight loss than that achieved with the same dose of Ozempic or a similar weight loss achieved with a lower dose of Ozempic. For "food", a score of 0 means that the reduction in food intake is the same as that of Ozempic. A score higher than 0 indicates that for a given weight change, the reduction in food intake is less than that achieved by Ozempic. Thus, a high score indicates that the analogue achieves good weight loss with minimal reduction in food intake.

[0743] In Vivo Efficacy Study: Repeated Dose Feeding Study in Male Wistar Rats

[0744] In these studies, male Wistar rats (Charles River) that were allowed to eat ad libitum received a total of five subcutaneous injections of saline or an exemplary peptide of the present invention over a period of 10 days, with a single injection on each of days 1, 3, 6, 8, and 10 of the study. Within the study, the dose levels were fixed and ranged between 2 and 5 nmol / kg in different studies. The comparator compound was semaglutide and its administered dose was 2 to 4 nmol / kg. The interval and total food intake from day 1 to day 12 of the study and the weight change over the same time period were calculated. The results for exemplary compounds 1 to 405 for which these data were available are presented in Figure 1 the column titled "rpt dose".

[0745] The average weight loss of the rats after repeated dosing was compared with the weight loss after administration of Ozempic (semaglutide) and vehicle control. Since the actual weight loss varied between animal groups and individual studies, the results are shown as the average response on a scale of 0 to 12 compared to Ozempic, where '7' = the same weight loss as Ozempic on day 12 of the study; less than '7' (down to '0') = less weight loss than Ozempic, and greater than '7' (up to '12') = greater weight loss than Ozempic.

[0746] The food intake of rats after repeated dosing was compared to that after administration of Ozempic (semaglutide) and vehicle control. Due to differences in food intake between animal groups and individual studies, the results are shown as the mean response on a scale of 0 to 12 compared to Ozempic and vehicle control, where '0' = the same food intake inhibition as Ozempic (substantial inhibition), '8' = no food intake inhibition compared to vehicle control on day 12 of the study, and '12' = greater food intake than vehicle control on day 12 of the study. Values between '0' and '8' and between '8' and '12' represent the rank between the fixed points of '0', '8', and '12'.

[0747] PK measurements for half-life assessment

[0748] Male Yorkshire pigs received a single subcutaneous injection of the test compound at the start of the study (0 hours). Blood samples were collected repeatedly from the pigs over the next 168 hours, plasma was separated and stored at -20 to -80 °C. Radioimmunoassay or mass spectrometry was used to quantify the plasma concentration of the test compound. The time taken for the concentration to fall from t max to half of C max was calculated and represents the half-life of the compound (t 1 / 2 ). Typically, the presented t 1 / 2 is the mean of four different animals.

[0749] Results

[0750] Figure 1 and 2 are tables providing the amino acid sequences and other structural information of the exemplary compounds of the present invention. For example, the amino acid sequence of exemplary compound No. 1 is as follows [SEQ ID NO:1]:

[0751]

[0752] and the Lys residue at position 42 carries a Z group on its ε-amino, where Z is

[0753]

[0754] where R is a C 14 straight-chain alkylene, and

[0755] R 1 is CO 2 H.

[0756] The figure also summarizes the results of in vivo feeding efficacy studies using the exemplary peptides of the present invention as discussed above.

[0757] In the rightmost column, the figure shows receptor potency data at the human glucagon and GLP-1 receptors where the exemplified peptides are overexpressed in Chinese hamster ovary (CHO) cells. The biological activity was evaluated by the potency of the peptides to stimulate cAMP production in CHO cells as described above. The values provided for each exemplified compound are the glucagon:GLP-1 activity ratios.

[0758] As can be seen from the figure, rats that were allowed free access to food and administered the exemplified peptides of the present invention achieved a reduced weight gain or a weight loss compared to rats administered saline. This supports that the compounds of the present invention are particularly effective in improving metabolism and that the compounds can be used to treat conditions such as obesity. However, the amount of food consumed by the rats administered the exemplified peptides was similar to or greater than the amount of food consumed by the rats administered saline. There was no effect or only a very small effect on food intake, indicating a reduced side effect related to nausea for the compounds. As discussed above, rodents are unable to vomit, but rodents experiencing nausea are likely to delay eating. For the peptides of the present invention, no evidence of animals delaying food consumption was observed.

