Use of co-agonists of the glp-1 and amylin receptors

Abstract

This invention relates to a compound comprising a GLP-1 receptor agonist and an amyloid receptor agonist. This invention also relates to a pharmaceutical formulation comprising such a compound suitable for (but not limited to) oral administration. The compound and the pharmaceutical formulation comprising the compound can be used in individuals suffering from overweight, obesity, and / or related comorbidities.

Description

Technical Field

[0001] This invention relates to a compound comprising a GLP-1 receptor agonist and an amyloid receptor agonist. It also relates to a pharmaceutical formulation comprising such a compound suitable for (but not limited to) oral administration. The compound and pharmaceutical formulations comprising the compound are suitable for use in individuals who are overweight or obese with or without related comorbidities; individuals with diabetes with or without related comorbidities; individuals with cardiovascular disease, non-alcoholic steatohepatitis (NASH), and cognitive impairment such as that caused by Alzheimer's disease. Prior Technology

[0002] Overweight and obesity are abnormal or excessive accumulations of body fat that pose a risk to an individual's overall health. A body mass index (BMI) of over 25 is considered overweight, while a BMI of over 30 is considered obese. Obesity is a major risk factor for many serious diseases, including type 2 diabetes and its associated comorbidities, and cardiovascular diseases such as heart disease and stroke, which are leading causes of death worldwide. Obesity is now recognized by the World Health Organization (WHO) as an epidemic problem, even among children: 1.9 billion adults worldwide were reported to be obese in 2016; and 38.3 million children under the age of five were reported to be obese in 2019. According to the WHO, 422 million people worldwide have diabetes, and 1.6 million people die directly from diabetes each year. Therefore, there is a strong motivation for individuals and society to try to prevent and / or treat obesity.

[0003] When diet and exercise alone are insufficient to reduce the body mass index (BMI) of obese individuals to an acceptable level, the use of medications such as liraglutide, orlistat, and naltrexone-bupropion has been shown to induce weight loss. Nevertheless, bariatric surgery has been proven necessary in many cases. For long-term weight loss, bariatric surgery is currently the most effective treatment, but it is an invasive procedure involving high risks and significant costs for the patient. Therefore, effective minimally invasive treatments would represent a major advancement in obesity management.

[0004] Amyllin is a 37-amino acid polypeptide hormone secreted along with insulin by beta cells of the pancreas. The half-life of endogenous amyllin is approximately 15-20 minutes. It functions in several different organ systems, primarily through amyllin receptors 1-3 (AMYR1-3). Amyllin is an important regulator of energy metabolism in health and disease, inhibiting glucagon secretion, delaying gastric emptying, and signaling satiety and appetite suppression. Other effects of amyllin have also been reported, such as its effects on the cardiovascular system and bones.

[0005] Clinical studies have shown that amyloid receptor agonists can be used to treat overweight, obesity, type 1 diabetes, and / or type 2 diabetes. Currently, one product on the market (Symlin®) contains the amyloid receptor agonist (pramlintide acetate) as the active pharmaceutical ingredient. Symlin® is a subcutaneous medication approved for use in patients with type 1 or type 2 diabetes who are using basal and mealtime insulin but have failed to achieve desired glycemic control despite optimal insulin therapy. The use of pramlintide in overweight and obese patients has also been clinically studied. Pramlintide has a short biological half-life (less than 1 hour) and requires three daily doses. Therefore, patients receiving pramlintide treatment may experience significant diurnal variations in pramlintide plasma levels.

[0006] GLP-1 is a polypeptide hormone with 30 or 31 amino acids, synthesized and secreted by L cells in the gut endocrine system. GLP-1 is an incretin that reduces blood glucose levels in a glucose-dependent manner by increasing insulin secretion. Endogenous GLP-1 is rapidly degraded primarily by dipeptidyl peptidase-4 (DPP-4), resulting in a half-life of approximately 2 minutes.

[0007] Several commercially available products containing GLP-1 receptor agonists as active pharmaceutical ingredients have been approved for use in individuals with type 2 diabetes. These products include dulaglutide (Trulicity®), exenatide (Byetta®, Bydureon®), liraglutide (Victoza®), lixisenatide (Lyxumia®), and semaglutide (Ozempic®).

[0008] Semaglutide is the first GLP-1 receptor agonist approved in tablet form (Rybelsus®). It is safe and effective as a monotherapy and adjunctive therapy for the treatment of type 2 diabetes.

[0009] Two commercially available products containing GLP-1 receptor agonists as active pharmaceutical ingredients are approved for use in overweight or obese individuals with at least one weight-related comorbidity: liraglutide (Saxenda®) and semaglutide (Wegovy®). The maximum efficacy achievable with GLP-1 receptor agonists is limited by tolerability. Side effects such as nausea and vomiting become increasingly pronounced with increasing doses. The tolerability limitations of amyloid receptor agonist therapy are largely the same as those of GLP-1 receptor agonist therapy (and similar side effects such as nausea and vomiting). Therefore, it is also desirable to prolong the effects of amyloid receptors.

[0010] A fixed-dose combination of the amyloid receptor agonist caglitinide and the GLP-1 receptor agonist semaglutide is currently under investigation for the treatment of overweight and obesity (Lancet 2021; 397: 1736–48). The investigational drug product is a single liquid formulation for subcutaneous use. Clinical trials have shown that the combination of semaglutide and caglitinide resulted in greater weight loss in obese patients without significantly worsening side effects compared to the maximum approved dose of semaglutide monotherapy.

[0011] While current treatment options and investigational drugs offer promise, individuals who are overweight, obese, and / or have related comorbidities may at best desire only injectable pharmaceutical preparations or drug treatments with moderate efficacy. There remains a need in the field for more effective drugs that do not simultaneously cause a disproportionately increased degree of side effects and are suitable for oral administration. Summary of the Invention

[0012] This article discloses a GLP-1 receptor-amyloid receptor co-activator comprising a polypeptide (R1) according to Formula I: Z1-Z2-Z3, It includes 1-3 lysine (Lys, K) residues and does not contain disulfide bonds; wherein: ● Z1 is a GLP-1 receptor agonist peptide comprising up to 9 amino acid modifications relative to SEQ ID NO: 1 (human GLP-1(7-37)), provided that Z1 does not contain isoleucine (Ile, I) at position 22 relative to SEQ ID NO: 1, SEQ ID NO: 238, or SEQ ID NO: 255; ● Z2 is an optional peptide linker; ● Z3 contains C-terminal amides Furthermore, relative to SEQ ID NO: 79, it includes at most four amino acid-modified amyloid receptor agonist peptides, provided that Z3 does not contain proline (Pro, P) at position 12 relative to SEQ ID NO: 79, SEQ ID NO: 240, or SEQ ID NO: 256.

[0013] This article discloses a GLP-1 receptor-amyloid receptor co-activator comprising a polypeptide (R1) according to Formula I: Z1-Z2-Z3, It includes 1-3 lysine (Lys, K) residues and does not contain disulfide bonds; in: ● Z1 is a GLP-1 receptor agonist peptide that comprises up to 9 amino acid modifications, relative to SEQ ID NO: 1 (human GLP-1(7-37)). ● Z2 is an optional peptide linker; ● Z3 contains C-terminal amides And compared to SEQ ID NO: 79, it includes up to 7 amino acid-modified amyloid receptor agonist peptides.

[0014] This article reveals that the GLP-1 receptor-amyloid receptor co-activator further includes 1-3 elongated portions attached via 1-3 lysine residues.

[0015] A preferred compound is "compound 0111", that is: H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine

[0016] This article discloses a GLP-1 receptor-amyloid receptor co-activator for use as a pharmaceutical. This article discloses a GLP-1 receptor-amyloid receptor co-activator for the treatment of individuals with an initial body mass index (BMI) of 27 or higher (such as 30 or higher), who, depending on the circumstances, have at least one comorbidity, cardiovascular disease, non-alcoholic steatohepatitis, and / or cognitive impairment such as Alzheimer's disease.

[0017] This article discloses a pharmaceutical formulation comprising a GLP-1 receptor-amyloid receptor co-activator and a pharmaceutically acceptable excipient.

[0018] [Sequence List] SEQ ID NO: 1 represents the amino acid sequence of human GLP-1 (7-37). SEQ ID NO: 2-78 represents the amino acid sequence of the backbone of a GLP-1 receptor agonist peptide. SEQ ID NO: 79-88 represents the amino acid sequence of the backbone of an amyloid receptor agonist peptide. SEQ ID NO: 89-116 represents the amino acid sequence of an optional peptide linker. SEQ ID NO: 117-236 represents the amino acid sequence of the polypeptide backbone of an example GLP-1 receptor-amyloid receptor co-activator. SEQ ID NO: 237 represents the amino acid sequence of human glucagon. SEQ ID NO: 238 represents the amino acid sequence of the GLP-1 receptor agonist (peptide Z1) according to Formula II. SEQ ID NO: 239 represents the amino acid sequence of the optional peptide linker Z2. SEQ ID NO: 240 represents the amino acid sequence of the amyloid receptor agonist (peptide Z3) according to Formula III. SEQ ID NO: 241-245 represent the amino acid sequences of the polypeptide backbone within the illustrative comparative compounds. SEQ ID NO: 246 represents the amino acid sequence of the polypeptide backbone within semaglutide. SEQ ID NO: 247 represents the amino acid sequence of the polypeptide backbone within pramlinpeptide. SEQ ID NO: 248 represents the amino acid sequence of the polypeptide backbone within the caglinide. SEQ ID NO: 249 represents the amino acid sequence of salmon calcitonin. SEQ ID NO: 250 represents the amino acid sequence of the polypeptide backbone within compound 1806. SEQ ID NO: 251-254 represent the amino acid sequences of the polypeptide backbone within the illustrative comparative compounds. SEQ ID NO: 255 represents the amino acid sequence of the GLP-1 receptor agonist (peptide Z1) according to Formula II. SEQ ID NO: 256 represents the amino acid sequence of the amyloid receptor agonist (peptide Z3) according to Formula III. Simple Explanation of the Diagram

[0019] [Figure 1] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0020] [Figure 2] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0021] [Figure 3] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0022] [Figure 4] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0023] [Figure 5] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0024] [Figure 6] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0025] [Figure 7] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0026] [Figure 8] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0027] [Figure 9] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0028] [Figure 10] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0029] [Figure 11] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0030] [Figure 12] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0031] [Figure 13] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0032] [Figure 14] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0033] [Figure 15] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0034] [Figure 16] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0035] [Figure 17] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0036] [Figure 18] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0037] [Figure 19] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0038] [Figure 20] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0039] [Figure 21] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0040] [Figure 22] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0041] [Figure 23] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0042] [Figure 24] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0043] [Figure 25] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0044] [Figure 26] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0045] [Figure 27] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0046] [Figure 28] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0047] [Figure 29] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0048] [Figure 30] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0049] [Figure 31] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0050] [Figure 32] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0051] [Figure 33] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0052] [Figure 34] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0053] [Figure 35] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0054] [Figure 36] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0055] [Figure 37] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0056] [Figure 38] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0057] [Figure 39] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0058] [Figure 40] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0059] [Figure 41] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0060] [Figure 42] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0061] [Figure 43] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0062] [Figure 44] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0063] [Figure 45] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0064] [Figure 46] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0065] [Figure 47] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0066] [Figure 48] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0067] [Figure 49] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0068] [Figure 50] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0069] [Figure 51] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0070] [Figure 52] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0071] [Figure 53] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0072] [Figure 54] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0073] [Figure 55] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0074] [Figure 56] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0075] [Figure 57] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0076] [Figure 58] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0077] [Figure 59] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0078] [Figure 60] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0079] [Figure 61] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0080] [Figure 62] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0081] [Figure 63] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0082] [Figure 64] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0083] [Figure 65] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0084] [Figure 66] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0085] [Figure 67] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0086] [Figure 68] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0087] [Figure 69] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0088] [Figure 70] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0089] [Figure 71] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0090] [Figure 72] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0091] [Figure 73] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0092] [Figure 74] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0093] [Figure 75] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0094] [Figure 76] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0095] [Figure 77] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0096] [Figure 78] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0097] [Figure 79] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0098] [Figure 80] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0099] [Figure 81] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0100] [Figure 82] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0101] [Figure 83] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0102] [Figure 84] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0103] [Figure 85] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0104] [Figure 86] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0105] [Figure 87] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0106] [Figure 88] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0107] [Figure 89] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0108] [Figure 90] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0109] [Figure 91] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0110] [Figure 92] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0111] [Figure 93] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0112] [Figure 94] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0113] [Figure 95] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0114] [Figure 96] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0115] [Figure 97] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0116] [Figure 98] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0117] [Figure 99] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0118] [Figure 100] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0119] [Figure 101] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0120] [Figure 102] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0121] [Figure 103] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0122] [Figure 104] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0123] [Figure 105] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0124] [Figure 106] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0125] [Figure 107] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0126] [Figure 108] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0127] [Figure 109] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0128] [Figure 110] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0129] [Figure 111] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0130] [Figure 112] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0131] [Figure 113] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0132] [Figure 114] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0133] [Figure 115] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0134] [Figure 116] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0135] [Figure 117] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0136] [Figure 118] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0137] [Figure 119] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0138] [Figure 120] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0139] [Figure 121] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0140] [Figure 122] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0141] [Figure 123] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0142] [Figure 124] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0143] [Figure 125] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0144] [Figure 126] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0145] [Figure 127] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0146] [Figure 128] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0147] [Figure 129] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0148] [Figure 130] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0149] [Figure 131] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0150] [Figure 132] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0151] [Figure 133] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0152] [Figure 134] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0153] [Figure 135] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0154] [Figure 136] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0155] [Figure 137] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0156] [Figure 138] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0157] [Figure 139] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0158] [Figure 140] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0159] [Figure 141] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0160] [Figure 142] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0161] [Figure 143] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0162] [Figure 144] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0163] [Figure 145] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0164] [Figure 146] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0165] [Figure 147] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0166] [Figure 148] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0167] [Figure 149] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0168] [Figure 150] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0169] [Figure 151] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0170] [Figure 152] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0171] [Figure 153] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0172] [Figure 154] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0173] [Figure 155] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0174] [Figure 156] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0175] [Figure 157] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0176] [Figure 158] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0177] [Figure 159] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0178] [Figure 160] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0179] [Figure 161] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0180] [Figure 162] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0181] [Figure 163] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0182] [Figure 164] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0183] [Figure 165] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0184] [Figure 166] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0185] [Figure 167] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0186] [Figure 168] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0187] [Figure 169] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0188] [Figure 170] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0189] [Figure 171] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0190] [Figure 172] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0191] [Figure 173] illustrates a compound manufactured according to the present invention, which is further described in Example 1.

[0192] [Figure 174] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0193] [Figure 175] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0194] [Figure 176] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0195] [Figure 177] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0196] [Figure 178] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0197] [Figure 179] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0198] [Figure 180] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0199] [Figure 181] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0200] [Figure 182] illustrates one of the comparative compounds produced, which is further described in Example 1.

[0201] [Figure 183] illustrates amyloid receptor agonists. Implementation

[0202] This invention relates to a compound comprising an amyloid receptor agonist and a GLP-1 receptor agonist. The compound disclosed herein is capable of activating or "agonizing" both the GLP-1 receptor and amyloid receptor systems: it is a "GLP-1 receptor-amyloid receptor co-agonist". The compound may further comprise one, two, or three extended portions.

[0203] The compounds disclosed in this article can be effective GLP-1 receptor agonists.

[0204] The compounds disclosed in this article can be effective amyloid receptor agonists.

[0205] The compound disclosed in this paper can provide an approximate degree of activation to both receptor systems; that is, it can be "balanced." Relatively "balanced" receptor activation is advantageous because the relative proportions of the GLP-1 receptor agonist and the amyloid receptor agonist moiety are fixed on the molecule; it is impossible to titrate these two receptor agonists relative to each other. Finally, when the molecule is "balanced," it can activate both hormonal systems upon administration without producing side effects that outweigh the benefits.

[0206] A compound is considered "unbalanced" if it is highly effective against one receptor but much less effective against another. For example, a compound that is highly effective against the GLP-1 receptor system (e.g., EC50 < 50 pM) but less effective against the amyloid receptor system (e.g., EC50 > 200 pM) is "unbalanced"; that is, it is likely to behave like a pure GLP-1 receptor agonist. Such a compound will not achieve optimal efficacy against either hormone system because the side effects of GLP-1 receptor activation will also prevent the administration of sufficiently high doses to activate the amyloid hormone system. Conversely, if the compound is highly effective against amyloid receptors (e.g., EC50 < 50 pM) but has relatively low efficacy against GLP-1 receptors (e.g., EC50 > 200 pM), the opposite may occur.

[0207] Furthermore, the compounds disclosed in this paper have a longer half-life compared to their natural ligands. The longer biological half-life of the compounds disclosed in this paper relative to the dosing interval reduces the variability of steady-state exposure.

[0208] The compounds disclosed in this paper are orally bioavailable and therefore suitable for administration to individuals in need. Both the polypeptide backbone and the extended portion were designed and modified to obtain compounds possessing all of the above properties. [Receptor agonists] [ ]

[0209] " "[Receptor agonist]" or "agonist" is a ligand, such as a compound that binds to and activates a biological receptor to produce a biological response. A complete agonist can be defined as an agonist that elicits a response of the same magnitude as the natural ligand (see, for example, "Principles of Biochemistry", AL Lehninger, DL Nelson, MM Cox, 2nd ed., Worth Publishers, 1993, p. 763). Receptors can be activated by endogenous agonists (such as endogenous hormones) or exogenous agonists (such as pharmaceuticals). [Co-activating agent]

[0210] In the context of this invention, " "[Co-activators]" are compounds comprising two different ligands, each of which binds to a designated biological receptor to produce a biological response characteristic of the natural ligand. The co-activators disclosed herein refer to "GLP-1-amyloid co-activators" or "GLP-1 receptor-amyloid receptor co-activators". [GLP-1] [Receptor] [-] [Amyloid receptor co-activators]

[0211] The compound disclosed in this article is " [GLP-1] [Receptor] [-] "[Amyloid receptor co-activator]" or "GLP-1-amyloid receptor co-activator". This GLP-1 receptor-amyloid receptor co-activator includes a GLP-1 receptor activator, an optional peptide linker, and an amyloid receptor activator. The GLP-1 receptor activator component binds to and activates the GLP-1 receptor, while the amyloid receptor activator component at least binds to and activates the human amyloid 3 receptor (AMYR3).

[0212] The molecular form may be a single-chain polypeptide backbone comprising one, two, or three lysine (Lys, K) residues. The molecular form may also be a single-chain polypeptide backbone comprising one, two, or three cysteine ​​(Cys, C) residues. The molecular form may further comprise one to three elongated moieties. These elongated moieties may be covalently bound to the lysine (Lys, K) or cysteine ​​(Cys, C) residues.

[0213] The amide moiety at the C-terminus of the amyloid receptor agonist must be free to maintain maximum biological activity. Therefore, the C-terminal residue of the GLP-1 receptor agonist is covalently linked to either the optional linker or the N-terminal residue of the amyloid receptor agonist, and the N-terminal residue of the amyloid receptor agonist is covalently linked to either the optional linker or the C-terminal residue of the GLP-1 receptor agonist. When present, the linker comprises 1-30 naturally occurring amino acids.

[0214] The polypeptide backbone of this GLP-1 receptor-amyloid receptor co-activator contains lysine residues. The polypeptide backbone of this GLP-1 receptor-amyloid receptor co-activator may include one or two lysine residues. Alternatively, the polypeptide backbone of this GLP-1 receptor-amyloid receptor co-activator may include one lysine residue.

[0215] The polypeptide backbone of this GLP-1 receptor-amyloid receptor co-activator may include 1, 2, or 3 cysteine ​​residues. The polypeptide backbone of this GLP-1 receptor-amyloid receptor co-activator may include 1 or 2 cysteine ​​residues. The polypeptide backbone of this GLP-1 receptor-amyloid receptor co-activator may include 1 cysteine ​​residue.

[0216] The polypeptide backbone of this GLP-1 receptor-amyloid receptor co-activator may be referred to as "R1" in this paper and is described by Formula I: Z1-Z2-Z3, Z1 is a GLP-1 receptor agonist peptide, Z2 is an optional peptide linker, and Z3 is an amyloid receptor agonist peptide.

[0217] Compared to wild-type GLP-1 (7-37) (SEQ ID NO: 1), Z1 may include up to 9 amino acid modifications. The C-terminus of Z1 is attached to Z2 (when Z2 is present) or Z3 (when Z2 is absent).