[0759] Half-life:

[0760] The half-lives of selected compounds of the present invention were measured. The results for the "Group I" exemplified compound group are as follows:

[0761] Example Compound reference Half-life / h Semaglutide 56 507 G5943 112 544 G6070 83 549 G6077 110 587 G6129 84 588 G6130 65 640 G6204 135 642 G6213 109 646 G6218 42 647 G6219 106 649 G6221 84 652 G6224 116 701 G6363 66 704 G6368 96 705 G6370 84 706 G6372 110 707 G6373 103 708 G6374 105

[0762] In the foregoing description, when integers or elements having known, obvious or foreseeable equivalent forms are referred to, such equivalent forms are incorporated herein as if set forth separately. The true scope of the present invention should be determined with reference to the claims, which should be construed to cover any such equivalent forms. The reader will also understand that the integers or features of the present invention described as being preferred, advantageous, convenient, etc. are optional and do not limit the scope of the independent claims. Further, it should be understood that although such optional integers or features may be beneficial in some embodiments of the present invention, in other embodiments, such optional integers or features may be undesirable and thus may not be present.

Claims

1. A compound of formula (I): XW-Y1-Y2 Formula (I) in X is the amino acid sequence: His1-Xaa2-Xaa3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Xaa10-Ser11-Xaa12-Xaa13-Leu14-Xaa15-Xaa 16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe22-Xaa23-Xaa24-Trp25-Leu26-Xaa27-Xaa28-Xaa29-[SEQ ID NO:742] W is the amino acid sequence: -Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-[SEQ ID NO:795]; Y1 is the amino acid sequence: -Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Lys42-Xaa43-Xaa44[SEQ ID NO:744] and the lysine residue at position 42 is substituted at its ε-amino group by a Y2 group and Y2 is: Z-Xaa45-Xaa46-Xaa47-Xaa48-[SEQ ID NO:745] and Z is a group of the formula: Where R is C8-C 28 an alkylene group or an alkenylene group, and R 1 is CO2H, And wherein the compound of formula (I) is selected from: Instance No. 136: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Thr47-His48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 163: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly47-Ser48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 167: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gly47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 168: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-His3 1-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly45-Ser46-Gly47-Ser48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 169: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Thr47-His48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 176: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-His3 1-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly45-Ser46-Gly47-Ser48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 195: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Asn47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 196: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gln47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 197: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly46-Gln47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 198: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 199: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Thr47-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 200: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-His47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 201: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn47-His48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 202: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Thr47-His48-; Z=i; R is C 14 Straight chain alkylene; Instance No. 203: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-His48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 204: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 205: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 211: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gly47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 255: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gly47-Thr48-; Z=i; R is C 20 Straight chain alkylene; Instance No. 256: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-His3 1-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly45-Ser46-Gly47-Ser48-; Z=i; R is C 20 Straight chain alkylene; Instance No. 260: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gly47-Thr48-; Z=i; R is C 22 Straight chain alkylene; Instance No. 261: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-His3 1-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly45-Ser46-Gly47-Ser48-; Z=i; R is C 22 Straight chain alkylene; Instance No. 262: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 263: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 264: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn48-; Z=i; R is C 20 Straight chain alkylene; Instance No. 265: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln48-; Z=i; R is C 20 Straight chain alkylene; Instance No. 266: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 267: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Lys42; Y2=Z-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 268: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Gly39-Lys42; Y2=Z-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 269: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 270: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln47-Gly48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 271: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly47-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 272: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly47-Gln48-; Z=i; R is C 22 Straight chain alkylene; Instance No. 273: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gly47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 276: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 277: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gly47-Thr48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 278: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 289: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gly47-Thr48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 290: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly47-Ser48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 301: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn47-His48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 314: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn47-His48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 315: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn47-His48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 316: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gln47-His48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 317: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn47-His48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 319: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn47-His48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 321: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn47-His48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 323: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn47-His48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 325: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 327: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 329: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 340: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Ser46-Gly47-Thr48-; Z=i; R is C 14 Straight chain alkylene; Instance No. 341: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His3 0-His31-His32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Gly47-Ser48-; Z=i; R is C 14 Straight chain alkylene; Instance No. 366: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Gly47-Ser48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 367: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Thr45-Gly46-Ser47-Gly48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 368: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 369: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Gln48-; Z=i; R is C 16 Straight chain alkylene; Instance No. 412: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-His30-H