[0218] Z2 is an optional peptide linker. When present, its N-terminus is attached to the C-terminus of Z1, and its C-terminus is attached to the N-terminus of Z3.

[0219] Z3 may include up to 7 amino acid modifications relative to SEQ ID NO: 79. The C-terminus of Z3 is modified with an amide group. The N-terminus of Z3 is attached to the C-terminus of Z2 (when Z2 is present) or to the C-terminus of Z1 (when Z2 is absent).

[0220] Z1-Z2-Z3 includes one, two, or three lysine and / or cysteine ​​residues. Each lysine and / or cysteine ​​residue may be covalently linked to an elongation portion, which may be referred to as "R2-R3", where "R2" is an optional linker and "R3" is an elongator.

[0221] This GLP-1 receptor-amyloid receptor co-activator exhibits many properties that allow it to be used as a pharmaceutical product, as described in this article.

[0222] This GLP-1 receptor-amyloid receptor co-activator is effective on both the GLP-1 receptor and the amyloid receptor. The in vitro potency of the GLP-1 receptor-amyloid receptor co-activator on the GLP-1 receptor and the amyloid-3 receptor can be measured as described in methods 1 and 2, respectively. The potency of this compound can be described by its EC50 value. EC50 represents the concentration at which 50% of the maximum effect is observed. The lower the EC50 value, the more effective the compound.

[0223] When tested as described in Method 1, the EC50 value of the GLP-1 receptor-amyloid receptor co-activator disclosed herein may be less than 300 pM, such as less than 200 pM, such as less than 150 pM, preferably less than 100 pM, such as less than 75 pM, even more preferably less than 50 pM, such as less than 40 pM, such as less than 30 pM, such as less than 20 pM, such as less than 10 pM.

[0224] When tested as described in Method 2, the EC50 value of the GLP-1 receptor-amyloid receptor co-activator disclosed herein may be less than 300 pM, such as less than 200 pM, such as less than 150 pM, preferably less than 100 pM, such as less than 75 pM, preferably less than 50 pM, such as less than 40 pM, such as less than 30 pM, such as less than 20 pM, such as less than 10 pM.

[0225] The pharmacological (including half-life) effects of the GLP-1 receptor-amyloid receptor co-activators disclosed in this article in vivo were evaluated as described in Examples 4 and 5.

[0226] The half-life of GLP-1 receptor-amyloid receptor co-activators in animals can be as long as 125 hours or longer. The half-life of GLP-1 receptor-amyloid receptor co-activators in animals can be at least 4 hours. The half-life of GLP-1 receptor-amyloid receptor co-activators can be greater than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 hours. The half-life of GLP-1 receptor-amyloid receptor co-activators can be 15-60 hours, such as 20-55 hours, such as 25-50 hours.

[0227] GLP-1 receptor-amyloid receptor co-activators can be orally bioavailable; that is, they exist in the bloodstream after oral administration.

[0228] The GLP-1 receptor-amyloid receptor co-activator disclosed herein can reduce food intake in individuals. Administration of the GLP-1 receptor-amyloid receptor co-activator disclosed herein may result in a sharp decrease in food intake. The in vivo effects of the GLP-1 receptor-amyloid receptor co-activator on food intake in rats can be assessed as described in Example 5. Within 0–24 hours following a single subcutaneous injection of 10 nmol / kg of the co-activator, administration of the GLP-1 receptor-amyloid receptor co-activator disclosed herein resulted in food intake in rats of 0–90%, such as 0–80%, such as 0–70%, such as 0–60%, preferably 0–50%, and even more preferably 0–40% relative to the carrier, where 0% relative to the carrier means that the rats did not eat. Within 24-48 hours following a single subcutaneous injection of 10 nmol / kg of the co-activator described herein, administration of the GLP-1 receptor-amyloid receptor co-activator disclosed herein resulted in a food intake in rats of 0-90% relative to the carrier, such as 0-80%, such as 0-70%, such as 0-60%, preferably 0-50%, and even more preferably 0-40%, where a food intake relative to the carrier of 0% means that the rats did not eat. [GLP-1]

[0229] The term "GLP-1" or "natural GLP-1" herein refers to human glucagon-like peptide-1 (GLP-1(7-37)), as shown in SEQ ID NO: 1 in the sequence listing. In the sequence listing, these amino acid residues are numbered consecutively from 1 to 31. Therefore, the first amino acid in wild-type human GLP-1(7-37) (i.e., the N-terminal histidine) is numbered "1" in SEQ ID NO: 1. [GLP-1] [Receptor agonists] [ ]

[0230] The compounds disclosed herein include GLP-1 receptor agonists. A "GLP-1 receptor agonist" can be defined as a ligand capable of binding to the GLP-1 receptor and producing a biological response similar to that of the natural ligand (glucagon-like peptide-1 (GLP-1)). A "complete" GLP-1 receptor agonist can be defined as a GLP-1 receptor agonist capable of eliciting a biological response of the same magnitude as GLP-1.

[0231] Example 4 of WO2006 / 097537 discloses semaglutide as an example of an exogenous GLP-1 receptor agonist.

[0232] GLP-1 receptor agonists must have a free N-terminus. Therefore, the compounds disclosed herein include GLP-1 receptor agonists with their C-terminus attached to the optional peptide or the amyloid receptor agonist.

[0233] This GLP-1 receptor agonist includes the peptide "Z1".

[0234] The compounds disclosed herein may include GLP-1 receptor agonists of peptide variants of GLP-1(7-37) (SEQ ID NO: 1). These GLP-1 receptor agonists may be derivatives of peptide variants of GLP-1(7-37).

[0235] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 lysine residue and up to 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0236] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 lysine residue and up to 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0237] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 lysine residue and up to 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0238] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 lysine residue and up to 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0239] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 lysine residue and up to 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0240] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 lysine residue and up to 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0241] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 lysine residue and up to 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0242] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 lysine residue and up to 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0243] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 9 amino acid modifications relative to wild-type human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0244] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0245] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0246] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0247] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0248] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0249] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0250] The GLP-1 receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The GLP-1 receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0251] The GLP-1 receptor agonist, relative to the amino acid sequence and numbering of human GLP-1 (7-37), may include a phenylalanine residue (Phe, F), tryptophan (Trp, W), or tyrosine (Tyr, Y) residue at position 28. Its numbering is shifted by -6 relative to SEQ ID NO: 1, as shown in Formula II and SEQ ID NO: 238 and SEQ ID NO: 255. Therefore, the GLP-1 receptor agonist, relative to SEQ ID NO: 1, SEQ ID NO: 238, or SEQ ID NO: 255, may include a phenylalanine residue (Phe, F), tryptophan (Trp, W), or tyrosine (Tyr, Y) residue at position 22. The GLP-1 receptor agonist, relative to SEQ ID NO: 1, SEQ ID NO: 238, or SEQ ID NO: 255, may not include isoleucine (Ile, I) at position 22.

[0252] The GLP-1 receptor agonist, relative to the amino acid sequence and numbering of human GLP-1 (7-37), may include isoleucine (Ile, I), leucine (Leu, L), or valine (V) residues at position 29. Its numbering is shifted by -6 relative to SEQ ID NO: 1, as shown in Formula II and SEQ ID NO: 238 and SEQ ID NO: 255. Therefore, the GLP-1 receptor agonist, relative to SEQ ID NO: 1, SEQ ID NO: 238, or SEQ ID NO: 255, may include isoleucine (Ile, I), leucine (Leu, L), or valine (V) residues at position 23.

[0253] The amino acid sequence and numbering of this GLP-1 receptor agonist relative to human GLP-1 (7-37) may include Imp (imidazolium acrylamide or deaminohistidine) of Formula 1 at position 7. Its numbering is shifted by -6 relative to SEQ ID NO: 1, as shown in Formula II, SEQ ID NO: 238, and SEQ ID NO: 255. Chemical Formula 1:

[0254] The amino acid sequence and numbering of this GLP-1 receptor agonist relative to human GLP-1 (7-37) may include Aib (α-aminoisobutylene, α-aminoisobutyric acid, or α-methylalanine) of Formula 2 at position 8. Its numbering is shifted by -6 relative to SEQ ID NO: 1, as shown in Formula II, SEQ ID NO: 238, and SEQ ID NO: 255. Chemical formula 2:

[0255] The GLP-1 receptor agonist may include a lysine (Lys, K) residue at any of positions 9, 10, 12, 16, 17, 20, 21, 24, 25, 28, 29, 30 or 31 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0256] The GLP-1 receptor agonist disclosed in this article may have Formula II, which is illustrated in the sequence listing (SEQ ID NO: 238) as follows: Xaa1-Xaa2-Glu-Gly-Thr-Phe-Thr-Ser-Xaa9-Xaa10-Ser-Xaa12-Tyr-Leu-Glu-Xaa16-Xaa17 -Ala-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Leu-Val-Xaa28-Xaa29-Xaa30-Xaa31, in Xaa1 is His (H) or Imp. Xaa2 can be Aib, Ala (A), Gly (G), or Trp (W). Xaa9 is Cys (C), Asp (D), or Lys (K). Xaa10 is Cys (C), Lys (K), or Val (V). Xaa12 is Cys (C), Lys (K), Arg (R), or Ser (S). Xaa16 can be Cys (C), Glu (E), Gly (G), or Lys (K). Xaa17 is Cys (C), Gln (Q), or Lys (K). Xaa19 is either Ala (A) or Val (V). Xaa20 is Cys (C), Lys (K), or Arg (R). Xaa21 can be Cys (C), Glu (E), or Lys (K). Xaa22 represents Phe (F), Trp (W), or Tyr (Y). Xaa23 is Ile (I), Leu (L), or Val (V). Xaa24 can be Ala (A), Cys (C), Glu (E), or Lys (K). Xaa25 is Cys (C), Lys (K), or Trp (W). Xaa28 can be Cys (C), Lys (K), or Arg (R). Xaa29 is Cys (C), Lys (K), or Gly (G). Xaa30 is Cys (C), Ala (A), Gly (G), Lys (K), Arg (R), or does not exist. Xaa31 is Ala (A), Cys (C), Lys (K), Gly (G), Gln (Q) or does not exist.

[0257] Those familiar with this technology typically refer to the standard human wild-type GLP-1 (7-37) nomenclature to describe the amino acid modifications of GLP-1 receptor agonists. In the literature, the first amino acid in GLP-1 (7-37) is referred to as number 7, and subsequent amino acid residues are numbered accordingly, ending with glycine, number 37.

[0258] Therefore, those familiar with this technology may number the residues in Formula II as follows, where Xaa1 in Formula II corresponds to Xaa7 in GLP-1(7-37), and so on: Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Xaa15-Xaa16-Ser-Xaa18-Tyr-Leu-Glu-Xaa22-Xaa23 -Ala-Xaa25-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Leu-Val-Xaa34-Xaa35-Xaa36-Xaa37, in: Xaa7 is His (H) or Imp. Xaa8 is Aib, Ala (A), Gly (G), Trp (W), Xaa15 is Cys (C), Asp (D), or Lys (K). Xaa16 is Cys (C), Lys (K), or Val (V). Xaa18 is Cys (C), Lys (K), Arg (R), or Ser (S). Xaa22 can be Cys (C), Glu (E), Gly (G), or Lys (K). Xaa23 is Cys (C), Gln (Q), or Lys (K). Xaa25 is either Ala (A) or Val (V). Xaa26 can be Cys (C), Lys (K), or Arg (R). Xaa27 is Cys (C), Glu (E), or Lys (K). Xaa28 can be Phe (F), Trp (W), or Tyr (Y). Xaa29 is Ile (I), Leu (L), or Val (V). Xaa30 is Ala (A), Cys (C), Glu (E), or Leu (L). Xaa31 represents Cys (C), Lys (K), or Trp (W). Xaa34 is Cys (C), Lys (K), or Arg (R). Xaa35 is Cys (C), Lys (K), or Gly (G). Xaa36 is Cys (C), Ala (A), Gly (G), Lys (K), Arg (R), or does not exist. Xaa37 is Ala (A), Cys (C), Lys (K), Gly (G), Gln (Q) or does not exist.

[0259] The GLP-1 receptor agonist disclosed in this article may have Formula II, which is illustrated in the sequence listing (SEQ ID NO: 255) as follows: Xaa1-Xaa2-Glu-Gly-Thr-Phe-Thr-Ser-Xaa9-Xaa10-Ser-Xaa12-Tyr-Leu-Glu-Xaa16-Xaa17 -Ala-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Leu-Val-Xaa28-Xaa29-Xaa30-Xaa31, in Xaa1 is His (H) or Imp. Xaa2 can be Aib, Ala (A), Gly (G), or Trp (W). Xaa9 represents Asp (D) or Lys (K). Xaa10 is either Lys (K) or Val (V). Xaa12 is Lys (K), Arg (R), or Ser (S). Xaa16 can be Glu (E), Gly (G), or Lys (K). Xaa17 is either Gln(Q) or Lys(K). Xaa19 is either Ala (A) or Val (V). Xaa20 is either Lys (K) or Arg (R). Xaa21 is either Glu (E) or Lys (K). Xaa22 is Phe (F), Xaa23 is Ile (I), Xaa24 can be Ala (A), Glu (E), or Lys (K). Xaa25 is either Lys (K) or Trp (W). Xaa28 is either Lys(K) or Arg(R). Xaa29 is either Lys (K) or Gly (G). Xaa30 is Ala (A), Gly (G), Lys (K), Arg (R), or does not exist. Xaa31 is Ala (A), Lys (K), Gly (G), Gln (Q) or does not exist.

[0260] The sequence in the sequence listing can be used to describe the GLP-1 receptor agonist peptide (Z1). The GLP-1 receptor co-agonists disclosed herein may include a GLP-1 receptor agonist peptide (Z1) selected from any of the GLP-1 receptor agonists depicted in SEQ ID NO: 2-78.

[0261] The GLP-1 receptor agonists disclosed herein activate or enhance the GLP-1 receptor. This term refers to the ability to bind to the GLP-1 receptor and initiate signal transduction pathways, thereby eliciting insulinotropic effects or other physiological effects as known in this art. The GLP-1 receptor activity of the GLP-1 receptor agonists disclosed herein can be tested as described in Examples 2 (in vitro), 4, and 5 (in vivo).

[0262] The more potent the compound, the lower its EC50 value. A compound with an EC50 value below approximately 50 pM is considered a very potent GLP-1 receptor agonist. A compound with an EC50 value between 50 and 250 pM is considered to have moderate potency. A compound with an EC50 value between 250 and 1000 pM is considered to have poor potency. A compound with an EC50 value exceeding 1000 pM is considered inactive.

[0263] The EC50 of this GLP-1 receptor agonist in the human GLP-1 receptor function assay (see Assay 1) may be about 300 pM or lower. The EC50 of this GLP-1 receptor agonist in the human GLP-1 receptor function assay may be about 200 pM or lower. The EC50 of this GLP-1 receptor agonist in the human GLP-1 receptor function assay may be about 150 pM or lower. The EC50 of this GLP-1 receptor agonist in the human GLP-1 receptor function assay may be about 100 pM or lower. The EC50 of this GLP-1 receptor agonist in the human GLP-1 receptor function assay may be about 90 pM or lower. The EC50 of this GLP-1 receptor agonist in the human GLP-1 receptor function assay may be about 80 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays may be approximately 70 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays may be approximately 60 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays may be approximately 50 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays may be approximately 40 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays may be approximately 30 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays may be approximately 25 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays may be approximately 20 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 19 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 18 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 17 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 16 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 15 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 14 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 13 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 12 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor function assays may be approximately 11 pM or lower.The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays can be approximately 10 pM or lower. The EC50 of this GLP-1 receptor agonist in human GLP-1 receptor functional assays can be approximately 5 pM or lower.

[0264] GLP-1 receptor agonists may have the same or similar potency as human GLP-1(7-37) or semaglutide. [Amyloids] [ ]

[0265] The term "amyloid" in this document refers to a polypeptide having the same amino acid sequence as endogenous amyloids (such as human amyloids). [Amyloid receptor] [ ]

[0266] This amyloid receptor agonist can activate or enhance the calcitonin receptor (CTR) and / or amyloid receptors (AMYRs). The amyloid receptor system consists of a heterodimer of two components: the calcitonin receptor (CTR) and one of three receptor-modifying proteins (RAMP1–3), resulting in three possible complexes, AMYR1–3. Unless otherwise specified, "amyloid receptor" refers at least to amyloid receptor 3 (AMYR3). Nevertheless, some cross-reactivity can be expected. [Amyloid receptor agonists] [ ]

[0267] The compounds disclosed herein include amyloid receptor agonists. An "amyloid receptor agonist" can be defined as a chemical entity capable of binding to and activating an amyloid receptor. In the context of this invention, an "amyloid receptor agonist" can at least bind to and activate the AMYR3 complex. This amyloid receptor agonist can also agonize calcitonin receptors and AMYR1-2.

[0268] Examples of endogenous amyloid receptor agonists are human amyloid and human calcitonin. Examples of exogenous amyloid receptor agonists are pramlintide and caglionetide (as described in WO2012 / 168432).

[0269] The amyloid receptor agonists disclosed in this paper include the "Z3" peptide. These agonists also include a C-terminal amide, which is essential for biological activity.

[0270] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 7 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 7 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 lysine residue and up to 7 amino acid modifications relative to SEQ ID NO: 79.

[0271] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 6 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 6 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 lysine residue and up to 6 amino acid modifications relative to SEQ ID NO: 79.

[0272] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 5 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 5 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 lysine residue and up to 5 amino acid modifications relative to SEQ ID NO: 79.

[0273] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 4 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 4 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 lysine residue and up to 4 amino acid modifications relative to SEQ ID NO: 79.

[0274] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 3 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 3 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 lysine residue and up to 3 amino acid modifications relative to SEQ ID NO: 79.

[0275] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and up to 2 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and up to 2 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 lysine residue and up to 2 amino acid modifications relative to SEQ ID NO: 79.

[0276] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 lysine residues and at most one amino acid modification relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 lysine residues and at most one amino acid modification relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 lysine residue and at most one amino acid modification relative to SEQ ID NO: 79.

[0277] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 7 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 7 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 7 amino acid modifications relative to SEQ ID NO: 79.

[0278] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 6 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 6 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 6 amino acid modifications relative to SEQ ID NO: 79.

[0279] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 5 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 5 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 5 amino acid modifications relative to SEQ ID NO: 79.

[0280] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 4 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 4 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 4 amino acid modifications relative to SEQ ID NO: 79.

[0281] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 3 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 3 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 3 amino acid modifications relative to SEQ ID NO: 79.

[0282] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and up to 2 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and up to 2 amino acid modifications relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and up to 2 amino acid modifications relative to SEQ ID NO: 79.

[0283] The amyloid receptor agonist may include a polypeptide comprising 0, 1, 2, or 3 cysteine ​​residues and at most 1 amino acid modification relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 or 2 cysteine ​​residues and at most 1 amino acid modification relative to SEQ ID NO: 79. The amyloid receptor agonist may include a polypeptide comprising 1 cysteine ​​residue and at most 1 amino acid modification relative to SEQ ID NO: 79.

[0284] The amyloid receptor agonist may not include proline at position 12 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0285] The amyloid receptor agonist may include lysine (Lys, K) residues at any of positions 1, 2, 3, 7, 14, 18, 20, 23 or 29 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0286] The GLP-1 receptor-amyloid receptor co-activators disclosed herein may include amyloid receptor activators according to Formula III (SEQ ID NO: 240): Xaa1-Xaa2-Xaa3-Leu-Ser-Thr-Xaa7-Ala-Leu-Gly-Arg-Leu-Ser-Xaa14-Glu-Leu-Hi s-Xaa18-Leu-Xaa20-Thr-Leu-Xaa23-Arg-Thr-Glu-Thr-Gly-Xaa29-Gly-Ser-Xaa32, in Xaa1 is Ala (A), Cys (C), Lys (K), or does not exist. Xaa2 is Cys (C), Lys (K), or Ser (S). Xaa3 can be Cys (C), Glu (E), Lys (K), or Arg (R). Xaa7 can be Ala (A), Cys (C), Glu (E), or Lys (K). Xaa14 can be Ala (A), Cys (C), or Lys (K). Xaa18 can be Cys (C), Glu (E), Lys (K), or Gln (Q). Xaa20 can be Ala (A), Cys (C), or Lys (K). Xaa23 is Cys (C), Lys (K), or Pro (P). Xaa29 is Cys (C), Ser (S), or Lys (K), and Xaa32 is either Pro (P) or Tyr (Y).