is31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Thr45-Gly46-Ser47-Gly48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 521: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln2 8-Ser29-His30-Gln31-His32-Pro33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 536: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 537: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 538: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-His33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 542: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-G ln28-Ser29-Gln30-Gln31-His32-Glu33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 543: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-G ln28-Ser29-Gln30-Gln31-His32-Glu33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 544: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-G ln28-Ser29-His30-Gln31-His32-Pro33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 549: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 550: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-His31-Gln32-Gln33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 552: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-His32-Gln33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 553: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-Gln33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 581: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-G ln28-Ser29-His30-Gln31-Gln32-Pro33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 588: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln2 8-Ser29-His30-Gln31-Gln32-His33-Glu34-Ser35-Pro36-Pro37-Pro38-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 589: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-Gly47-Ser48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 590: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-G ln28-Ser29-His30-Gln31-Gln32-His33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 595: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-G ln28-Ser29-His30-Gln31-His32-Glu33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 597: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln2 8-Ser29-His30-Gln31-His32-Glu33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 598: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-Glu34-Ser35-Pro36-Pro37-Pro38-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 602: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 603: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 604: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-His31-Gln32-His33-Glu34-Ser35-Pro36-Pro37-Pro38-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 605: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 606: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln2 8-Ser29-His30-Gln31-His32-Glu33-Ser34-Pro35-Pro36-Pro37-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 632: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-His32-Gln33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 636: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-His32-Gln33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 638: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-His32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 639: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-Gln31-His32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 642: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 643: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-Gln31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 646: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 647: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-H is30-His31-Gln32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 652: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-His33-Glu34-Ser35-Pro36-Pro37-Pro38-Gly39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 653: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-Glu34-Ser35-Pro36-Pro37-Pro38-Gly39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 654: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-His31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 655: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-Ser34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 656: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 657: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-Gln30-His31-Gln32-His33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 658: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-Gln30-Gln31-His32-Glu33-Ser34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 660: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-His31-Gln32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 661: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 663: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu2 7-Gln28-Ser29-Gln30-Gln31-His32-Glu33-Ser34-Pro35-Pro36-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 671: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-G ln28-Ser29-Gln30-Gln31-His32-Glu33-Ser34-Ser35-Gly36-Ala37-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 672: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-G ln28-Ser29-His30-Gln31-His32-Glu33-Ser34-Ser35-Gly36-Ala37-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 673: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln2 8-Ser29-His30-Gln31-Gln32-His33-Glu34-Ser35-Ser36-Ala37-Ser38-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 678: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser29-Gln30-Gln31-His32-Glu33-Ser34-Ser 35-Gly36-Ala37-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 682: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu2 7-Gln28-Ser29-His30-His31-Gln32-Gln33-His34-Glu35-Gly36-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 691: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-His31-Gln32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Gly39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 695: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-His31-Gln32-Gln33-His34-Glu35-Ser36-Ser37-Ser38-Gly39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 700: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-His33-Glu34-Ser35-Pro36-Pro37-Pro38-Gly39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 701: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-Gln33-His34-Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 704: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Arg20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-His33-Glu34-Ser35-Pro36-Pro37-Pro38-Gly39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 705: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Arg20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-His33-Pro34-Ser35-Pro36-Pro37-Pro38-Gly39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 706: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-His33-Pro34-Ser35-Pro36-Pro37-Pro38-Gly39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 707: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-Gln31-Gln32-His33-Pro34-Ser35-Ser36-Ser37-Ser38-Ala39-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 708: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-Pro34-Ser35-Ser36-Ser37-Ala38-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 709: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-His20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-Pro34-Ser35-Ser36-Ser37-Ala38-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene; Instance No. 711: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-His34-Pro35-Ser36-Ser37-Ser38-Ala39-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 712: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-Ser2 9-His30-His31-Gln32-Gln33-His34-Pro35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42; Y2=Z-; Z=i; R is C 18 Straight chain alkylene; Instance No. 725: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Gln20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-Pro34-Ser35-Ser36-Ser37-Ala38-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 a straight chain alkylene group; and Instance No. 726: His1-AIB2-His3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Lys12-Tyr13-Leu14-As p15-Ala16-Lys17-Arg18-Ala19-Arg20-Glu21-Phe22-Ile23-Glu24-Trp25-Leu26-Leu27-Gln28-S er29-His30-Gln31-Gln32-His33-Pro34-Ser35-Ser36-Ser37-Ala38-Lys42; Y2=Z-Asn48-; Z=i; R is C 18 Straight chain alkylene.

2. The compound according to claim 1, wherein W is an amino acid sequence: -His30-Gln31-His32-Pro33-Ser34-[SEQ ID NO:756]; and wherein the compound of formula (I) is selected from: Example Nos. 521 and 544; -His30-Gln31-Gln32-His33-Glu34-[SEQ ID NO:776]; and wherein the compound of formula (I) is selected from: Example Nos. 588, 598, 652, 653, 673, 700 and 704; -His30-Gln31-His32-Gln33-His34-[SEQ ID NO:780]; and wherein the compound of formula (I) is selected from: Example Nos. 552, 632, 636, 638 and 639; -His30-His31-Gln32-Gln33-His34-[SEQ ID NO:766]; and wherein the compound of formula (I) is selected from: Example Nos. 549, 550, 646, 647, 660, 682, 691, 695, 701 and 712; -Gln30-Gln31-His32-Glu33-Ser34-[SEQ ID NO: 770]; and wherein the compound of formula (I) is selected from: Example Nos. 542, 543, 658, 663, 671 and 678; or -His30-Gln31-Gln32-His33-Pro34-[SEQ ID NO:792]; and wherein the compound of formula (I) is selected from: Example Nos. 705, 706, 707, 708, 709, 725 and 726.

3. The compound according to claim 1 or 2, wherein Y1 is an amino acid sequence: -Pro35-Pro36-Pro37-Lys42 [SEQ ID NO: 797]; and wherein the compound of formula (I) is selected from: Example Nos. 521, 542, 543, 544, 581, 589, 590, 595, 597 and 606; -Ser35-Pro36-Pro37-Pro38-Lys42 [SEQ ID NO: 798]; and wherein the compound of formula (I) is selected from: Example Nos. 588, 598 and 604; -Glu35-Ser36-Pro37-Pro38-Pro39-Gly40-Lys42 [SEQ ID NO: 799]; and wherein the compound of formula (I) is selected from: Example Nos. 163, 167, 168, 169, 255, 256, 260, 261, 273, 276, 321, 323, 325, 638, 639, 642, 643, 646, 647 and 701; -Glu35-Ser36-Pro37-Pro38-Pro39-Lys42 [SEQ ID NO: 800]; and wherein the compound of formula (I) is selected from: Example Nos. 319, 327, 549, 602, 603, 605, 654, 655, 656, 657, 658, 660 and 661; -Ser35-Gly36-Ala37-Lys42 [SEQ ID NO: 801]; and wherein the compound of formula (I) is selected from: Example Nos. 671 and 672; -Ser35-Pro36-Pro37-Pro38-Gly39-Lys42 [SEQ ID NO: 802]; and wherein the compound of formula (I) is selected from: Example Nos. 652, 653, 700, 704, 705 and 706; -Ser35-Ser36-Ser37-Ser38-Ala39-Lys42 [SEQ ID NO: 803]; and wherein the compound of formula (I) is Example No. 707; or -Ser35-Ser36-Ser37-Ala38-Lys42 [SEQ ID NO: 804]; and wherein the compound of formula (I) is selected from: Example Nos. 708, 709, 725 and 726.