[0287] The GLP-1 receptor-amyloid receptor co-activators disclosed in this article may include amyloid receptor activators according to Formula III: Xaa1-Xaa2-Xaa3-Leu-Ser Thr-Xaa7-Ala-Leu-Gly-Arg-Leu-Ser-Xaa14-Glu-Leu-His-Xaa18-Leu-Xaa20-Thr-Leu-Xaa23-Arg-Thr-Glu-Thr-Gly-Xaa29-Gly-Ser-Xaa32, in Xaa1 is Ala (A), Lys (K), or does not exist. Xaa2 is either Lys(K) or Ser(S). Xaa3 can be Glu (E), Lys (K), or Arg (R). Xaa7 can be Ala (A), Glu (E), or Lys (K). Xaa14 is either Ala (A) or Lys (K). Xaa18 can be Glu (E), Lys (K), or Gln (Q). Xaa20 represents Ala (A) or Lys (K). Xaa23 is either Lys (K) or Pro (P). Xaa29 is either Ser (S) or Lys (K), and Xaa32 is either Pro (P) or Tyr (Y).

[0288] The amyloid receptor agonist may include the polypeptide (Z3) represented by any of SEQ ID NO: 79-88. Therefore, the polypeptide backbone of the amyloid receptor agonist (Z3) disclosed herein can be described with reference to the sequences in the sequence listing.

[0289] The amyloid receptor agonists disclosed herein enhance or activate amyloid receptors. The amyloid activity of the amyloid agonists disclosed herein can be tested as described in Examples 2 (in vitro), 4, and 5 (in vivo).

[0290] The more potent the compound, the lower its EC50 value. A compound with an EC50 value below approximately 50 pM is considered a very potent amyloid receptor agonist. A compound with an EC50 value between 50 and 250 pM is considered to have moderate potency. A compound with an EC50 value between 250 and 1000 pM is considered to have poor potency. A compound with an EC50 value exceeding 1000 pM is considered inactive.

[0291] The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay (see Assay 2) may be about 300 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 250 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 200 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 150 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 100 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 90 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 80 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be approximately 70 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be approximately 60 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be approximately 50 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be approximately 40 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be approximately 30 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be approximately 25 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be approximately 20 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be approximately 19 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 18 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 17 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 16 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 15 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 14 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 13 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 12 pM or lower. The EC50 of this amyloid receptor agonist in the human amyloid receptor function assay may be about 11 pM or lower. The EC50 of this amyloid receptor agonist in human amyloid receptor function assays can be approximately 10 pM or lower.The EC50 of this amyloid receptor agonist in human amyloid receptor function assays can be approximately 5 pM or lower.

[0292] The amyloid receptor agonists disclosed in this article may have the same or similar potency as pramlinpeptide, salmon calcitonin, or compound 1806. [Peptide linker] [ ]

[0293] The GLP-1 receptor-amyloid receptor co-activator polypeptide backbone R1 disclosed herein may include an optional peptide linker Z2 represented by formula IV (SEQ ID NO: 239): Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa1 6-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30 Xaa1-30 is absent or independently selected from any 7 naturally occurring or positive amino acid residues.

[0294] Therefore, the optional peptide linker may include 1-30 positive amino acid residues. The optional peptide linker may include 1-25 positive amino acid residues. The optional peptide linker may include 1-20 positive amino acid residues, such as 1-15, 1-10, or 1-5 positive amino acid residues.

[0295] In the context of optional peptide linkers, Xaa can be selected from any non-aromatic amino acid residue. Xaa can be a charged amino acid. Xaa can be a polar amino acid. Xaa can be a hydrophobic amino acid.

[0296] Xaa can be selected from the group consisting of alanine (Ala, A), cysteine ​​(Cys, C), glutamic acid (E), glycine (G), isoleucine (Ile, I), lysine (Lys, K), glutamic acid (Q), serine (S) and / or proline (Pro, P).

[0297] Xaa can be selected from the group consisting of alanine (A), glutamic acid (E), glycine (G), isoleucine (I), lysine (K), glutamic acid (Q), serine (S) and / or proline (P).

[0298] The optional peptide linker (Z2) may be any of the peptide linkers shown in SEQ ID NO: 89-116. The optional peptide linker (Z2) may be any of the peptide linkers listed in Table 1. [surface] [1] [Optional peptide linkers] [(Z2)] [SEQ ID] [Peptide linker] [SEQ ID] [Peptide linker] - E 100 EGQEPGG - GE 101 QEPGQAPE - GG 102 QAPGQEPE - EA 103 QEPKGQAP - EGE 104 GGGGGGGK - GGE 105 GGGGSGGGE - GKE 106 GQEPGQEPE 89 EGGE 107 KQEPGQEPE 90 GGGE 108 GQEKGQEPE 91 GGGG 109 QEPGQAPKE 92 KGGG 110 QEPKGQAPE 93 EAEAE 111 GGGGGGGGE 94 GGGGE 112 GQEPGQEPKE 95 EGEGEE 113 KGQEPGQAPE 96 EGGGGG 114 EGGGGGGGGGE 97 KGGGGE 115 GGGGGGGGGGGE 98 EGEGEKE 116 GGGGGGGGGGGGGGGE 99 EGGGGGE [Polypeptide] [ ]

[0299] As used in this article, "polypeptide" or "peptide" refers to a compound composed of a series of amino acid residues linked together by amide (or peptide) bonds.

[0300] The polypeptide backbone of the GLP-1 receptor-amyloid receptor co-activator (R1) disclosed in this article typically includes 60-85 amino acid residues linked together by peptide bonds. R1 comprises peptides Z1-Z2-Z3, which are GLP-1 receptor activator (Z1), optional peptide linker (R2), and amyloid receptor activator (Z3) peptides. [Amino acids]

[0301] Amino acids are molecules containing an amino group and a carboxylic acid group, and, depending on the circumstances, one or more additional groups commonly referred to as side chains.

[0302] The term "amino acid" includes both normal amino acids (which are genetically encoded) and non-natural amino acids.

[0303] Non-limiting examples of non-natural amino acids include Aib (□-aminoisobutyric acid), deaminohistidine (alternative name 3-(imidazol-4-yl)propionic acid, abbreviated as Imp (imidazolyl)), and d-isomers of normal amino acids.

[0304] All amino acid residues within a polypeptide for which an optical isomer is not specified should be understood herein to refer to the l-isomer (unless otherwise specified).

[0305] The GLP-1 receptor agonist peptide (Z1) disclosed herein may have up to 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). The amyloid receptor agonist peptide (Z3) disclosed herein may have up to 7 amino acid modifications relative to SEQ ID NO: 79. In this document, "amino acid modification" refers to the substitution, addition, or deletion of an amino acid at a given position in the reference sequence. [Extended Section] [ ]

[0306] The GLP-1 receptor-amyloid receptor co-activator disclosed herein may further include one, two, or three "elongation moieties". The elongation moieties may be represented by the general formula "R2-R3", where R2 is an optional linker and R3 is an elongator. Each elongation moieties are attached to a lysine or cysteine ​​residue in the polypeptide backbone (R1) of the compound.

[0307] The extended portion can consist of an extension subunit.

[0308] The extension may include a connector and an extension.

[0309] The extension may include a connector and two extensions.

[0310] When the linker (R2) is present, the extended portion is attached to the polypeptide backbone (R1) via R2. When the linker (R2) is absent, R3 is attached to the polypeptide backbone.

[0311] The extended portions (R2-R3) can attach to lysine residues ("Z1" in Z1-Z2-Z3) in the GLP-1 receptor agonist portion of the polypeptide backbone. The extended portions can also attach to lysine residues ("Z2" in Z1-Z2-Z3) in an optional peptide linker portion of the polypeptide backbone. The extended portions can also attach to lysine residues ("Z3" in Z1-Z2-Z3) in the amyloid receptor agonist portion of the polypeptide backbone. When the extended portions attach to lysine residues via amide bonding, the GLP-1 receptor-amyloid receptor co-agonist is considered to be "amide-ized".

[0312] The GLP-1 receptor-amyloid receptor co-activator disclosed herein may include a single lysine residue with a single elongated portion attached thereto.

[0313] The GLP-1 receptor-amyloid receptor co-activators disclosed herein may include two lysine residues and two elongated moieties. The compounds disclosed herein may include two lysine residues and two identical elongated moieties.

[0314] The GLP-1 receptor-amyloid receptor co-activators disclosed herein may include three lysine residues and three elongated moieties. The compounds disclosed herein may include three lysine residues and three identical elongated moieties.

[0315] The extended portion may attach to a cysteine ​​residue ("Z1" in Z1-Z2-Z3) in the GLP-1 receptor agonist portion of the polypeptide backbone. The extended portion may attach to a cysteine ​​residue ("Z2" in Z1-Z2-Z3) in an optional peptide linker portion of the polypeptide backbone. The extended portion may attach to a cysteine ​​residue ("Z3" in Z1-Z2-Z3) in the amyloid receptor agonist portion of the polypeptide backbone. When the extended portion is attached to a cysteine ​​residue via a thioether bond, the GLP-1 receptor-amyloid receptor co-agonist is considered to be "acetylated".

[0316] The GLP-1 receptor-amyloid receptor co-activator disclosed in this article may include a single cysteine ​​residue with a single elongated portion attached thereto.

[0317] The GLP-1 receptor-amyloid receptor co-activators disclosed herein may include two cysteine ​​residues and two identical elongated moieties.

[0318] The compounds disclosed herein may include three cysteine ​​residues and three identical elongated moieties.

[0319] When a GLP-1 receptor-amyloid receptor co-activator comprises two or three extended portions, such extended portions are similar, preferably substantially identical, or best of all identical.

[0320] In the context of chemical portions such as the extended portions disclosed herein, any suitable computer program and / or algorithm known in the art can be used to determine similarity and / or consistency.

[0321] Those skilled in this art can describe compounds that include an extended portion as "derivatives." For example, "amyloid derivatives" are understood to be amyloid receptor agonists that include an extended portion.

[0322] Therefore, the term "extended moiety" refers to a synthetic moiety with an extended half-life that includes an "elongator" (R3) and an optional "side-chain linker" or "linker" (R2). R2 can add R3 to the side chain of the lysine or cysteine ​​residue of the polypeptide backbone R1 of the GLP-1 receptor-amyloid receptor co-activator.

[0323] The extended portion can bind albumin nonvalently, thereby promoting the circulation of the GLP-1 receptor-amyloid receptor co-activator in the bloodstream and prolonging its half-life. Therefore, those familiar with this technique may also refer to the extended portion as the "albumin-binding portion".

[0324] The elongator (R3) may include a amide group. The amide group may be branched or unbranched. The amide group may be saturated or unsaturated. The elongator (R3) may include an aliphatic amide group. The amide group may be branched or unbranched. The amide group may be saturated or unsaturated.

[0325] The elongator (R3) may include a distal carboxylic acid group.

[0326] The elongator (R3) may include a fatty acid group.

[0327] The elongator ("R3") may include a fatty acid group and a amide group.

[0328] The elongator (R3) may include a distal carboxylic acid group and a amide group.

[0329] The elongator (R3) may include an alkyl group.

[0330] The elongator (R3) may include an aryl group.

[0331] The elongator (R3) may include a tetrazolium group.

[0332] The elongator (R3) may include a sulfonic acid group.

[0333] The elongator (R3) may include a phenoxy group.

[0334] The elongator (R3) may include a benzoic acid group.

[0335] The elongator (R3) may include the following defined groups: Chemical formula 3: HOOC-(CH2)n-CO-*, where n is an integer in the range of 8-30. It can also be called C(n+2) diacid or... Chemical formula 3b: , where n is an integer in the range of 8-30.

[0336] The elongator (R3) may include 8 to 30 carbon atoms. The elongator (R3) may include 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 carbon atoms.

[0337] The elongator (R3) may include 6 to 30 consecutive –CH2- groups. The elongator (R3) may include a carbon chain comprising at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 consecutive –CH2- groups.

[0338] The elongator (R3) may include 12-26 carbon atoms. The "elongator" or "side chain" may include 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 carbon atoms.

[0339] The elongator (R3) may include 10-26 consecutive –CH2- groups. The elongator (R3) may include a carbon chain comprising at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 consecutive –CH2- groups.

[0340] The elongator (R3) may include 16-22 carbon atoms. The compound may include a single elongation portion comprising a side chain having 16, 17, 18, 19, 20, 21, or 22 carbon atoms.

[0341] The elongator (R3) may include 14-20 consecutive –CH2- groups. The elongator (R3) may include a carbon chain comprising 14, 15, 16, 17, 18, 19 or 20 consecutive –CH2- groups.

[0342] The elongator (R3) may include 16-22 consecutive carbon atoms and 14-20 consecutive –CH2- groups.

[0343] The elongator (R3) may include 16 consecutive carbon atoms and 14 consecutive –CH2- groups.

[0344] The elongator (R3) may include 18 consecutive carbon atoms and 16 consecutive –CH2- groups.

[0345] The elongator (R3) may include 20 consecutive carbon atoms and 18 consecutive –CH2- groups.

[0346] The elongator (R3) may include 22 consecutive carbon atoms and 20 consecutive –CH2- groups.

[0347] The GLP-1 receptor-amyloid receptor co-activator may include two elongation moieties, each comprising 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The GLP-1 receptor-amyloid receptor co-activator may include two elongation moieties, wherein each elongator (R3) comprises 12, 13, 14, 15, 16, 17, or 18 consecutive –CH2- groups.

[0348] The GLP-1 receptor-amyloid receptor co-activator may include two C14 diacids, two C16 diacids, or two C18 diacids.

[0349] The GLP-1 receptor-amyloid receptor co-activator may include three elongation moieties, each of which includes an elongator comprising 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The GLP-1 receptor-amyloid receptor co-activator may include three elongation moieties, wherein the elongator (R3) comprises 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive –CH2- groups.

[0350] The extended portion (R2-R3) can be covalently attached to the lysine residue of the polypeptide backbone (R1). The extended portion can be attached via a amide bond formed between the carboxylic acid group of the extended portion and the ε-amine group of the lysine residue.

[0351] The extended portion (R2-R3) can be covalently attached to a cysteine ​​residue of the polypeptide backbone (R1). The extended portion can be attached via a thioether formed between the extended portion and the sulfur atom of the cysteine ​​residue of the backbone.

[0352] As described above, the compounds disclosed herein may include one, two, or three lysine or cysteine ​​residues and one, two, or three elongated portions (R2-R3) thereon, wherein each elongated portion is attached to a side chain of a single lysine or cysteine ​​residue.

[0353] The extended portion can be attached to the polypeptide backbone (R1) disclosed herein via a lysine (K) residue at any of positions 9, 10, 12, 16, 17, 20, 21, 24, 25, 28, 29, 30, or 31 of the GLP-1 receptor agonist portion of the polypeptide backbone (Z1) relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0354] The extended portion can be attached to the polypeptide backbone (R1) via the lysine (K) residue of the optional linker (Z2).

[0355] The extended portion can be attached to the polypeptide backbone (R1) via a lysine (K) residue at any of positions 1, 2, 3, 7, 10, 14, 18, 20, 23 or 29 of the amyloid receptor agonist portion of the polypeptide backbone (Z3) relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0356] The extended portion can be attached to the polypeptide backbone (R1) via a cysteine ​​(C) residue at any of positions 9, 10, 12, 16, 17, 20, 21, 24, 25, 28, 29, 30 or 31 relative to SEQ ID NO: 238.

[0357] The extended portion can be attached to the polypeptide backbone (R1) via a cysteine ​​(C) residue of an optional linker portion of the polypeptide backbone (Z2).

[0358] The extended portion can be attached to the polypeptide disclosed herein via a cysteine ​​(C) residue in the amyloid receptor agonist portion of the polypeptide backbone (Z3). The cysteine ​​residue can be located at any of positions 1, 2, 3, 7, 10, 14, 18, 20, 23, or 29 relative to SEQ ID NO: 240.

[0359] The GLP-1 receptor-amyloid receptor co-activators disclosed herein may include an elongator (R3) selected from any of those illustrated in Table 2. In Table 2, R2 represents the optional linker that connects the illustrated elongator (R3) to the polypeptide backbone (R1). R1 ​​is not shown in the table. [surface] [2] [:Extended son] [(R3)] Extended sub-number structure The compound 1 3-(9-hydroxynonoxy)benzoic acid 0235 (2x) 2 4-(9-hydroxynonoxy)benzoic acid 0096 (2x), 0097 (2x), 0098 (2x), 0099 (2x), 0100 (2x), 0101 (2x), 0231 (2x), 0232 (2x), 0233 (2x), 0234 (2x), 3 4-(10-hydroxydecyloxy)benzoic acid 0255 (2x) 4 C14 diacid 0039 (2x), 0484 (2x), 0635 (3x) 5 C16 diacid 0560, 0564 (2x), 0630 (2x), 0631 (2x), 0634 (2x), 0072 (2x), 0073 (2x), 0074 (2x), 0075 (2x), 0076 (2x), 0077 (2x), 0086 (2x), 0087 (2x), 0105 (2x), 0259 (2x), 0260 (2x), 0261 (2x), 0280 (2x), 0281 (2x), 0284 (2x), 0285 (2x), 0292 (2x), 0294 (2x), 0295 (2x), 0296 (2x), 0297 (2x), 0299 (2x), 0396 (2x), 0397 (2x), 0411 (2x), 0475 (2x), 0482 (2x), 0483 (2x), 0509 (2x), 0516 (2x), 0528 (2x), 0575 (2x), 0576 (2x), 0577 (2x), 0578 (2x), 0629 (2x) 6 C18 diacid 0658, 0656, 0007, 0009, 0010, 0019, 0026, 0040, 0042, 0051, 0052, 0083, 0084, 0085, 0092, 0093, 0111, 0114, 0115, 0132, 0144, 0151, 0156, 0191, 0271, 0273, 0472, 0637, 0639, 0640, 0648, 0044, 0045, 0159, 0661, 0662, 0660, 0131 (2x), 0160 (2x), 0056 (2x), 0057 (2x), 0071 (2x), 0089 (2x), 0090 (2x), 0106 (2x), 0109 (2x), 0116 (2x), 0127 (2x), 0128 (2x), 0129 (2x), 0110 (2x) 7 C20 diacid 0636, 0632, 0633, 0141, 0142, 0659, 0657, 0094, 0157, 0202, 0473, 0474, 0502, 0529, 0562, 0565, 0580, 0581, 0638, 0552, 0663, 0035, 0095, 0120, 0254, 0263, 0264, 0265, 0266, 0267, 0268, 0269, 0270, 0272, 0414, 0415, 0416, 0417, 0431, 0440, 0503, 0504, 0511, 0512, 0518, 0539, 0561, 0433, 0434, 0435, 0436, 0437, 0438, 0439, 0506, 0179, 0180 8 C16-sulfonic acid 0654 9 C17-Tetraazole 0102, 0103, 0124, 0125, 0145, 0146, 0147, 0655

[0360] As described above, the extension ("R2-R3") may include an optional side chain connector "R2".

[0361] The optional sidechain connector (R2) may include Ado, Aeep or Aeeep, sulfadiazine, Trx, ε-Lys, Ahx, Glu, γGlu, Gly, Ser, Ala, Thr and / or a key.

[0362] The optional side chain connector may include at least one portion represented by the following chemical formula: Chemical formula 4a: *―NH-(CH2)2-(O-(CH2)]kO-(CH2)n-CO-*. Chemical formula 4b: , Where k is an integer in the range of 1-5, and n is an integer in the range of 1-5. When k=1 and n=1, this connecting element can be called Ado, or 8-amino-3,6-dioxaoctyl, which can be represented by the following chemical formula: Chemical formula 5a: *-NH-(CH2)2-O-(CH2)2-O-CH2-CO-*. or Chemical formula 5b: . When k=1 and n=2, this connecting element can be called Aeep, which can be represented by the following chemical formula: Chemical formula 6: *-NH-(CH2)2-O-(CH2)2-O-(CH2)2-CO-*, or Chemical formula 6b: When k=2 and n=2, this connecting element can be called Aeeep, which can be represented by the following chemical formula: Chemical formula 7a:*-NH-(CH2)2-O-(CH2)2O-(CH2)2-O-(CH2)2-CO-*, or Chemical formula 7b: .

[0363] The optional side-chain linker may include a sulfonylurea-C4 moiety. The sulfonylurea-C4 group is a sulfonylurea group attached to a 4-butyryl group and has the following chemical formula: Chemical formula 9a:*NH-S(O)2-CH2-CH2-CH2-CO-* Chemical formula 9b: .