4. The compound according to claim 1, wherein Y2 is an amino acid sequence, wherein: Xaa45 is absent; Xaa46 does not exist; Xaa47 is Gly, Asn, or absent; Xaa48 is Ser, His, Asn or absent. Z = i; and R is for C 16 or C 18 Straight chain alkylene; And wherein the compound of formula (I) is selected from: Instance No.: 163, 201, 203, 204, 262, 290, 301, 314, 315, 317, 319, 321, 323, 325, 327, 329, 366, 368, 521, 536, 537, 538, 542, 543, 544, 549, 550, 552, 553, 581, 588, 589, 590, 595, 597, 598, 602, 603, 604 04, 605, 606, 632, 636, 638, 639, 642, 643, 646, 647, 652, 653, 654, 655, 656, 657, 658, 660, 661, 663, 671, 672, 673, 678, 682, 691, 695, 700, 701, 704, 705, 706, 707, 708, 709, 711, 712, 725 and 726.

5. The compound according to claim 4, wherein Y2 is: Z-Gly47-Ser48-; Instance No.: 163, 290, 366 and 589; Z-Asn47-His48-; Example No.: 201, 301, 314, 315, 317, 319, 321 and 323; Z-； Instance No.: 537, 538, 542, 543, 544, 550, 552, 553, 581, 588, 590, 595, 636, 638, 642, 646, 653, 654, 655, 656, 657, 658, 660, 661, 663, 671, 672, 673, 682, 691, 695, 701, 711, and 712; or Z-Asn48- Instance No.: 204, 262, 264, 325, 327, 329, 368, 521, 536, 549, 597, 598, 602, 603, 604, 605, 606, 632, 639, 643, 647, 652, 678, 700, 704, 705, 706, 707, 708, 709, 725, and 726.

6. The compound according to claim 1, wherein Z is a group of the formula: and R is C 16 or C 18 Straight chain alkylene; And wherein the compound of formula (I) is selected from: Instance No.: 136, 163, 167, 168, 169, 176, 195, 196, 197, 198, 199, 200, 201, 203, 204, 205, 211, 262, 263, 266, 267, 268, 269, 270, 271, 273, 276, 277, 278, 289, 290, 301, 314, 315, 316, 317, 319, 321, 323, 325, 327, 329, 366, 367, 368, 369, 412, 521, 536, 537, 538, 542, 543 , 544, 549, 550, 552, 553, 581, 588, 589, 590, 595, 597, 598, 602, 603, 604, 605, 606, 632, 636, 638, 639, 642, 643, 646, 647, 652, 653, 654, 655, 656, 657, 658, 660, 661, 663, 671, 672, 673, 678, 682, 691, 695, 700, 701, 704, 705, 706, 707, 708, 709, 711, 712, 725 and 726.

7. A derivative of a compound according to any one of claims 1 to 6, or a salt of such a derivative, comprising one or more derivatizations selected from the group consisting of amidation, cyclization, lipidation and pegylation.

8. A composition comprising a compound, derivative or salt according to any one of claims 1 to 7 together with a pharmaceutically acceptable carrier and optionally an additional therapeutic agent.

9. Use of a compound, derivative or salt according to any one of claims 1 to 7, or a composition according to claim 8 for the preparation of a medicament for treating or preventing diabetes, obesity, heart disease, stroke and non-alcoholic fatty liver disease in a subject, so as to increase the subject's energy expenditure, improve the subject's insulin release, improve the subject's carbohydrate metabolism, improve the subject's lipid profile, reduce appetite, reduce food intake, reduce calorie intake, improve the subject's glucose tolerance, or for the preparation of a medicament for providing cardioprotection.

10. The use according to claim 9, wherein the drug for providing cardioprotection is a drug for providing cardioprotection to a subject after myocardial infarction.

11. Use of a compound, derivative or salt according to any one of claims 1 to 7, or a composition according to claim 8 and an additional therapeutic agent for the preparation of a medicament for treating or preventing diabetes, obesity, heart disease, stroke and non-alcoholic fatty liver disease in a subject, so as to increase the subject's energy expenditure, improve the subject's insulin release, improve the subject's carbohydrate metabolism, improve the subject's lipid profile, reduce appetite, reduce food intake, reduce calorie intake, improve the subject's glucose tolerance, or for the preparation of a medicament for providing cardioprotection.

12. An application device, wherein: The composition of claim 8 is present in the administration device, and the administration device is used for subcutaneous injection into humans.

13. The applicator according to claim 12, wherein the applicator is a syringe.

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