[0364] This optional side-chain linker may include Trx. Trx is also known as tranexamic acid (trans-4-(aminomethyl)cyclohexanecarboxylic acid) and has the following chemical formula: Chemical formula 10a:*-NH-CH2-(C6H10)-CO-* or Chemical formula 10b: .

[0365] The optional side chain linker may include ε-lysine (ε-Lys).

[0366] The optional side chain linker may include lysine (Lys).

[0367] This optional side-chain linker may include Ahx. Ahx is also known as aminohexanoic acid (6-aminohexanoic acid) and is defined as: Chemical formula 11a:*-NH-(CH2)5-CO-* or Chemical formula 11b: .

[0368] The optional side-chain linker may include a Glu diradical, such as that of formula 12: The Glu diradical can be contained p times, where p is an integer in the range of 1 to 3.

[0369] Chemical formula 12 can also be called γ-Glu (or simply γGlu) because it is the γ-carboxyl group of the amino acid glutamic acid, used here to connect to another linker element, or to the ε-amino group of the lysine. As explained above, the other linker element can be, for example, another Glu residue or an Ado molecule. The amino group of Glu forms a amide bond with the carboxyl group of the extended portion, or with, for example, the carboxyl group of an Ado molecule (if present), or with, for example, the γ-carboxyl group of another Glu (if present).

[0370] The GLP-1 receptor-amyloid receptor co-activators disclosed herein may include a side chain linker (R2) selected from any of those shown in Table 3. In Table 3, "R1" represents the polypeptide backbone (Z1-Z2-Z3), R2 (shown) represents the side chain linker, and "R3" represents the elongator. [surface] [3] [:Optional connector] [(] [「] [R2] [」] [) ] Connector Sub-number structure The compound 1 0564 2 0630 (2x) 3 0636 4 0621 (2x), 0632, 0633, 0634 (2x) 5 0141, 0142, 0131 (2x), 0160 (2x) 6 658, 659 7 656, 657 8 0560, 0007, 0009, 0010, 0019, 0026, 0040, 0042, 0051, 0052, 0083, 0084, 0085, 0092, 0093, 0111, 0114, 0115, 0132, 0144, 0151, 0156, 0191, 0271, 0273, 0472, 0637, 0639, 0640, 0648, 0094, 0457, 0202, 0473, 0474, 0502, 0529, 0562, 0565, 0580, 0581, 0638, 0654, 0655, 0635 (3x), 0235 (2x), 0096 (2x), 0097 (2x), 0098 (2x), 0099 (2x), 0100 (2x), 0101 (2x), 0231 (2x), 0232 (2x), 0233 (2x), 0234 (2x), 0255 (2x), 0039 (2x), 0484 (2x), 0072 (2x), 0073 (2x), 0074 (2x), 0075 (2x), 0076 (2x), 0077 (2x), 0086 (2x), 0087 (2x), 0105 (2x), 0259 (2x), 0260 (2x), 0261 (2x), 0280 (2x), 0281 (2x), 0284 (2x), 0285 (2x), 0292 (2x), 0294 (2x), 0295 (2x), 0296 (2x), 0297 (2x), 0299 (2x), 0396 (2x), 0397 (2x), 0411 (2x), 0475 (2x), 0482 (2x), 0483 (2x), 0509 (2x), 0516 (2x), 0528 (2x), 0575 (2x), 0576 (2x), 0577 (2x), 0578 (2x), 0629 (2x), 0056 (2x), 0057 (2x), 0071 (2x), 0089 (2x), 0090 (2x), 0106 (2x), 0109 (2x), 0116 (2x), 0127 (2x), 0128 (2x), 0129 (2x) 9 0044, 0045, 0159, 0552, 0110 (2x) 10 0661 11 0662, 0663 12 0660 13 0102, 0103, 0124, 0125, 0145, 0146, 0147 14 0035, 0095, 0120, 0254, 0263, 0264, 0265, 0266, 0267, 0268, 0269, 0270, 0272, 0414, 0415, 0416, 0417, 0431, 0440, 0503, 0504, 0511, 0512, 0518, 0539, 0561, 0179 15 0433, 0434, 0435, 0436, 0437, 0438, 0439, 0506, 0180

[0371] Co-activators may exist in different stereoisomers having the same molecular formula and bonded atomic sequence, but differing only in the three-dimensional orientation of their atoms in space. The experimental section illustrates the stereoisomerism of the exemplary co-activators, using standard nomenclature for names and structures. Unless otherwise stated, this invention relates to all stereoisomers of the embodied derivatives. [Generation Method] [ ]

[0372] The compounds disclosed herein can be produced, for example, by typical peptide synthesis, such as solid-phase peptide synthesis using t-Boc or Fmoc chemical reactions or other recognized techniques, see, for example, Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley & Sons, 1999; Florencio Zaragoza Dörwald, “Organic Synthesis on Solid Phase”, Wiley-VCH Verlag GmbH, 2000; and “Fmoc Solid Phase Peptide Synthesis”, edited by WC Chan and PD White, Oxford University Press, 2000.

[0373] Alternatively, where peptide expression is permitted, the compound can be produced by recombinant methods, for example by culturing host cells containing DNA sequences encoding and capable of expressing peptides in a suitable nutrient medium. Non-limiting examples of host cells suitable for expressing these peptides include *Escherichia coli*, *Saccharomyces cerevisiae*, and mammalian BHK or CHO cell lines.

[0374] Co-activators containing non-natural amino acids and / or covalently attached substituents can be manufactured as described in the experimental section.

[0375] Specific examples of methods for preparing many of the disclosed compounds are included in these examples.

[0376] A further aspect of this invention relates to a method for preparing the peptides described herein.

[0377] A further aspect of the present invention relates to a method for preparing the receptor co-activator described herein.

[0378] In one embodiment, the method for preparing the compound as described herein includes a step of solid-phase peptide synthesis. Substituents may be constructed sequentially as part of solid-phase peptide synthesis or manufactured separately and attached via lysine residues after peptide synthesis.

[0379] In one embodiment, the compound is produced by a two-step process in which two peptide fragments are linked together after a substituent is attached to one of the peptide fragments. [Pharmaceutical Compositions] [ ]

[0380] This article also discloses a pharmaceutical composition comprising the GLP-1 receptor-amyloid receptor co-activator disclosed herein. Pharmaceutical compositions comprising the GLP-1 receptor-amyloid receptor co-activator or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients can be prepared using methods known to those skilled in the art.

[0381] The term "pharmaceuticalally acceptable excipient" refers to any component in the pharmaceutical composition that is not an active pharmaceutical ingredient. Excipients can be functional or inert and can be used for one or more purposes. For example, excipients can enhance the absorption of the active substance. Excipients can be buffers, antimicrobial preservatives, isotonic agents, carriers, loading agents, fillers, binders, lubricants, slip agents, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, and emulsifiers. The amount of each excipient used can vary within the range known in the art.

[0382] This pharmaceutical composition is suitable for oral administration. Techniques and excipients that can be used to formulate pharmaceutical compositions for oral administration are described in the Handbook of Pharmaceutical Excipients (e.g., 8th edition, edited by Sheskey et al., American Medical Association and Pharmaceutical Publishers, Royal Society of Medicine Publications (2017) and subsequent editions); and Remington: The Science and Practice of Pharmacy (e.g., 22nd edition, edited by Remington and Allen, Pharmaceutical Publishers (2013) and subsequent editions).

[0383] The pharmaceutical formulation may be a solid pharmaceutical formulation (e.g., compressed tablets or capsules) containing the active pharmaceutical ingredient, which may be a freeze-dried or spray-dried composition, and may be dissolved before use or used in combination with excipients in the formulation.

[0384] The pharmaceutical composition may be a solid formulation containing the compound disclosed herein (N-[8-(2-hydroxybenzoyl)amino]octanoate) and one or more other excipients as described in the art. For example, the solid formulation may be one of those described in WO 2012 / 080471, WO2013 / 139694, WO 2013 / 189988, WO 2019 / 149880, WO2019 / 215063 or WO2021 / 219710.

[0385] Alternatively, the pharmaceutical composition may be a liquid formulation, such as an aqueous formulation. Such liquid compositions are suitable for oral or non-gastrointestinal administration. Liquid compositions suitable for injection may be prepared using techniques known in the pharmaceutical industry, which involve dissolving and mixing the components as needed to obtain the desired final product. Therefore, the compounds described herein are dissolved in a suitable buffer solution at a suitable pH according to a procedure. The composition may be sterilized, for example, by sterile filtration. Techniques and excipients that can be used to prepare liquid formulations are described in the *Handbook of Pharmaceutical Excipients* (e.g., 8th edition, edited by Sheskey et al., American Pharmaceutical Association and Pharmaceutical Publishers, Royal Medical Society Publications (2017) and subsequent editions); and *Remington: The Science and Practice of Pharmaceutics* (e.g., 22nd edition, edited by Remington and Allen, Pharmaceutical Publishers (2013) and subsequent editions). [Medical Indications]

[0386] The GLP-1 receptor-amyloid receptor co-activator disclosed in this article can be used as a pharmaceutical product.

[0387] The GLP-1 receptor-amyloid receptor co-activators disclosed in this article can be used for the following medical treatments: (i) Prevention and / or treatment of various forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes mellitus, MODY (adult-onset diabetes in young adults), gestational diabetes, and / or for lowering HbA1c; [ ] (ii) Delaying or preventing the progression of diabetes, such as the progression of type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulin-dependent type 2 diabetes, and / or delaying the progression of non-insulin-dependent type 2 diabetes to insulin-dependent type 2 diabetes; (iii) Prevention and / or treatment of eating disorders, such as obesity, by reducing food intake, losing weight, suppressing appetite, or inducing satiety; treatment or prevention of bulimia, bulimia nervosa, and / or obesity caused by the administration of antipsychotic drugs or steroids; reduction of gastric motility; and / or delay of gastric emptying; (iv) Maintaining weight after successful weight loss (induced by medication or through diet and exercise) – i.e., preventing weight gain after successful weight loss; (v) Prevention and / or treatment of cardiovascular disease, such as delaying or reducing the development of major adverse cardiovascular events (MACE) selected from the following groups: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, hospitalization for unstable angina, and hospitalization for heart failure; (vi) Prevention and / or treatment of nonalcoholic steatosis (NASH); (vii) Prevention and / or treatment of cognitive impairments such as those caused by Alzheimer's disease.

[0388] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In yet another specific embodiment, the indication is (iii). In some embodiments, the indication is (iv). In some embodiments, the indication is (v). In some embodiments, the indication is (vi). In some embodiments, the indication is (vii). In some embodiments, the indication is type 2 diabetes and / or obesity.

[0389] The term "treatment," as used herein, refers to any medical intervention for a human or other vertebrate individual in need. This individual is expected to have undergone a physical examination by a medical or veterinary practitioner who has provided a provisional or final diagnosis that may indicate that the use of this particular treatment is beneficial to the health of the human or vertebrate. The timing and purpose of the treatment may vary from individual to individual, depending on the individual's current health condition. Therefore, the treatment may be preventative, palliative, symptomatic, and / or curative.

[0390] In some embodiments, the indication is (i) and (iii). In some embodiments, the indication is (ii) and (iii).

[0391] In some embodiments, the obese individual is a human being, such as an adult or a child (including infants, children, and adolescents).

[0392] Body Mass Index (BMI) is a measure of body fat, based on height and weight. The formula is BMI = weight (kg) / height (m)². An obese human individual may have a BMI ≥ 30; this individual may also be described as obese. In obese human individuals, a BMI may be ≥ 35 or ≥ 30 to < 40. In some embodiments, this obesity is severe obesity or morbid obesity, where the individual's BMI may be ≥ 40.

[0393] In some embodiments, the present invention relates to a method for treating or preventing overweight, optionally in the presence of at least one weight-related comorbidity. In some embodiments, the present invention relates to using a formulation to treat or prevent overweight, optionally in the presence of at least one weight-related comorbidity. In some embodiments, the overweight individual is a human being, such as an adult or a child (including infants, children, and adolescents). In some embodiments, the overweight human individual may have a BMI ≥25, such as a BMI ≥27, such as a BMI ≥30, such as a BMI ≥35, or a BMI ≥40. In some embodiments, the overweight human individual has a BMI in the range of 25 to <30 or 27 to <30. In some embodiments, the weight-related comorbidity is selected from the group consisting of hypertension, diabetes (such as type 2 diabetes), dyslipidemia, high cholesterol, and obstructive sleep apnea.

[0394] The term "weight loss" can include the treatment or prevention of obesity and / or overweight.

[0395] In some embodiments, the compounds disclosed herein may be used as an adjunct to a low-calorie diet and increased physical activity for chronic weight management in adult or pediatric patients who have at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, or dyslipidemia) and an initial body mass index (BMI) of 30 kg / m2 or higher (obese) or 27 kg / m2 or higher (overweight). [Dosage frequency] [ ]

[0396] The GLP-1 receptor-amyloid receptor co-activator disclosed in this article can be administered approximately once daily, such as once every 12-36 hours, once every 18-30 hours, or once approximately every 24 hours.

[0397] The GLP-1 receptor-amyloid receptor co-activator disclosed in this article can be administered approximately every other day, such as once every 36-60 hours, once every 42-54 hours, or once approximately every 48 hours.

[0398] The GLP-1 receptor-amyloid receptor co-activator disclosed in this article can be administered approximately twice daily, such as once every 6-18 hours, once every 9-15 hours, or once approximately every 12 hours.

[0399] The following is a list of non-limiting embodiments of the present invention. [Example] [ ] 1. A GLP-1 receptor-amyloid receptor co-activator comprising a polypeptide (R1) according to Formula I: Z1-Z2-Z3, It includes 1-3 lysine (Lys, K) residues, and may exclude disulfide bonds depending on the situation; wherein: ● Z1 is a GLP-1 receptor agonist peptide that comprises up to 9 amino acid modifications, relative to SEQ ID NO: 1 (human GLP-1(7-37)). ● Z2 is an optional peptide linker; ● Z3 contains C-terminal amides And compared to SEQ ID NO: 79, it includes up to 7 amino acid-modified amyloid receptor agonist peptides. 2. A GLP-1 receptor-amyloid receptor co-activator comprising a polypeptide (R1) according to Formula I: Z1-Z2-Z3, It includes 1-3 lysine (Lys, K) and / or cysteine ​​(Cys, C) residues, and does not contain disulfide bonds; wherein: ● Z1 is a GLP-1 receptor agonist peptide that comprises up to 9 amino acid modifications, relative to SEQ ID NO: 1 (human GLP-1(7-37)). ● Z2 is an optional peptide linker; ● Z3 contains C-terminal amides And compared to SEQ ID NO: 79, it includes up to 7 amino acid-modified amyloid receptor agonist peptides. 3. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments further includes 1-3 elongated portions (R2-R3) of the polypeptide (R1) attached via the 1-3 lysine residues. 4. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising 1-3 lysine residues. 5. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising 1-2 lysine residues. 6. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising one lysine residue. 7. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising 1-3 cysteine ​​residues. 8. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising 1-2 cysteine ​​residues. 9. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising one cysteine ​​residue. 10. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises 0-3 lysine (Lys, K) residues at any of positions 9, 10, 12, 16, 17, 20, 21, 24, 25, 28, 29, 30 and / or 31 or a combination thereof relative to SEQ ID NO: 238 or SEQ ID NO: 255. 11. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises two lysine (Lys, K) residues at the following positions relative to SEQ ID NO: 238 or SEQ ID NO: 255: ● 12 and 21, 30 or 31, or ● 21 and 30 or 31. 12. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises two lysine (Lys, K) residues at the following positions relative to SEQ ID NO: 238 or SEQ ID NO: 255: ● 12 and 21 or 31, or ● 21 and 31. 13. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) may include a lysine residue (Lys, K) at any of positions 12, 17, 20, 21, 28, 30 or 31. 14. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) includes a lysine residue (Lys, K) at position 31. 15. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the peptide linker (Z2) comprises 0-3 lysine (K) residues. 16. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the peptide linker (Z2) comprises 1-2 lysine (Lys, K) residues. 17. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the peptide linker (Z2) comprises one lysine (Lys, K) residue. 18. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the peptide linker (Z2) comprises 0-3 cysteine ​​(Cys, C) residues. 19. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the peptide linker (Z2) comprises 1-2 cysteine ​​(Cys, C) residues. 20. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the peptide linker (Z2) comprises one cysteine ​​(Cys, C) residue. 21. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) comprises 0-3 lysine (Lys, K) residues. 22. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) comprises 0-3 cysteine ​​(Cys, C) residues. 23. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) comprises 1-3 lysine (Lys, K) residues at any of positions 1, 2, 3, 7, 14, 18, 20, 23 and / or 29 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 24. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) includes one lysine (Lys, K) residue at any of positions 14, 18, 20, 23, 29 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 25. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) includes a lysine (Lys, K) residue at position 18 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 26. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising the GLP-1 receptor activator (Z1) according to Formula II (SEQ ID NO: 238). Xaa1-Xaa2-Glu-Gly-Thr-Phe-Thr-Ser-Xaa9-Xaa10-Ser-Xaa12-Tyr-Leu-Glu-Xaa16-Xaa17 -Ala-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Leu-Val-Xaa28-Xaa29-Xaa30-Xaa31, And among them Xaa1 is His (H) or Imp. Xaa2 can be Aib, Ala (A), Gly (G), or Trp (W). Xaa9 is Cys (C), Asp (D), or Lys (K). Xaa10 is Cys (C), Lys (K), or Val (V). Xaa12 is Cys (C), Lys (K), Arg (R), or Ser (S). Xaa16 can be Cys (C), Glu (E), Gly (G), or Lys (K). Xaa17 is Cys (C), Gln (Q), or Lys (K). Xaa19 is either Ala (A) or Val (V). Xaa20 is Cys (C), Lys (K), or Arg (R). Xaa21 can be Cys (C), Glu (E), or Lys (K). Xaa22 represents Phe (F), Trp (W), or Tyr (Y). Xaa23 is Ile (I), Leu (L), or Val (V). Xaa24 can be Ala (A), Cys (C), Glu (E), or Lys (K). Xaa25 is Cys (C), Lys (K), or Trp (W). Xaa28 can be Cys (C), Lys (K), or Arg (R). Xaa29 is Cys (C), Lys (K), or Gly (G). Xaa30 is Ala (A), Cys (C), Gly (G), Lys (K), Arg (R), or does not exist. Xaa31 is Ala (A), Cys (C), Lys (K), Gly (G), Gln (Q) or does not exist. 27. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising the GLP-1 receptor activator (Z1) according to Formula II (SEQ ID NO: 255). Xaa1-Xaa2-Glu-Gly-Thr-Phe-Thr-Ser-Xaa9-Xaa10-Ser-Xaa12-Tyr-Leu-Glu-Xaa16-Xaa17 -Ala-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Leu-Val-Xaa28-Xaa29-Xaa30-Xaa31, And among them Xaa1 is His (H) or Imp. Xaa2 can be Aib, Ala (A), Gly (G), or Trp (W). Xaa9 represents Asp (D) or Lys (K). Xaa10 is either Lys (K) or Val (V). Xaa12 is Lys (K), Arg (R), or Ser (S). Xaa16 can be Glu (E), Gly (G), or Lys (K). Xaa17 is either Gln(Q) or Lys(K). Xaa19 is either Ala (A) or Val (V). Xaa20 is either Lys (K) or Arg (R). Xaa21 is either Glu (E) or Lys (K). Xaa22 represents Phe (F), Trp (W), or Tyr (Y). Xaa23 is Ile (I), Leu (L), or Val (V). Xaa24 can be Ala (A), Glu (E), or Lys (K). Xaa25 is either Lys (K) or Trp (W). Xaa28 is either Lys(K) or Arg(R). Xaa29 is either Lys (K) or Gly (G). Xaa30 is Ala (A), Gly (G), Lys (K), Arg (R), or does not exist. Xaa31 is Ala (A), Lys (K), Gly (G), Gln (Q) or does not exist. 28. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises phenylalanine (Phe, F), tryptophan (W), or tyrosine (Tyr, Y) at position 22 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 29. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises phenylalanine (Phe, F) at position 22 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 30. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises isoleucine (Ile, I), leucine (Leu, L), or valine (Val, V) at position 23 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 31. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises isoleucine (Ile, I) at position 23 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 32. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising the GLP-1 receptor activator (Z1) according to Formula II (SEQ ID NO: 255). Xaa1-Xaa2-Glu-Gly-Thr-Phe-Thr-Ser-Xaa9-Xaa10-Ser-Xaa12-Tyr-Leu-Glu-Xaa16-Xaa1 7-Ala-Xaa19-Xaa20-Xaa21-Phe-Ile-Xaa24-Xaa25-Leu-Val-Xaa28-Xaa29-Xaa30-Xaa31, in Xaa1 is His (H) or Imp. Xaa2 can be Aib, Ala (A), Gly (G), or Trp (W). Xaa9 represents Asp (D) or Lys (K). Xaa10 is either Lys (K) or Val (V). Xaa12 is Lys (K), Arg (R), or Ser (S). Xaa16 can be Glu (E), Gly (G), or Lys (K). Xaa17 is either Gln(Q) or Lys(K). Xaa19 is either Ala (A) or Val (V). Xaa20 is either Lys (K) or Arg (R). Xaa21 is either Glu (E) or Lys (K). Xaa24 can be Ala (A), Glu (E), or Lys (K). Xaa25 is either Lys (K) or Trp (W). Xaa28 is either Lys(K) or Arg(R). Xaa29 is either Lys (K) or Gly (G). Xaa30 is Ala (A), Gly (G), Lys (K), Arg (R), or does not exist. Xaa31 is Ala (A), Lys (K), Gly (G), Gln (Q) or does not exist. 33. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, Where Z1 is Xaa1-Xaa2-Glu-Gly-Thr-Phe-Thr-Ser-Xaa9-Xaa10-S-Xaa12-Tyr-Leu-Glu-Xaa16-Xaa17 -Ala-Xaa19-Xaa20-Xaa21-Phe-Ile-Xaa24-Xaa25-Leu-Val-Xaa28-Xaa29-Xaa30-Xaa31, And among them Xaa1 is His (H) or Imp. Xaa2 can be Aib, Ala (A), Gly (G), or Trp (W). Xaa9 is either Cys (C) or Asp (D). Xaa10 is either Cys (C) or Val (V). Xaa12 is Cys (C), Arg (R), or Ser (S). Xaa16 is Cys (C), Glu (E), or Gly (G). Xaa17 is either Cys (C) or Gln (Q). Xaa19 is either Ala (A) or Val (V). Xaa20 is either Cys (C) or Arg (R). Xaa21 is either Cys (C) or Glu (E). Xaa24 can be Ala (A), Cys (C), or Glu (E). Xaa25 is either Cys (C) or Trp (W). Xaa28 is either Cys (C) or Arg (R). Xaa29 is either Cys (C) or Gly (G). Xaa30 is Cys (C), Ala (A), Gly (G), Arg (R), or does not exist. Xaa31 is Ala (A), Cys (C), Gly (G), Gln (Q) or does not exist. 34. 35. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) comprises leucine (Leu, L) at position 12 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 36. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) includes leucine (Leu12) at position 12 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 37. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the optional linker Z2 system is absent or includes 1-30, 1-25 or 1-20 naturally occurring amino acid residues (SEQ ID NO 239). 38. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the optional linker Z2 comprises 0-20 amino acid residues selected from the group consisting of Ala (A), Glu (E), Gly (G), Lys (K), Pro (P) and Gln (Q). 39. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the optional linker Z2 is one of those listed in Table 1. 40. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising the amyloid receptor activator peptide (Z3) according to Formula III (SEQ ID NO: 240): Xaa1-Xaa2-Xaa3-Leu-Ser Thr-Xaa7-Ala-Leu-Gly-Arg-Leu-Ser-Xaa14-Glu-Leu-His-Xaa18-Leu-Xaa20-Thr-Leu-Xaa23-Arg-Thr-Glu-Thr-Gly-Xaa29-Gly-Ser-Xaa32, in Xaa1 is Ala (A), Cys (C), Lys (K), or does not exist. Xaa2 is Cys (C), Lys (K), or Ser (S). Xaa3 can be Cys (C), Glu (E), Lys (K), or Arg (R). Xaa7 can be Ala (A), Cys (C), Glu (E), or Lys (K). Xaa14 can be Ala (A), Cys (C), or Lys (K). Xaa18 can be Cys (C), Glu (E), Lys (K), or Gln (Q). Xaa20 can be Ala (A), Cys (C), or Lys (K). Xaa23 is Cys (C), Lys (K), or Pro (P). Xaa29 is Cys (C), Ser (S), or Lys (K), and Xaa32 is either Pro (P) or Tyr (Y). 41. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, comprising the amyloid receptor activator (Z3) according to Formula III (SEQ ID NO: 256): Xaa1-Xaa2-Xaa3-Leu-Ser-Thr-Xaa7-Ala-Leu-Gly-Arg-Leu-Ser-Xaa14-Glu-Leu-Hi s-Xaa18-Leu-Xaa20-Thr-Leu-Xaa23-Arg-Thr-Glu-Thr-Gly-Xaa29-Gly-Ser-Xaa32, in Xaa1 is either Ala (A) or Lys (K) or does not exist. Xaa2 is either Lys(K) or Ser(S). Xaa3 can be Glu (E), Lys (K), or Arg (R). Xaa7 can be Ala (A), Glu (E), or Lys (K). Xaa14 is either Ala (A) or Lys (K). Xaa18 can be Glu (E), Lys (K), or Gln (Q). Xaa20 represents Ala (A) or Lys (K). Xaa23 is either Lys (K) or Pro (P). Xaa29 is either Ser (S) or Lys (K), and Xaa32 is either Pro (P) or Tyr (Y). 42. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises 2, 3, 4, 5, 6, 7, 8 or 9 amino acid modifications relative to human GLP-1 (7-37). 43. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) comprises replacing one or two naturally occurring amino acids with one or two non-natural amino acids. 44. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) is located at position 7 relative to human GLP-1 (7-37), or at position 1 relative to SEQ ID NO: 238 or SEQ ID NO: 255, comprising imidazole acrylamide (Imp). 45. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) is located at position 8 relative to human GLP-1 (7-37), or at position 2 relative to SEQ ID NO: 238 or SEQ ID NO: 255, comprising α-aminoisobutylene (Aib). 46. ​​The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator peptide (Z1) is located at any of positions 8, 25, 30 or 37 relative to human GLP-1 (7-37), or at any of positions 2, 19, 24 or 31 relative to SEQ ID NO: 238 or SEQ ID NO: 255, comprising alanine (Ala, A). 47. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) comprises an arginine residue (Arg, R) at either position 26 or 34 relative to human GLP-1 (7-37) or at either position 18 or 26 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 48. A GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) comprises an aspartic acid residue (Asp, D) at position 15 relative to human GLP-1 (7-37) or at position 9 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 49. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) comprises glutamic acid residues (Glu, E) at any of positions 22, 27, or 30 relative to human GLP-1 (7-37), or at any of positions 16, 21, or 24 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 50. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) comprises a glycine residue (Gly, G) at position 8 or 36 relative to human GLP-1 (7-37), or at position 2 or 30 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 51. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) comprises a histidine residue (His, H) at position 7 relative to human GLP-1 (7-37) or at position 1 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 52. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) comprises a serine residue (Ser, S) at position 18 relative to human GLP-1 (7-37) or at position 12 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 53. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) comprises tryptophan residues (Trp, W) at either position 8 or 31 relative to human GLP-1 (7-37) or at either position 2 or 25 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 54. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the GLP-1 receptor activator (Z1) comprises a valine residue (Val, V) at either position 16 or 25 relative to human GLP-1 (7-37) or at either position 10 or 19 relative to SEQ ID NO: 238 or SEQ ID NO: 255. 55. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) comprises 0, 1, 2, 3 or 4 amino acid modifications relative to SEQ ID NO: 79. 56. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) comprises 0, 1, 2 or 3 amino acid modifications relative to SEQ ID NO: 79. 57. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) comprises 0, 1 or 2 amino acid modifications relative to SEQ ID NO: 79. 58. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) comprises 0 or 1 amino acid modification relative to SEQ ID NO: 79. 59. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) includes a lysine (Lys, K) residue at any of positions 1, 2, 3, 7, 10, 14, 18, 20, 23 or 29 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 60. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) includes a lysine (Lys, K) residue at any of positions 2, 14, 18, 20, 23 or 29 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 61. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) includes an arginine (Arg, R) residue at position 3 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 62. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) includes a Glu (E) residue at position 7 relative to SEQ ID NO: 240 or SEQ ID NO: 256. 63. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the amyloid receptor activator peptide (Z3) includes Leu (L) at position 12 relative to SEQ ID NO: 79. 64. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein Z1 is a GLP-1 receptor activator selected from the group consisting of SEQ ID NO: 2-78. 65. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein Z2 is an amino acid residue or peptide as shown in Table 1. 66. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein Z3 is an amyloid receptor activator peptide (Z3) selected from the group consisting of SEQ ID NO: 79-88. 67. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments further includes an extended portion attached to each lysine residue. 68. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein each lysine residue is acylated. 69. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the extended portion comprises C14-C20 diacid. 70. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the extended portion comprises C14 diacid, C16 diacid, C18 diacid, C20 diacid, C18-tetrazole, C14-sulfonic acid, 4-(9-hydroxynonoxy)benzoic acid, 4-(10-hydroxydecoxy)benzoic acid or 3-(9-hydroxynonoxy)benzoic acid. 71. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments comprises two C14 diacids, C16 diacids, or C18 diacids. 72. The GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments comprises three C14 diacids. 73. A GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments, wherein the lysine is attached to any of the optional linkers ("R2") shown in Table 3. 74. A GLP-1 receptor-amyloid receptor co-activator comprising any polypeptide selected from SEQ ID NO: 117-236. 75. A GLP-1 receptor-amyloid receptor co-activator comprising any of the identified individuals in Example 1a. 76. A pharmaceutically acceptable salt of a GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments. 77. A pharmaceutical formulation of a GLP-1 receptor-amyloid receptor co-activator as described in any of the foregoing embodiments. 78. The pharmaceutical preparations described in the foregoing embodiments are intended for oral administration. 79. The pharmaceutical preparations described in the foregoing embodiments are solid pharmaceutical preparations. 80. The solid pharmaceutical preparations described in the foregoing embodiments are tablets. 81. The tablets as described in the foregoing embodiments comprise sodium N-(8-(2-hydroxybenzoyl)amino)octanoate and magnesium stearate. 82. The tablets as described in the foregoing examples comprise 75-600 mg of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate and 7-8.5 mg of magnesium stearate. 83. The pharmaceutical preparation described in any of Examples 71-76 is administered approximately once daily, such as once every 12-36 hours, such as once every 18-30 hours, such as once every 24 hours. 84. The GLP-1 receptor-amyloid receptor co-activator as described in any of Examples 1-76 or the formulation as described in any of Examples 77-83 is used as a pharmaceutical product. 85. The GLP-1 receptor-amyloid receptor co-activator as described in any of Examples 1-76 or the formulation as described in any of Examples 77-83 is used to treat individuals with an initial body mass index (BMI) of 27 or higher (such as 30 or higher). 86. The GLP-1 receptor-amyloid receptor co-activator as described in any of Examples 1-76 or the formulation as described in any of Examples 77-83 is used to treat an individual with an initial body mass index (BMI) of 27 or with at least one weight-related comorbidity. 87. The GLP-1 receptor-amyloid receptor co-activator as described in any of Examples 1-76 or the formulation as described in any of Examples 77-83, intended as an adjunct to a low-calorie diet and increased physical activity for long-term weight management in adult individuals with an initial body mass index (BMI) of 30 kg / m2 or higher (obese) or 27 kg / m2 or higher (overweight) in the presence of at least one weight-related comorbidity. 88. The use as described in the foregoing embodiments, wherein the comorbidity is diabetes and / or cardiovascular disease. 89. The GLP-1 receptor-amyloid receptor co-activator as described in any of Examples 1-76 or the formulation as described in any of Examples 77-83 is used to treat individuals with diabetes (such as type II diabetes). 90. The GLP-1 receptor-amyloid receptor co-activator as described in any of Examples 1-76 or the formulation as described in any of Examples 77-83 is used for the treatment and / or prevention of cardiovascular disease. 91. The GLP-1 receptor-amyloid receptor co-activator as described in any of Examples 1-76 or the formulation as described in any of Examples 77-83 is used to treat NASH. 92. The GLP-1 receptor-amyloid receptor co-activator as described in any of Examples 1-76 or the formulation as described in any of Examples 77-83 is used for the treatment and / or prevention of cognitive impairment such as Alzheimer's disease. [Example] [Example] [1] [:] [GLP-1] [Receptor] [-] Synthesis of Amyloid Receptor Co-activators and Comparative Compounds

[0400] This example provides identification of various compounds according to the present invention, their manufacturing materials, and their synthesis methods.

[0401] The identification, manufacturing materials, and synthesis methods of the comparative compounds described herein are also provided. [ Materials and Methods ] [ ] [List of Abbreviations] [ ]

[0402] The following abbreviations are used in alphabetical order: Ac: Acetyl Aib: α-Aminoisobutyric acid AUC: Area under the curve Boc: Tertiary butoxycarbonyl DCM: Dichloromethane DIC: Diisopropylcarbodiimide DIPEA: N,N-diisopropylethylamine or Hünig base DMF: Dimethylformamide DODT: 3,6-dioxa-1,8-octanedithiol DTT: Dithiothreitol EDTA: Ethylenediaminetetraacetic acid ELISA: Enzyme Immunosorbent Assay Fmoc: 9-Genomethoxycarbonyl HFIP: 1,1,1,3,3,3-Hexafluoro-2-propanol or hexafluoroisopropanol HOBt: 1-Hydroxybenzotriazole HPLC: High Performance Liquid Chromatography HAS: Human serum albumin Imp: Imidazolyl iv: Intravenous LCMS or LC-MS: Liquid Chromatography-Mass Spectrometry Analysis MeCN: Acetonitrile Mtt: 4-Methyltriphenylmethyl NHS: N-hydroxysuccinimide NMP: N-methylpyrrolidone Oxyma Pure®: Cyano-hydroxyimino-ethyl acetate PK: Pharmacokinetics QTof: Quantitative Time of Flight sc: subcutaneous SD: Standard Deviation SEC-HPLC: Size Exclusion High Performance Liquid Chromatography SEM: Mean Standard Error tBu: Tertiary Butyl TFA: Trifluoroacetic acid TIS: Triisopropylsilane Trt: Triphenylmethyl or Triphenylmethyl Trx: Tranexamic acid UPLC: Ultra-high performance liquid chromatography [ General preparation method ] [ ]

[0403] This section relates to methods for solid-phase peptide synthesis (SPPS method, including methods for self-replicate peptide cleavage, removal of protecting groups, and purification). It also includes LCMS methods for detecting and characterizing the resulting peptides.

[0404] The resins used to prepare C-terminal peptide amides are PAL amide AM resin (loaded, for example, 0.6 mmol / g), H-Rink Amide-ChemMatrix resin (loaded, for example, 0.5 mmol / g), Rink Amide AM polystyrene resin (loaded, for example, 0.3-0.7 mmol / g), Tentagel® Rink Amide resin (loaded, for example, 0.2-0.3 mmol / g), or similar resins suitable for SPPS.

[0405] The Fmoc-protected amino acid derivatives used include the recommended standards: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc -Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH or Fmoc-Trp-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Aib-OH, etc., are provided by (e.g.) AAPPTEC, Anaspec, Bachem, ChemImpex, Iris Biotech, Midwest Biotech, Gyros Protein Technologies, or Novabiochem. Other constructive blocks, such as Fmoc-pseudoproline and similar derivatives, are used for some difficult-to-produce sequences. When no other specified form is available, the native L-form amino acid is used. Reagents with pre-loaded Boc groups (e.g., Boc-His(Trt)-OH for peptides with His at the N-terminus) or by replacing the N-terminal Fmoc protecting group with a Boc protecting group after attaching an amino acid to the N-terminus of the peptide. Fmoc-Lys(Mtt)-OH and similar derivatives (such as (but not limited to) Fmoc-Lys(ivDDE)) with orthogonal protecting groups at the ε-amino group position are used in examples with side chains. The ε-amino derivative will be released using a suitable orthogonal deprotecting agent (such as HFIP in DCM), and the side chain is constructed by progressively loading SPPS or by directly coupling the ε-amino functional group to the side chain of an activated ester (e.g., NHS ester) to build a block.

[0406] When using SPPS to progressively attach side chains, the following appropriately protected building blocks may be used, such as (but not limited to) Fmoc-8-amino-3,6-dioxanoic acid (Fmoc-OEG-OH), Fmoc-tranexamic acid (Fmoc-Trx-OH), Fmoc-Glu-OtBu, octadecanoic acid monotert-butyl, nonadecanoic acid monotert-butyl, eicosanoic acid monotert-butyl, hexadecanoic acid monotert-butyl, tetradecanoic acid monotert-butyl, or 4-(9-carboxynonoxy)benzoic acid tritert-butyl. All operations described below shall be performed on a synthetic scale of 50–450 μmol. SPPS of peptide backbone:

[0407] SPPS is performed using Fmoc-based chemicals on a SymphonyX solid-phase peptide synthesizer from Protein Technologies (Tucson, AZ 85714 USA). Fmoc deprotection is achieved using 20% ​​piperidine in DMF containing 0 to 0.2 M Oxyma. Peptide coupling is performed using DIC / Oxyma Pure®. An amino acid / Oxyma Pure® solution (0.3 M / 0.3 M in DMF, 3-12 times molar excess) is added to the resin, followed by the same molar equivalents of DIC (0.6-1.5 M in DMF) and trimethylpyridine (1.5 M in DMF). To complete the stepwise assembly, follow these steps: 1) Pre-swell the resin with DMF; 2) Deprotect the Fmoc by treating 1-5 times with 20% piperidine in DMF containing 0-0.2 M Oxyma Pure®, for 5-30 minutes each time; 3) Wash with DMF to remove trace amounts of piperidine; 4) Couple the Fmoc-amino acid, where 3-12 equivalents of the Fmoc-amino acid are used as a 0.3 M solution of Oxyma Pure® in DMF, mixed with an equal molar volume of DIC and trimethylpyridine for 1-12 hours. Repeat this coupling step once or twice if using sterically hindered amino acids; 5) Wash with DMF to remove excess reagent; 6) Finally, wash with DCM upon completion of the assembly to prepare the resin for attaching modifying groups to the amino acid side chains.

[0408] Alternatively, SPPS is performed using Fmoc-based chemicals on a SymphonyX solid-phase peptide synthesizer from Protein Technologies (Tucson, AZ 85714 USA). Fmoc deprotection is achieved using 20% ​​piperidine in DMF containing 0 to 0.2 M Oxyma. Peptide coupling is performed using DIC / Oxyma Pure®. An amino acid / Oxyma Pure® solution (0.3 M / 0.3 M in DMF, 3-12 times molar excess) is added to the resin, followed by the same molar equivalent of DIC (0.6 M in DMF). To complete the stepwise assembly, follow these steps: 1) Pre-swell the resin with DMF; 2) Deprotect the Fmoc by treating 1-5 times with 20% piperidine in DMF containing 0-0.2 M Oxyma Pure®, for 5-30 minutes each time; 3) Wash with DMF to remove trace amounts of piperidine; 4) Couple the Fmoc-amino acid, where 3-12 equivalents of the Fmoc-amino acid are mixed with an equimolar volume of DIC as a 0.3 M solution of Oxyma Pure® in DMF for 1-12 hours. Repeat this coupling step once or twice if using sterically hindered amino acids; 5) Wash with DMF to remove excess reagent; 6) Finally, wash with DCM upon completion of the assembly to prepare the resin for attaching modifying groups to the amino acid side chains.

[0409] Alternatively, protected peptide resins are synthesized using a manufacturer-supplied machine protocol based on the Fmoc strategy on a solid-phase peptide synthesizer Prelude (Protein Technologies, Tucson, USA). Coupling is performed using DIC (dicyclohexylcarbodiimide) and Oxyma Pure (ethyl 2-cyano-2-(hydroxyimino)-ethyl acetate, Merck, Novabiochem, Switzerland) mediated in NMP. Fmoc-amino acid coupling is performed using an amino acid in 4-8 times excess (4-8 equivalents) relative to the resin substitute, as described above. Coupling times range from 1 hour to 6 hours. Fmoc-Arg(pbf)-OH is coupled using a double coupling procedure (1 hour + 1 hour). Stepwise solid-phase assembly was performed on Prelude using the following steps: 1) Deprotection (removal of Fmoc) using 20-25% piperidine in NMP for 2 x 4-10 minutes; 2) Washing with DMF and DCM (removal of piperidine); 3) Coupling of Fmoc-amino acids (0.3 M Fmoc-amino acids in DMF and 0.3 M Fmoc-amino acids in Oxyma Pure), for coupling with an excess of 3-10 equivalents initiated by adding 1 / 10 volume of 3 M DIC in DMF and 1 / 10 volume of trimethylpyridine in DMF for 1-4 hours. Mixing was completed by occasional bubbling with nitrogen; 4) Washing (removal of excess amino acids and reagents using DMF and DCM). The final step included washing with DCM to prepare the resin for attaching modifying groups to the lysine side chains. Linkage of the protected peptide backbone with side chains bound to resin:

[0410] Before washing with piperidine, DMF and DCM, the N-ε-lysine Mtt protecting group is removed by washing the resin with a suitable orthogonal deprotection mixture (such as (but not limited to) 20-30% HFIP in DCM containing 0-5% TIS) in multiple cycles (e.g., 1 x 5 min and 2 x 20 min).

[0411] The amide formation can be performed manually or on a solid-phase peptide synthesizer (such as, but not limited to, the SymphonyX solid-phase peptide synthesizer from Protein Technologies (Tucson, AZ 85714 USA), as described in the "SPPS of Peptide Backbone" method section) using the stepwise addition of building blocks such as, but not limited to, Fmoc-8-amino-3,6-dioxanoic acid (Fmoc-OEG-OH, Fmoc-Glu-OtBu, Fmoc-tranexamic acid (Fmoc-Trx-OH)). The introduction of a fatty acid moiety can be achieved using suitable building blocks such as, but not limited to, octadecanoic acid monotert-butyl ester, eicosanoic acid monotert-butyl ester, hexadecanoic acid monotert-butyl ester, tetradecanoic acid monotert-butyl ester, or 4-(9-carboxynonoxy)benzoic acid tributyl ester.

[0412] Alternatively, the side chain portion can be loaded in one step, as described in the first part of this section, by directly constructing a block with a suitable side chain containing an activated ester (e.g., NHS) after removing the Mtt group. Cleavage and purification of resin-bound peptides

[0413] Following synthesis, the resin is washed with DCM, and the peptide resin is treated with a TFA mixture in the presence of 1-20% by volume of a scavenger (such as, but not limited to, water, TIS, DTT, and DODT). This cleavage reaction is typically carried out at room temperature for 1-3 hours. Alternatively, the cleavage reaction can be carried out at a higher temperature (e.g., 50°C) for a shorter time (15-60 minutes). After the cleavage reaction, the crude peptide is precipitated using cold (e.g., 5°C) diethyl ether. The precipitate is washed with diethyl ether and dissolved in a suitable mixture of water and MeCN. Alternatively, a suitable water-soluble co-solvent (such as acetic acid) can be used.

[0414] The crude peptide solution was purified by reverse-phase preparative HPLC (Waters Deltaprep 4000) on a C18-silica column. Dissolution was performed by gradually increasing the gradient with a MeCN aqueous solution containing 0.1% TFA. The fractions were analyzed by analytical UPLC. Fractions containing the purified target peptide were combined and lyophilized.

[0415] Alternatively, or when further purification is required, the separated crude peptide or lyophilized peptide TFA salt is dissolved in a neutral (e.g., pH 7-8) aqueous buffer based on a common salt (such as, but not limited to, sodium hydrogen phosphate), and purified using reverse-phase preparative HPLC (Waters Deltaprep 4000) on a C18-silica column. Dissolution is performed with a gradually increasing gradient of MeCN in an aqueous sodium phosphate solution (5-100 mM, pH 7-8). The fractions are analyzed by analytical UPLC. Fractions containing the purified target peptide are combined and acidified with TFA until pH 2, and diluted with water until the MeCN concentration is <20%. This solution is then purified using reverse-phase preparative HPLC (Waters Deltaprep 4000) on a C18-silica column. Dissolution is performed with a gradually increasing gradient of MeCN in an aqueous solution containing 0.1% TFA. The fractions are analyzed by analytical UPLC. The fractions containing the pure target peptide were combined and freeze-dried. LCMS Qualitative Methods: [ ] LCMS34:

[0416] LCMS34 was performed on a device consisting of a Waters Acquity UPLC H Class system and a Waters Xevo G2-XS QTof. The precipitate solutions were: A: 0.1% formic acid in MQ aqueous solution; B: 0.1% formic acid in MeCN solution.

[0417] Analysis was performed at RT (column temperature 40°C) by injecting an appropriate volume of sample onto a column with gradient A and B dissolution. UPLC conditions, detector settings, and mass spectrometer settings were as follows: Column: Acquity BEH, C-18, 1.7µm, 2.1mm x 50mm. Gradient: Linear 5%–95% B at 0.4 ml / min over 4.0 min. Detection: MS resolution mode; Ionization method: ES. Scan: 50–4000 amu. LCMS36:

[0418] LCMS_36 was performed on a device consisting of a Waters Acquity UPLC H Class system and a Waters Xevo G2-XS QTof. The solutions were: A: 0.1% formic acid in MQ aqueous solution; B: 0.1% formic acid in MeCN solution.

[0419] Analysis was performed at RT (column temperature 60°C) by injecting an appropriate volume of sample onto a column with gradient A and B elution. UPLC conditions, detector settings, and mass spectrometer settings were as follows: Column: Phenomenex Aeris, C-4, 3.6 µm widepore, 2.1 mm x 50 mm. Gradient: Stepwise gradient over 8 minutes; 5%–25% B during the first 1.0 minute interval, 25%–65% B during the 6-minute interval, 65%–95% B during the 0.5-minute interval, and 95% B isocratic during the 0.5-minute interval, elution at 0.4 ml / min. Detection: MS resolution mode; Ionization method: ES. Scan: 50–4000 amu. LCMS_ZQ:

[0420] LCMS_ZQ was performed on an LCMS instrument consisting of a Waters Acquity UPLC system, a Waters Acquity TUV detector, and a Waters Micromass ZQ 2000 detector. The solutions were: A: 0.05% TFA in MQ aqueous solution; B: 0.05% acetonitrile solution.

[0421] Analysis was performed at RT (column temperature 40°C) by injecting an appropriate volume (0.2–10 µl) of sample onto a column with gradient A and B dissolution. Column: Waters Acquity UPLC BEH, C-18, 1.7 µm, 2.1 mm x 50 mm. Gradient run time: 5-95% linearity after 4.5 min, followed by 95% B at 0.5 min, 95-5% B at 0.5 min, and 5% B at 0.5 min at a flow rate of 0.45 ml / min. Detection: Ionization method: positive electrospray; Scan range: 200–2048 (m / z); Capillary voltage: 3.0 kV; Cone voltage: 20 V; Scan time: 0.9 s; Inter-scan delay: 0.1 s; Detection mode: quadrupole. LCMS01:

[0422] LCMS_01 was performed on a setup consisting of a Waters Acquity UPLC system and an LCT Premier XE mass spectrometer from Micromass. Dissolution solutions: A: 0.1% formic acid in MQ aqueous solution; B: 0.1% formic acid in MeCN solution. Analysis was performed at RT (column temperature 40°C) by injecting appropriate volumes of sample onto the column and dissolving using gradients A and B. UPLC conditions, detector settings, and mass spectrometer settings were as follows: Column: Waters Acquity UPLC BEH, C-18, 1.7µm, 2.1mm x 50mm. Gradient: Linear 5% - 95% B at 0.4 ml / min over 4.0 min. Detection: 214 nm (analog output from TUV (tunable UV detector)). MS ionization mode: API-ES. Scan: 500-2000 atomic mass units (amu).

[0423] [, The compound manufactured , ] [Example] [1a] [Compounds according to the present invention] [ ] [Compound]

[0007] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C332 H531 N89 O112 Calculated molecular weight (average): 7561.3 g / mol Mass of a single isotope: 7556.9 g / mol LCMS34: Experimental value (M + 5H)5+ 1513.3 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 117. [Compound] [-0009] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGEGEEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C347 H552 N92 O121 Calculated molecular weight (average): 7948.6 g / mol Mass of a single isotope: 7944.0 g / mol LCMS34: Experimental value (M + 5H)5+ 1591 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGKGEGEGEEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 118. [Compound] [-0010] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGEGEGE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C353 H564 N96 O122 Calculated molecular weight (average): 8104.8 g / mol Mass of a single isotope: 8100.1 g / mol LCMS34: Experimental value (M + 5H)5+ 1622 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGEGEGEKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 119. [Compound]

[0019] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C362 H575 N97 O124 Calculated molecular weight (average): 8270.0144 g / mol Mass of a single isotope: 8265.1670 g / mol LCMS36: Experimental value (M + 5H)5+ 1654.85 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGQEPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 120. [Compound]

[0026] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C358 H570 N96 O121 Calculated molecular weight (average): 8154.9270 g / mol Mass of a single isotope: 8150.1400 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1631.04 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 121. [ ] [Compound]

[0035] Imp-AEGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C344 H552 N90 O113 Calculated molecular weight (average): 7756.5989 g / mol Mass of a single isotope: 7752.0214 g / mol LCMS01: Experimental value (M + 5H)5 + 1552 (most abundant) The amino acid sequence XAEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 122. [Compound]

[0039] HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(13-carboxytridecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxytridecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C359 H577 N91 O124 Calculated molecular weight (average): 8151.9580 g / mol Mass of a single isotope: 8147.1642 g / mol LCMS01: Experimental value (M + 5H)⁵ + 1631.6 (most abundant) The amino acid sequence HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 123. [Compound]

[0040] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C334 H534 N90 O113 Calculated molecular weight (average): 7618.3490 g / mol Mass of a single isotope: 7613.8806 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1524.92 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 124. [Compound]

[0042] H-Aib-EGTFTSDVSSYLEGQAAKEFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C336 H540 N90 O112 Calculated molecular weight (average): 7632.4186 g / mol Mass of a single isotope: 7627.9326 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1527.76 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 125. [Compound]

[0044] H-Aib-EGTFTSDVSSYLEGQAA-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexyl])-EFIAWLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C338 H543 N91 O113 Calculated molecular weight (average): 7689.4699 g / mol Mass of a single isotope: 7684.9541 g / mol LCMS34: Experimental value (M + 5H)5+ 1538.8 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 117. [Compound]

[0045] H-Aib-EGTFTSDVSSYLEGQAAKEFIAWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C342 H552 N92 O113 Calculated molecular weight (average): 7760.5909 g / mol Mass of a single isotope: 7756.0276 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1553.22 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 125. [ ] [Compound]

[0051] Imp-AEGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C334 H535 N89 O112 Calculated molecular weight (average): 7589.3508 g / mol Mass of a single isotope: 7584.8904 g / mol LCMS01: Experimental value (M + 5H)5+ 1519.1 (most abundant) The amino acid sequence XAEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 122. [Compound]

[0052] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C344 H549 N95 O118 Calculated molecular weight (average): 7903.6056 g / mol Mass of a single isotope: 7898.9879 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1581.7 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 126. [Compound]

[0056] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-EFIAWLVRGRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-QEPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C401 H645 N101 O136 Calculated molecular weight (average): 9057.0071 g / mol Mass of a single isotope: 9051.6660 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1812.4 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGKQEPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 127. [Compound]

[0057] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C398 H641 N101 O136 Calculated molecular weight (average): 9016.9432 g / mol Mass of a single isotope: 9011.6347 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1804.1 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGQEKGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 128. [Compound]

[0071] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C403 H648 N102 O137 Calculated molecular weight (average): 9114.0584 g / mol Mass of a single isotope: 9108.6874 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1823.7 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGQEPGQEPKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 129. [Compound]

[0072] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C367 H593 N93 O124 Calculated molecular weight (average): 8292.1840 g / mol Mass of a single isotope: 8287.2955 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1659.27 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 130. [Compound]

[0073] H-Aib-EGTFTSDVSSYLEGQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLVRGRGG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C368 H598 N96 O122 Calculated molecular weight (average): 8319.2557 g / mol Mass of a single isotope: 8314.3540 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1664.69 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAARKFIAWLVRGRGGKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 131. [Compound]

[0074] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLVRGRGG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C371 H602 N96 O124 Calculated molecular weight (average): 8391.3184 g / mol Mass of a single isotope: 8386.3752 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1679.1 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 132. [Compound]

[0075] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-EFIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C363 H584 N90 O124 Calculated molecular weight (average): 8193.0497 g / mol Mass of a single isotope: 8188.2159 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1639.45 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGKGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 133. [Compound]

[0076] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C367 H593 N93 O124 Calculated molecular weight (average): 8292.1840 g / mol Mass of a single isotope: 8287.2955 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1659.48 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGKGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 134. [Compound]

[0077] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLV-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C367 H593 N93 O124 Calculated molecular weight (average): 8292.1840 g / mol Mass of a single isotope: 8287.2955 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1659.48 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVKGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 135. [Compound]

[0083] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C364 H582 N100 O122 Calculated molecular weight (average): 8311.1127 g / mol Mass of a single isotope: 8306.2411 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1662.34 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGRKGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 136. [Compound]

[0084] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C364 H582 N100 O122 Calculated molecular weight (average): 8311.1127 g / mol Mass of a single isotope: 8306.2411 g / mol LCMS34: Experimental value (M + 5H)5+ 1663 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPKGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 137. [Compound]

[0085] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPGQAP-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C364 H582 N100 O122 Calculated molecular weight (average): 8311.1127 g / mol Mass of a single isotope: 8306.2411 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1662.24 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPGQAPKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 138. [Compound]

[0086] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C374 H602 N94 O129 Calculated molecular weight (average): 8479.3341 g / mol Mass of a single isotope: 8474.3436 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1696.69 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 139. [Compound]

[0087] HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C372 H598 N94 O129 Calculated molecular weight (average): 8451.2809 g / mol Mass of a single isotope: 8446.3123 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1691.08 (most abundant) The amino acid sequence HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 140. [Compound]

[0089] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C378 H610 N94 O129 Calculated molecular weight (average): 8535.4404 g / mol Mass of a single isotope: 8530.4062 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1707.9 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 139. [Compound]

[0090] HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C376 H606 N94 O129 Calculated molecular weight (average): 8507.3872 g / mol Mass of a single isotope: 8502.3749 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1702.49 (most abundant) The amino acid sequence HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 140. [Compound]

[0092] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C352 H561 N99 O122 Calculated molecular weight (average): 8131.8108 g / mol Mass of a single isotope: 8127.0737 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1627.5 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 141. [Compound]

[0093] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C360 H573 N103 O126 Calculated molecular weight (average): 8360.0161 g / mol Mass of a single isotope: 8355.1596 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1672.8 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 142. [Compound]

[0094] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C346 H553 N95 O118 Calculated molecular weight (average): 7931.6587 g / mol Mass of a single isotope: 7927.0192 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1587.2 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 126. [Compound]

[0095] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C354 H566 N96 O119 Calculated molecular weight (average): 8070.8536 g / mol Mass of a single isotope: 8066.1189 g / mol LCMS34: Experimental value (M + 5H)5+ 1615.0 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 126. [Compound]

[0096] HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C372 H583 N93 O130 Calculated molecular weight (average): 8438.1545 g / mol Mass of a single isotope: 8433.1868 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1688.65 (richest) The amino acid sequence HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 143. [Compound]

[0097] HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C380 H595 N97 O134 Calculated molecular weight (average): 8666.3598 g / mol Mass of a single isotope: 8661.2726 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1734.26 (most abundant) The amino acid sequence HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 144. [Compound]

[0098] HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C388 H607 N101 O138 Calculated molecular weight (average): 8894.5651 g / mol Mass of a single isotope: 8889.3585 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1779.88 (most abundant) The amino acid sequence HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 145. [Compound]

[0099] HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C381 H590 N94 O130 Calculated molecular weight (average): 8567.3131 g / mol Mass of a single isotope: 8562.2446 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1714.46 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 146. [Compound]

[0100] HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C389 H602 N98 O134 Calculated molecular weight (average): 8795.5184 g / mol Mass of a single isotope: 8790.3305 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1760.08 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 147. [Compound]

[0101] HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C397 H614 N102 O138 Calculated molecular weight (average): 9023.7237 g / mol Mass of a single isotope: 9018.4163 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1805.49 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 148. [Compound]

[0102] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(4-[17-(1H-tetraazol-5-yl)heptadecanylaminesulfonyl]butylyl)-ELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C311 H499 N89 O98 S Calculated molecular weight (average): 7084.8923 g / mol Mass of a single isotope: 7080.6520 g / mol LCMS01: Experimental value (M + 5H)5+ 1418 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 149. [Compound]

[0103] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(4-[17-(1H-tetraazol-5-yl)heptadecanylaminesulfonyl]butylyl)-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C322 H516 N92 O104 S Calculated molecular weight (average): 7372.1614 g / mol Mass of a single isotope: 7367.7637 g / mol LCMS01: Experimental value (M + 5H)5+ 1475 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 150. [Compound]

[0105] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGQEPGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C386 H620 N98 O133 Calculated molecular weight (average): 8761.6298 g / mol Mass of a single isotope: 8756.4764 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1753.31 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGQEPGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 151. [Compound]

[0106] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGQEPGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C390 H628 N98 O133 Calculated molecular weight (average): 8817.7361 g / mol Mass of a single isotope: 8812.5390 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1764.33 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGQEPGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 151. [Compound]

[0109] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C383 H619 N99 O130 Calculated molecular weight (average): 8690.5983 g / mol Mass of a single isotope: 8685.4869 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1738.9 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGKGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 152. [Compound]

[0110] H-Aib-EGTFTSDVSSYLEEQAAR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]hexyl])-FIAWLVRG-K([(2 S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexyl])-GGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C395 H643 N103 O132 Calculated molecular weight (average): 8946.9428 g / mol Mass of a single isotope: 8941.6768 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1790.3 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGKGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 152. [Compound]

[0111] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C343 H550 N94 O116 Calculated molecular weight (average): 7846.5973 g / mol Mass of a single isotope: 7842.0028 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1570.22 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [Compound]

[0114] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C339 H544 N92 O114 Calculated molecular weight (average): 7732.4947 g / mol Mass of a single isotope: 7727.9599 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1547.4 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 154. [Compound]

[0115] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C335 H538 N90 O112 Calculated molecular weight (average): 7618.3920 g / mol Mass of a single isotope: 7613.9169 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1524.6 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 150. [Compound]

[0116] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C375 H610 N96 O124 Calculated molecular weight (average): 8447.4247 g / mol Mass of a single isotope: 8442.4378 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1690.3 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 155. [Compound]

[0120] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C353 H567 N95 O117 Calculated molecular weight (average): 8013.8454 g / mol Mass of a single isotope: 8009.1338 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1603.63 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [Compound]

[0124] Imp-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(4-[17-(1H-tetraazol-5-yl)heptadecanylaminesulfonyl]butylyl)-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C322 H515 N91 O104 S Calculated molecular weight (average): 7357.1468 g / mol Mass of a single isotope: 7352.7528 g / mol LCMS01: Experimental value (M + 5H)5+ 1472 (most abundant) The amino acid sequence XXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 156. [Compound]

[0125] H-Aib-EGTFTSDVSSYLEEQAAR-K(4-[17-(1H-tetraazol-5-yl)heptadecanylaminesulfonyl]butyl)-FIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C319 H512 N92 O102 S Calculated molecular weight (average): 7300.0988 g / mol Mass of a single isotope: 7295.7426 g / mol LCMS01: Experimental value (M + 5H)5+ 1461 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 157. [Compound]

[0127] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C369 H598 N92 O123 Calculated molecular weight (average): 8291.2390 g / mol Mass of a single isotope: 8286.3367 g / mol LCMS34: Experimental value (M + 5H)5 + 1659.1 (richest) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 158. [Compound]

[0128] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C371 H600 N92 O125 Calculated molecular weight (average): 8349.2751 g / mol Mass of a single isotope: 8344.3421 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1670.7 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 159. [Compound]

[0129] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C377 H612 N96 O126 Calculated molecular weight (average): 8505.4608 g / mol Mass of a single isotope: 8500.4432 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1702.0 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 160 [Compound]

[0131] H-Aib-EGTFTSDVSSYLEEQAAR-K([(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl])-FIAWLVRGR-K([(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C347 H560 N90 O110 Calculated molecular weight (average): 7752.6963 g / mol Mass of a single isotope: 7748.0993 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1551.6 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 161. [Compound]

[0132] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C333 H532 N88 O113 Calculated molecular weight (average): 7576.3090 g / mol Mass of a single isotope: 7571.8588 g / mol LCMS34: Experimental value (M + 5H)5+ 1516.11 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 162. [Compound]

[0141] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C325 H520 N88 O106 Calculated molecular weight (average): 7356.1323 g / mol Mass of a single isotope: 7351.8005 g / mol LCMS01: Experimental value (M + 5H)5+ 1472 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 150. [Compound]

[0142] Imp-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C325 H519 N87 O106 Calculated molecular weight (average): 7341.1177 g / mol Mass of a single isotope: 7336.7896 g / mol LCMS01: Experimental value (M + 5H)5+ 1469 (most abundant) The amino acid sequence XXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 156. [Compound]

[0144] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLV-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C339 H541 N91 O116 Calculated molecular weight (average): 7747.4629 g / mol Mass of a single isotope: 7742.9232 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1550.39 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVKGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 163. [Compound]

[0145] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGRG-K(4-[17-(1H-tetraazol-5-yl)heptadecanylaminesulfonyl]butyl)-GGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C325 H521 N95 O105 S Calculated molecular weight (average): 7471.2527 g / mol Mass of a single isotope: 7466.8070 g / mol LCMS01: Experimental value (M + 5H)5+ 1495 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRGKGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 164 [Compound]

[0146] H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRG-K(4-[17-(1H-tetraazol-5-yl)heptadecanylaminesulfonyl]butyl)-GGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C319 H508 N90 O105 S Calculated molecular weight (average): 7316.0518 g / mol Mass of a single isotope: 7311.6899 g / mol LCMS01: Experimental value (M + 5H)5+ 1464 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIEWLVRGKGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 165 [Compound]

[0147] H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRG-K(4-[17-(1H-tetraazol-5-yl)heptadecanylaminesulfonyl]butyl)-ASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C313 H499 N87 O102 S Calculated molecular weight (average): 7144.8979 g / mol Mass of a single isotope: 7140.6255 g / mol LCMS01: Experimental value (M + 5H)5 + 1430 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIEWLVRGKASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 166. [ ] [Compound]

[0151] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C340 H546 N94 O114 Calculated molecular weight (average): 7774.5346 g / mol Mass of a single isotope: 7769.9817 g / mol LCMS34: Experimental value (M + 5H)5+ 1555.81 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 167. [Compound]

[0156] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGQAPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C358 H570 N96 O121 Calculated molecular weight (average): 8154.9270 g / mol Mass of a single isotope: 8150.1400 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1631.04 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGQAPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 168. [Compound]

[0157] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGQAPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C360 H574 N96 O121 Calculated molecular weight (average): 8182.9802 g / mol Mass of a single isotope: 8178.1713 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1636.65 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGQAPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 168. [Compound]

[0159] H-Aib-EGTFTSDVSSYLEGQAA-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexyl])-EFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C350 H561 N97 O119 Calculated molecular weight (average): 8031.7778 g / mol Mass of a single isotope: 8027.0828 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1607.2 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 126. [Compound]

[0160] H-Aib-EGTFTSDVSSYLEEQAAR-K([(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl])-FIAWLVRGRGGGGGGGG-K([(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C363 H584 N98 O118 Calculated molecular weight (average): 8209.1069 g / mol Mass of a single isotope: 8204.2710 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1642.7 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGGGGKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 169. [Compound]

[0179] H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EAEAEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C363 H581 N95 O123 Calculated molecular weight (average): 8244.0599 g / mol Mass of a single isotope: 8239.2129 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1648.86 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIEWLVRGRKEAEAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 170. [Compound]

[0180] H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-EAEAEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C369 H593 N97 O124 Calculated molecular weight (average): 8372.2322 g / mol Mass of a single isotope: 8367.3078 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1674.46 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIEWLVRGRKEAEAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 170. [Compound]

[0191] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQAPASRLSTEALGRLSAELHELATLPRTETGSGSP-acetylamine C362 H582 N102 O119 Calculated molecular weight (average): 8267.1065 g / mol Mass of a single isotope: 8262.2625 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1653.45 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPKGQAPASRLSTEALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 171. [Compound]

[0202] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C360 H574 N96 O121 Calculated molecular weight (average): 8182.9802 g / mol Mass of a single isotope: 8178.1713 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1636.67 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 121. [Compound]

[0231] HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-acetylamine C387 H602 N100 O131 Calculated molecular weight (average): 8751.5122 g / mol Mass of a single isotope: 8746.3519 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1751.09 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 172. [Compound]

[0232] HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-acetylamine C387 H602 N100 O131 Calculated molecular weight (average): 8751.5122 g / mol Mass of a single isotope: 8746.3519 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1751.17 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 173. [Compound]

[0233] HWEGTFTSDVSSYLEEQAAREFIEWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-GEGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-acetylamine C386 H597 N97 O133 Calculated molecular weight (average): 8724.4405 g / mol Mass of a single isotope: 8719.2933 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1745.54 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAAREFIEWLVRGKGEGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 174. [Compound]

[0234] HWEGTFTSDVSSYLEEQAAREFIEWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-GEGGGGGASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-acetylamine C386 H597 N97 O133 Calculated molecular weight (average): 8724.4405 g / mol Mass of a single isotope: 8719.2933 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1745.73 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAAREFIEWLVRGKGEGGGGGASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 175. [Compound]

[0235] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(3-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])--K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(3-carboxyphenoxy)decylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C371 H584 N94 O127 Calculated molecular weight (average): 8393.1603 g / mol Mass of a single isotope: 8388.2129 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1678.65 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGKKGGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 176. [Compound]

[0254] HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C361 H571 N97 O118 Calculated molecular weight (average): 8157.9755 g / mol Mass of a single isotope: 8153.1662 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1632.55 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 177. [Compound]

[0255] HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[11-(4-carboxyphenoxy)undecylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[11-(4-carboxyphenoxy)undecylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-acetylamine C389 H606 N100 O131 Calculated molecular weight (average): 8779.5653 g / mol Mass of a single isotope: 8774.3832 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1756.92 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 172. [Compound]

[0259] H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELH-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LATLPRTETGSGSP-acetylamine C372 H602 N98 O126 Calculated molecular weight (average): 8463.3413 g / mol Mass of a single isotope: 8458.3711 g / mol LCMS_ZQ: Experimental value (M + 5H)⁵ + 1693.6 (richest) The amino acid sequence HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHKLATLPRTETGSGSP has SEQ ID NO: 178. [Compound]

[0260] H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-acetylamine C374 H604 N98 O128 Calculated molecular weight (average): 8521.3774 g / mol Mass of a single isotope: 8516.3766 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1705.3 (most abundant) The amino acid sequence HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 179. [ ] [Compound]

[0261] H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-RTETGSGSP-acetylamine C372 H602 N98 O128 Calculated molecular weight (average): 8495.3401 g / mol Mass of a single isotope: 8490.3610 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1699.9 (most abundant) The amino acid sequence HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLKRTETGSGSP has SEQ ID NO: 180. [Compound]

[0263] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C345 H555 N91 O113 Calculated molecular weight (average): 7785.6401 g / mol Mass of a single isotope: 7781.0480 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1558.2 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 150. [Compound]

[0264] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C347 H555 N91 O116 Calculated molecular weight (average): 7857.6597 g / mol Mass of a single isotope: 7853.0327 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1572.5 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 181. [Compound]

[0265] H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C348 H559 N93 O115 Calculated molecular weight (average): 7885.7162 g / mol Mass of a single isotope: 7881.0752 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1577.9 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 182. [Compound]

[0266] H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C348 H558 N94 O116 Calculated molecular weight (average): 7914.7143 g / mol Mass of a single isotope: 7910.0654 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1583.9 (most abundant) The amino acid sequence HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 183. [Compound]

[0267] HWEGTFTSDVSSYLEEQAAREFIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C350 H551 N89 O115 Calculated molecular weight (average): 7845.6472 g / mol Mass of a single isotope: 7841.0003 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1570.1 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAAREFIEWLVRGKGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 184. [Compound]

[0268] HWEGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C360 H570 N96 O117 Calculated molecular weight (average): 8114.9508 g / mol Mass of a single isotope: 8110.1604 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1624.0 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 185. [Compound]

[0269] HWEGTFTSDVSSYLEEQAAREFIEWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C362 H572 N96 O119 Calculated molecular weight (average): 8172.9869 g / mol Mass of a single isotope: 8168.1658 g / mol LCMS_ZQ: Experimental value (M + 5H)⁵ + 1634.5 (single isotope) The amino acid sequence HWEGTFTSDVSSYLEEQAAREFIEWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 186. [Compound]

[0270] HWEGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C351 H555 N91 O114 Calculated molecular weight (average): 7873.7037 g / mol Mass of a single isotope: 7869.0429 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1575.4 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 187. [Compound]

[0271] HWEGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C341 H538 N90 O113 Calculated molecular weight (average): 7706.4556 g / mol Mass of a single isotope: 7701.9119 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1542.27 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 187. [Compound]

[0272] HWEGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C351 H554 N92 O115 Calculated molecular weight (average): 7902.7019 g / mol Mass of a single isotope: 7898.0330 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1581.4 (most abundant) The amino acid sequence HWEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 188. [Compound]

[0273] HWEGTFTSD-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C341 H537 N91 O114 Calculated molecular weight (average): 7735.4538 g / mol Mass of a single isotope: 7730.9020 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1547.9 (most abundant) The amino acid sequence HWEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 188. [Compound]

[0280] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-GGGGGEASELSTAALGRLSAELH-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-LATLPRTETGSGSP-acetylamine C371 H599 N95 O126 Calculated molecular weight (average): 8406.2867 g / mol Mass of a single isotope: 8401.3384 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1682.1 (richest) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGGEASELSTAALGRLSAELHKLATLPRTETGSGSP has SEQ ID NO: 189. [Compound]

[0281] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-GGGGGEASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-acetylamine C373 H601 N95 O128 Calculated molecular weight (average): 8464.3227 g / mol Mass of a single isotope: 8459.3439 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1693.7 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGGEASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 190. [Compound]

[0284] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-GGGGGEASELSTAALGRLSAELHELATL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethtyl]acetyl])-RTETGSGSP-acetylamine C371 H599 N95 O128 Calculated molecular weight (average): 8438.2855 g / mol Mass of a single isotope: 8433.3283 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1688.7 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGGEASELSTAALGRLSAELHELATLKRTETGSGSP has SEQ ID NO: 191. [Compound]

[0285] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-GGGGGEASELSTAALGRLSAELHELATLPRTETG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GSP-acetylamine C373 H601 N95 O127 Calculated molecular weight (average): 8448.3233 g / mol Mass of a single isotope: 8443.3490 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1690.7 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGGEASELSTAALGRLSAELHELATLPRTETGKGSP has SEQ ID NO: 192. [Compound]

[0292] H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-acetylamine C369 H597 N97 O125 Calculated molecular weight (average): 8392.2634 g / mol Mass of a single isotope: 8387.3340 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1679.24 (most abundant) The amino acid sequence HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 193. [Compound]

[0294] H-Aib-EGTFTSDVSSYLE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-QAAREFIAWLVRGRGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-acetylamine C369 H599 N97 O123 Calculated molecular weight (average): 8362.2805 g / mol Mass of a single isotope: 8357.3598 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1673.26 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEKQAAREFIAWLVRGRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 194. [Compound]

[0295] H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-acetylamine C369 H598 N96 O124 Calculated molecular weight (average): 8363.2652 g / mol Mass of a single isotope: 8358.3439 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1673.65 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 195. [Compound]

[0296] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-acetylamine C369 H599 N97 O123 Calculated molecular weight (average): 8362.2805 g / mol Mass of a single isotope: 8357.3598 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1673.46 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 196. [Compound]

[0297] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-RGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-acetylamine C372 H603 N97 O125 Calculated molecular weight (average): 8434.3431 g / mol Mass of a single isotope: 8429.3810 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1687.87 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRKRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 197. [Compound]

[0299] H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGEASELSTAALGRLSAELH-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LATLPRTETGSGSP-acetylamine C372 H603 N97 O125 Calculated molecular weight (average): 8434.3431 g / mol Mass of a single isotope: 8429.3810 g / mol LCMS34: Experimental value (M + 5H)5 + 1688 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHKLATLPRTETGSGSP has SEQ ID NO: 198. [Compound]

[0396] H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-acetylamine C374 H605 N97 O127 Calculated molecular weight (average): 8492.3792 g / mol Mass of a single isotope: 8487.3865 g / mol LCMS34: Experimental value (M + 5H)5 + 1699 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 199. [Compound]

[0397] H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATL-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-RTETGSGSP-acetylamine C372 H603 N97 O127 Calculated molecular weight (average): 8466.3419 g / mol Mass of a single isotope: 8461.3708 g / mol LCMS34: Experimental value (M + 5H)5+ 1694 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLKRTETGSGSP has SEQ ID NO: 200. [Compound]

[0411] H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETG-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GSP-acetylamine C374 H605 N97 O126 Calculated molecular weight (average): 8476.3798 g / mol Mass of a single isotope: 8471.3915 g / mol LCMS34: Experimental value (M + 5H)5+ 1696 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGKGSP has SEQ ID NO: 201. [Compound]

[0414] HAEGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C343 H550 N90 O114 Calculated molecular weight (average): 7758.5717 g / mol Mass of a single isotope: 7754.0007 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1551.88 (single isotope) The amino acid sequence HAEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 202. [Compound]

[0415] H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C344 H552 N90 O114 Calculated molecular weight (average): 7772.5983 g / mol Mass of a single isotope: 7768.0163 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1554.67 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 203. [Compound]

[0416] HAEGTFTS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-VSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C344 H553 N91 O113 Calculated molecular weight (average): 7771.6135 g / mol Mass of a single isotope: 7767.0323 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1555.3 (most abundant) The amino acid sequence HAEGTFTSKVSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 204. [Compound]

[0417] H-Aib-EGTFTS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-VSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C345 H555 N91 O113 Calculated molecular weight (average): 7785.6401 g / mol Mass of a single isotope: 7781.0480 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1558.1 (most abundant) The amino acid sequence HXEGTFTSKVSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 205. [Compound]

[0431] HAEGTFTSD-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C343 H549 N91 O115 Calculated molecular weight (average): 7787.5699 g / mol Mass of a single isotope: 7782.9908 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1558.67 (most abundant) The amino acid sequence HAEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 206. [Compound]

[0433] HWEGTFTSD-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C357 H566 N94 O116 Calculated molecular weight (average): 8030.8741 g / mol Mass of a single isotope: 8026.1280 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1607.09 (most abundant) The amino acid sequence HWEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 188. [Compound]

[0434] HWEGTFTSDVSSYLEE-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C357 H567 N93 O115 Calculated molecular weight (average): 8001.8760 g / mol Mass of a single isotope: 7997.1378 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1601.19 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 187. [Compound]

[0435] HWEGTFTSDVSSYLEEQAA-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-EFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C356 H563 N91 O116 Calculated molecular weight (average): 7973.8195 g / mol Mass of a single isotope: 7969.0953 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1595.67 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAAKEFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 207. [Compound]

[0436] H-Aib-EGTFTSDVSSYLEEQAA-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-EFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C349 H560 N90 O116 Calculated molecular weight (average): 7872.7141 g / mol Mass of a single isotope: 7868.0688 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1575.47 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAKEFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 208. [Compound]

[0437] HWEGTFTSDVSSYLEEQAAR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-FIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C357 H568 N94 O114 Calculated molecular weight (average): 8000.8912 g / mol Mass of a single isotope: 7996.1538 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1601.06 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 209. [Compound]

[0438] H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C353 H569 N93 O116 Calculated molecular weight (average): 7971.8485 g / mol Mass of a single isotope: 7967.1484 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1595.27 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIEWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 210. [Compound]

[0439] H-Aib-EGTFTSDVSSYLEEQAAR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-FIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C350 H565 N93 O114 Calculated molecular weight (average): 7899.7858 g / mol Mass of a single isotope: 7895.1273 g / mol LCMS34: Experimental value (M + 5H)5+ 1580.88 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 211. [Compound]

[0440] H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C344 H551 N91 O115 Calculated molecular weight (average): 7801.5964 g / mol Mass of a single isotope: 7797.0065 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1560.48 (single isotope) The amino acid sequence HXEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 212. [Compound]

[0472] HAEGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C333 H533 N89 O113 Calculated molecular weight (average): 7591.3236 g / mol Mass of a single isotope: 7586.8697 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1519.18 (most abundant) The amino acid sequence HAEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 202. [Compound]

[0473] HWEGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C343 H542 N90 O113 Calculated molecular weight (average): 7734.5088 g / mol Mass of a single isotope: 7729.9432 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1547.82 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 187. [Compound]

[0474] HAEGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C335 H537 N89 O113 Calculated molecular weight (average): 7619.3768 g / mol Mass of a single isotope: 7614.9010 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1524.8 (most abundant) The amino acid sequence HAEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 202. [Compound]

[0475] HAEGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C365 H589 N93 O125 Calculated molecular weight (average): 8280.1303 g / mol Mass of a single isotope: 8275.2591 g / mol LCMS34: Experimental value (M + 5H)5+ 1656.86 (most abundant) The amino acid sequence HAEGTFTSDKSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 213. [Compound]

[0482] HAEGTFTSDVS-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAVREFIA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C365 H599 N95 O125 Calculated molecular weight (average): 8318.2231 g / mol Mass of a single isotope: 8313.3435 g / mol LCMS_ZQ: Experimental value (M + 5H)⁵ + 1664.64 (richest) The amino acid sequence HAEGTFTSDVSKYLEEQAVREFIAKLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 214. [Compound]

[0483] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAVREFIA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C366 H601 N95 O125 Calculated molecular weight (average): 8332.2496 g / mol Mass of a single isotope: 8327.3592 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1667.47 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAVREFIAKLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 215. [Compound]

[0484] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxytridecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAVREFIA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxytridecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C362 H593 N95 O125 Calculated molecular weight (average): 8276.1433 g / mol Mass of a single isotope: 8271.2966 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1656.1 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAVREFIAKLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 215. [Compound]

[0502] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C345 H554 N94 O116 Calculated molecular weight (average): 7874.6505 g / mol Mass of a single isotope: 7870.0341 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1575.09 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [Compound]

[0503] H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C355 H569 N95 O119 Calculated molecular weight (average): 8071.8815 g / mol Mass of a single isotope: 8067.1393 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1614.52 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIEWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 216. [Compound]

[0504] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGRP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C358 H574 N96 O118 Calculated molecular weight (average): 8110.9606 g / mol Mass of a single isotope: 8106.1866 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1622.34 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRPKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 217. [Compound]

[0506] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino)hexyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C359 H579 N97 O118 Calculated molecular weight (average): 8142.0177 g / mol Mass of a single isotope: 8137.2288 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1629.33 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [Compound]

[0509] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELH-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LATLPRTETGSGSP-acetylamine C372 H604 N98 O124 Calculated molecular weight (average): 8433.3584 g / mol Mass of a single isotope: 8428.3970 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1687.55 (richest) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHKLATLPRTETGSGSP has SEQ ID NO: 218. [Compound]

[0511] H-Aib-EGTFTSDVSRYLEEQAAREFIEWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C358 H576 N98 O118 Calculated molecular weight (average): 8140.9898 g / mol Mass of a single isotope: 8136.2084 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1629.34 (most abundant) The amino acid sequence HXEGTFTSDVSRYLEEQAAREFIEWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 219. [Compound]

[0512] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C349 H561 N93 O115 Calculated molecular weight (average): 7899.7427 g / mol Mass of a single isotope: 7895.0909 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1580.31 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 154. [Compound]

[0516] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C374 H606 N98 O125 Calculated molecular weight (average): 8475.3950 g / mol Mass of a single isotope: 8470.4075 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1694.99 (single isotope) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 220. [Compound]

[0518] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C352 H565 N95 O116 Calculated molecular weight (average): 7983.8194 g / mol Mass of a single isotope: 7979.1232 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1597.7 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 221. [Compound]

[0528] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C377 H610 N98 O127 Calculated molecular weight (average): 8547.4577 g / mol Mass of a single isotope: 8542.4287 g / mol LCMS34: Experimental value (M + 5H)5 + 1710.41 (richest) The amino acid sequence HXEGTFTSDVSKYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 222. [Compound]

[0529] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C366 H586 N100 O122 Calculated molecular weight (average): 8339.1658 g / mol Mass of a single isotope: 8334.2724 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1668.7 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPKGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 137. [Compound]

[0539] H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C374 H599 N101 O123 Calculated molecular weight (average): 8478.3608 g / mol Mass of a single isotope: 8473.3721 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1696.5011 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPKGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 137. [Compound]

[0552] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C351 H566 N96 O117 Calculated molecular weight (average): 8002.8227 g / mol Mass of a single isotope: 7998.1291 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1600.55 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [Compound]

[0560] HGEGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C324 H517 N87 O110 Calculated molecular weight (average): 7391.0887 g / mol Mass of a single isotope: 7386.7536 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1478.31 (single isotope) The amino acid sequence HGEGTFTSDVSSYLEGQAAKEFIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 223. [Compound]

[0561] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C350 H563 N95 O115 Calculated molecular weight (average): 7941.7827 g / mol Mass of a single isotope: 7937.1127 g / mol LCMS01: Experimental value (M + 5H)⁵ + 1589.3 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 224. [ ] [Compound]

[0562] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C342 H550 N94 O114 Calculated molecular weight (average): 7802.5878 g / mol Mass of a single isotope: 7798.0130 g / mol LCMS01: Experimental value (M + 5H)5 + 1561.5 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 224. [ ] [Compound]

[0564] H-Aib-EGTFTSDVS-K([2-[2-[2-[[(2S)-2,6-bis[[2-[2-[2-[[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecaylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C385 H624 N100 O131 Calculated molecular weight (average): 8749.6655 g / mol Mass of a single isotope: 8744.5240 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1749.8 (single isotope) The amino acid sequence HXEGTFTSDVSKYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 221. [ ] [Compound]

[0565] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C344 H552 N94 O115 Calculated molecular weight (average): 7844.6245 g / mol Mass of a single isotope: 7840.0235 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1568.89 (single isotope) The amino acid sequence HXEGTFTSDVSKYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 221. [ ] [Compound]

[0575] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRQEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C379 H614 N100 O127 Calculated molecular weight (average): 8603.5243 g / mol Mass of a single isotope: 8598.4661 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1721.5 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIAWLVRGRQEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 225. [ ] [Compound]

[0576] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C378 H611 N99 O128 Calculated molecular weight (average): 8590.4824 g / mol Mass of a single isotope: 8585.4345 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1719.1 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 226. [ ] [Compound]

[0577] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C368 H596 N94 O123 Calculated molecular weight (average): 8305.2258 g / mol Mass of a single isotope: 8300.3272 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1661.9 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 227. [ ] [Compound]

[0578] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRQEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C369 H599 N95 O122 Calculated molecular weight (average): 8318.2677 g / mol Mass of a single isotope: 8313.3588 g / mol LCMS34: Experimental value (M + 5H)5+ 1664.5 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIAWLVRGRQEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 228. [ ] [Compound]

[0580] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGGASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C323 H519 N85 O106 Calculated molecular weight (average): 7289.0829 g / mol Mass of a single isotope: 7284.7834 g / mol LCMS01: Experimental value (M + 5H)⁵ + 1458.76 (most abundant) The amino acid sequence H-Aib-EGTFTSDVSSYLEEQAARKFIAWLVRGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 229. [ ] [Compound]

[0581] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C323 H518 N84 O107 Calculated molecular weight (average): 7290.0676 g / mol Mass of a single isotope: 7285.7674 g / mol LCMS01: Experimental value (M + 5H)5+ 1458.96 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 230. [ ] [Compound]

[0629] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C366 H591 N91 O123 Calculated molecular weight (average): 8234.1446 g / mol Mass of a single isotope: 8229.2788 g / mol LCMS01: Experimental value (M + 5H)⁵ + 1647.55 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 231. [ ] [Compound]

[0630] H-Aib-EGTFTSDVS-K(6-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]butyryl]amino]hexyl)-YLEEQAAR-K(6-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanylamino)butyryl]amino]butyryl]amino]hexyl)-FIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C364 H583 N91 O119 Calculated molecular weight (average): 8138.0621 g / mol Mass of a single isotope: 8133.2365 g / mol LCMS01: Experimental value (M + 5H)⁵ + 1628.55 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 231. [ ] [Compound]

[0631] H-Aib-EGTFTSDVS-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecaylamino)butyryl]amino]butyryl]amino]butyryl]amino]butyryl])-YLEEQAAR-K([(4S)-4- Carboxyl-4-[[(4S)-4-carboxyl-4-[[(4S)-4-carboxyl-4-[[(4S)-4-carboxyl-4-(15-carboxypentadecaylamino)butyryl]amino]butyryl]amino]butyryl]amino]butyryl])-FIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C372 H589 N93 O129 Calculated molecular weight (average): 8428.2028 g / mol Mass of a single isotope: 8423.2388 g / mol LCMS34: Experimental value (M + 5H)5 + 1686.7 (richest) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 231. [ ] [Compound]

[0632] H-Aib-EGTFTSDVS-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]butyryl]amino]butyryl]amino]butyryl])-YLEEQAAREFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C339 H536 N88 O116 Calculated molecular weight (average): 7700.4031 g / mol Mass of a single isotope: 7695.8748 g / mol LCMS34: Experimental value (M + 5H)5+ 1541.1 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAAREFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 232. [ ] [Compound]

[0633] H-Aib-EGTFTSDVSSYLEEQAAR-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]butyryl]amino]butyryl]amino]butyryl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C345 H549 N95 O117 Calculated molecular weight (average): 7899.6169 g / mol Mass of a single isotope: 7894.9930 g / mol LCMS34: Experimental value (M + 5H)5+ 1580.9 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 224. [ ] [Compound]

[0634] H-Aib-EGTFTSDVS-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecaylamino)butyryl]amino]butyryl]amino]butyryl]amino]butyryl])-YLEEQAAR-K([(4S)-4- Carboxyl-4-[[(4S)-4-carboxyl-4-[[(4S)-4-carboxyl-4-[[(4S)-4-carboxyl-4-(15-carboxypentadecaylamino)butyryl]amino]butyryl]amino]butyryl]amino]butyryl])-FIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C372 H592 N96 O127 Calculated molecular weight (average): 8441.2479 g / mol Mass of a single isotope: 8436.2817 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1689.1 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 233. [ ] [Compound]

[0635] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxytridecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4R)-4-carboxy-4-(13-carboxytridecylamino)butyryl]amine) [4S]-4-carboxy-4-(13-carboxy-tetrazylamino)butyryl]amino]ethoxy]ethoxy]aceryl]amino]amino]ethoxy]ethoxy]aceryl]aceryl]ethoxy]ethoxy]aceryl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C401 H654 N100 O135 Calculated molecular weight (average): 9036.0725 g / mol Mass of a single isotope: 9030.7384 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1807.05 (single isotope) The amino acid sequence HXEGTFTSDVSKYLEEQAARKFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 234. [ ] [Compound]

[0636] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]butyryl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRQEAASELSTAALGRLSAELHQLATLPRTETGSGSP-acetylamine C352 H565 N95 O119 Calculated molecular weight (average): 8031.8176 g / mol Mass of a single isotope: 8027.1080 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1606.3 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIEWLVRGRQEAASELSTAALGRLSAELHQLATLPRTETGSGSP has SEQ ID NO: 235. [ ] [Compound]

[0637] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGSGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C352 H564 N98 O121 Calculated molecular weight (average): 8104.8286 g / mol Mass of a single isotope: 8100.0992 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1621.8 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGSGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 236. [ ] [Compound]

[0638] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGSGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C354 H568 N98 O121 Calculated molecular weight (average): 8132.8817 g / mol Mass of a single isotope: 8128.1305 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1627.5 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGSGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 236. [ ] [Compound]

[0639] H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C340 H546 N94 O114 Calculated molecular weight (average): 7774.5346 g / mol Mass of a single isotope: 7769.9817 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1556.0 (most abundant) The amino acid sequence HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 224. [ ] [Compound]

[0640] H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C342 H548 N94 O115 Calculated molecular weight (average): 7816.5713 g / mol Mass of a single isotope: 7811.9922 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1564.3 (most abundant) The amino acid sequence HXEGTFTSDVSKYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 221. [ ] [Compound]

[0648] HWEGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C350 H553 N95 O116 Calculated molecular weight (average): 7947.7027 g / mol Mass of a single isotope: 7943.0293 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1590.5 (most abundant) The amino acid sequence HWEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 185. [ ] [Compound]

[0654] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(16-sulfonic acid-hexadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C341 H548 N94 O117 S Calculated molecular weight (average): 7868.6244 g / mol Mass of a single isotope: 7863.9541 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1573.79 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0655] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[17-(1H-tetrazol-5-yl)heptadecylamino]butyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C343 H550 N98 O114 Calculated molecular weight (average): 7870.6253 g / mol Mass of a single isotope: 7866.0253 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1574.2 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0656] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]hexyryl]amino]hexyryl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C343 H552 N96 O112 Calculated molecular weight (average): 7812.6290 g / mol Mass of a single isotope: 7808.0449 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1562.61 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0657] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]hexyl]amino]hexyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C345 H556 N96 O112 Calculated molecular weight (average): 7840.6821 g / mol Mass of a single isotope: 7836.0762 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1568.21 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0658] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(6-[6-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]hexyrylamino]hexyryl)-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C343 H550 N94 O112 Calculated molecular weight (average): 7782.5997 g / mol Mass of a single isotope: 7778.0231 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1556.6 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0659] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(6-[6-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]hexyrylamino]hexyryl)-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C345 H554 N94 O112 Calculated molecular weight (average): 7810.6529 g / mol Mass of a single isotope: 7806.0544 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1562.21 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0660] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C337 H539 N93 O113 Calculated molecular weight (average): 7701.4409 g / mol Mass of a single isotope: 7696.9289 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1540.38 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0661] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C349 H561 N95 O119 Calculated molecular weight (average): 7991.7537 g / mol Mass of a single isotope: 7987.0767 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1598.41 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0662] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]aceryl]amino]ethoxy]ethoxy]aceryl]amino]ethoxy]ethoxy]aceryl]amino]ethoxy]ethoxy]aceryl]amino]ethoxy]ethoxy]aceryl]ethoxy]ethoxy]aceryl]ethoxy]ethoxy]aceryl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C355 H572 N96 O122 Calculated molecular weight (average): 8136.9102 g / mol Mass of a single isotope: 8132.1506 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1627.42 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Compound]

[0663] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyryl]amino]ethoxy]ethoxy]aceryl]amino]ethoxy]ethoxy]aceryl]amino]ethoxy]ethoxy]aceryl]amino]ethoxy]ethoxy]aceryl]amino]ethoxy]ethoxy]aceryl]ethoxy]ethoxy]aceryl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetamide C357 H576 N96 O122 Calculated molecular weight (average): 8164.9633 g / mol Mass of a single isotope: 8160.1819 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1633.03 (single isotope) The amino acid sequence HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. [ ] [Example] [1b] [Compare compounds] [ ] [Compare compounds]

[0164] H-Aib-EGTFTSDVSSYLEGQAAKEIFAWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C342 H552 N92 O113 Calculated molecular weight (average): 7760.5909 g / mol Mass of a single isotope: 7756.0276 g / mol LCMS34: Experimental value (M + 5H)5+ 1553.02 (most abundant). [Compound]

[0185] H-Aib-EGTFTSDVSSYLEGQAAKEFIAWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexyl])-GGEASELSTAALGRPSAELHELATLPRTETGSGSP-acetylamine C341 H548 N92 O113 Calculated molecular weight (average): 7744.5484 g / mol Mass of a single isotope: 7739.9963 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1549.81 (most abundant) [Compare compounds]

[0015] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEPCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-acetyl C384 H596 N106 O124 S2 Calculated molecular weight (average): 8745.6068 g / mol Mass of a single isotope: 8740.3031 g / mol LCMS_ZQ: Experimental value (M + 5H)5+ 1749.9 (most abundant) [Compare compounds]

[0016] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyhepta-amino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-CNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-acetyl C425 H669 N111 O137 S2 Calculated molecular weight (average): 9589.6509 g / mol Mass of a single isotope: 9583.8236 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1918.9 (most abundant) [Compare compounds]

[0668] H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxy-heptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEP-K([(4S)-4-carboxy-4-[(4S)-4-carboxy-4-(15-carboxy-pentadecaylamino)butyryl]amino]butyryl])-CNTATCATQRLADFLRHSSPNFGAIPSSTNVGSRTY-acetylamine C419 H655 N111 O135 S2 Calculated molecular weight (average): 9471.4767 g / mol Mass of a single isotope: 9465.7242 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1895.2 (most abundant) [Compare compounds]

[0671] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl])-GGGGEKCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-acetylamine C378 H588 N104 O120 S2 Calculated molecular weight (average): 8573.4681 g / mol Mass of a single isotope: 8568.2547 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1715.4 (most abundant) [Compare compounds]

[0672] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptaacetylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEKCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-acetyl C376 H590 N106 O120 S2 Calculated molecular weight (average): 8579.4760 g / mol Mass of a single isotope: 8574.2765 g / mol LCMS_ZQ: Experimental value (M + 5H)5 + 1716.8 (most abundant) [Compare compounds]

[0167] H-Aib-EGTFTSDVSSYLEEQAAREIFAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine C353 H567 N95 O117 Calculated molecular weight (average): 8013.8454 g / mol Mass of a single isotope: 8009.1338 g / mol LCMS34: Experimental value (M + 5H)⁵⁺ 1603.63 (most abundant) [Compare compounds]

[0192] H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanylamino)methyl]cyclohexylcarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRPSAELHELATLPRTETGSGSP-acetylamine C352 H563 N95 O117 Calculated molecular weight (average): 7997.8029 g / mol Mass of a single isotope: 7993.1025 g / mol LCMS34: Experimental value (M + 5H)⁵ + 1600.63 (most abundant) [Example] [1c] [Amyloid receptor agonists] [Compound]

[1806] EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C141 H236 N42 O52 Calculated molecular weight (average): 3351.6327 g / mol Mass of a single isotope: 3349.7114 g / mol LCMS_ZQ: Experimental value (M + 3H)³ + 1118.4 (most abundant) [ ] [Example] [2] [Compound for] [GLP-1] [and the potency of amyloid receptors] [ ]

[0424] The potency of these compounds was tested as described in methods 1 and 2. [ Determination method ] [ 1 ] [ Humans ] [ GLP-1 ] [ In vitro titer determination of receptor ] [ ]

[0425] To determine the ability of these compounds to activate and enhance the GLP-1 receptor (GLP-1R), in vitro potency assays were performed in cells expressing the human GLP-1 receptor, as described below. [Measurement Principle] [ ]

[0426] Activation of the GLP-1 receptor leads to an increase in cyclic adenosine monophosphate (cAMP) concentration in cells. Transcription is then initiated by a promoter containing multiple copies of the cAMP response element (CRE). Therefore, GLP-1 receptor activity can be measured by introducing a CRE-luciferase reporter gene into young hamster kidney (BHK) cells that co-express the GLP-1 receptor. [Cells and assay reagents] [ ]

[0427] Stable transfected cell lines expressing the human GLP-1 receptor and the CRE-Luc reporter gene (BHK 467-12A KZ-10, prepared according to methods known to those skilled in the art) were cultured in DMEM (Gibco, 61965-026) to prepare cell stock solutions. The DMEM was supplemented with 10% FBS (Gibco, 16140-071), 1% Pen / Strep (Gibco, 15140-122), 1 mM Na-pyruvate (Gibco, 11360-039), 1 mg / mL G418 (Gibco, 10131-027), and 240 nM MTX (Pfizer, 15936). Wash approximately 80-90% confluenced cells once with PBS and loosen them from the cell culture flask using Versene (Gibco, 15040-033). After centrifugation, lyse the cell clumps and dilute them at 1.5 x 10⁶ cells per mL in DMEM medium (Gibco, 61965-026), supplemented with 20% FBS (Gibco, 16140-071), 1% Pen / Strep (Gibco, 15140-122), 1 mM Na-Pyrovate (Gibco, 11360-039), 1 mg / mL G418 (Gibco, 10131-027), 240 nM MTX (Pfizer, 15936), and 10% DMSO (Sigma, D2650). Aliquot the cells and store at -180°C until use.

[0428] The assay buffer consisted of DMEM without phenol red (Gibco, 11880-028), supplemented with 1X GlutaMAX (Gibco, 35050-038), 10 mM HEPES (Gibco, 15630-056), 1% (w / v) ovalbumin (Sigma, A5503), and 0.1% (v / v) Pluronic F-68 (Gibco, 24040-032). [process] [ ]

[0429] To perform this assay, the comparative compound and GLP-1 receptor-amyloid receptor co-activator were serially diluted (10-fold dilution, 8 concentrations per compound) in HAS-free assay buffer in 96-well plates, typically starting at approximately 100–200 nM. GLP-1R / CRE-Luc cell stock was thawed in a 37°C water bath, washed once with PBS, and diluted in assay buffer to 100,000 cells per mL. At each dilution, 50 µL aliquots of the comparative compound or GLP-1 receptor-amyloid receptor co-activator were transferred to 96-well assay plates (ThermoFisher, 237105) containing 50 µL of cell suspension (5,000 cells per well). The assay plates were incubated at 37°C in 5% CO2 for 3 hours, followed by the addition of 100 µL of SteadyLite Plus (PerkinElmer, 6066759) to each well, and then incubated at room temperature for 5 minutes. Seal the disc and incubate at room temperature for 30 minutes with gentle shaking, while protecting from light. Detect fluorescence on a fluorescent optical disc reader (e.g., Synergy 2 (BioTek)). Calculate the EC50 value [pM] using GraphPad Prism or by applying a four-parameter logic mode (Hill slope = 1) with nonlinear curve fitting via TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA). [ Determination method ] [ 2 ] [ In vitro titer determination of human amyloid receptor ]

[0430] To determine the ability of these compounds to activate and enhance the effects of amyloid receptors, in vitro potency assays can be performed in cells expressing human amyloid receptor (hAmyR3), as described below. [Measurement Principle] [ ]

[0431] Activation of hAmyR3 leads to an increase in cAMP concentration in cells. Therefore, transcription is initiated by a promoter containing multiple copies of the cAMP response element (CRE). Thus, hAmyR3 activity can be measured by introducing a CRE-luciferase reporter gene into young hamster kidney (BHK) cells that co-express hAmyR3. [Cells and assay reagents]

[0432] BHK cell lines were stably transfected with the human calcitonin receptor (a) and CRE-reactive luciferase (CRE-Luc) reporter gene (Hollex-1 cell line, obtained from Zymogentics, as described in U.S. Patent No. 5,622,839) using methods known to those skilled in the art. The cell lines were then further transfected with human receptor-modified protein 3 (RAMP3) using standard methods. This converted the human calcitonin receptor to the human amyloid-3(a) receptor.

[0433] Stable transfected BHK hAmyR3 / CRE-Luc cells were cultured in DMEM (Gibco, 31966-021) medium supplemented with 10% FBS (Gibco, 1640-071), 1% Pen / Strep (Gibco, 15140-122), 0.5 mg / mL Geneticin (Gibco, 10131-027), 0.4 mg / mL Hygromycin (Invitrogen, 1068701), and 250 nM Methotrexate (Sigma, A6770). Approximately 80-90% confluence of cells was washed once with PBS and released from the cell flask using Versene (Gibco, 15040-033). After centrifugation, the cell clusters were lysed and diluted at 2.5 x 10⁶ cells per mL in Recovery™ Cell Culture Freezing Medium (Gibco, 12648-010). The cells were aliquoted and stored at -180°C until use.

[0434] The assay buffer consisted of DMEM without phenol red (Gibco, 11880-028), supplemented with 1X GlutaMAX (Gibco, 35050-038), 10 mM HEPES (Gibco, 15630-056), and 0.1% (w / v) ovalbumin (Sigma, A5503). [process] [ ]

[0435] To perform this assay, BHK hAmyR3 / CRE-Luc cells were thawed, washed once with PBS, and seeded at a density of 4,000 cells per well in white 384-well culture dishes (PerkinElmer, 6007688) containing 40 µL of growth medium the day before the experiment. The dishes were incubated overnight at 37°C in 5% CO2. On the day of the assay, the cells were washed three times with assay buffer. The comparative compound and the GLP-1 receptor-amyloid receptor co-activator were serially diluted in assay buffer in 96-well dishes (7-fold dilution, 7 concentrations of each compound, with one well containing only assay buffer), typically starting at approximately 10–100 nM, and each concentration was added in 30 µL to the 384-well assay dish containing cells. After adding 30 µL of SteadyLite Plus (PerkinElmer, 6066759) to each well, the assay dish was incubated at 37°C in 5% CO2 for 3 hours. The test discs were sealed and incubated at room temperature for 5 minutes with gentle shaking while protected from light, followed by 30 minutes without shaking. Fluorescence was detected on a fluorescent optical disc reader (e.g., Synergy 2 (BioTek)). EC50 values ​​[pM] were calculated using GraphPad Prism or with the aid of TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA) using a four-parameter logic model with nonlinear curve fitting (Hill slope = 1.5, sharing the bottom reaction in each disc). [Example] [2a] [:] [GLP-1] [Receptor] [-] [Amyloid receptor co-activators for] [GLP-1] [and the potency of amyloid receptors] [ ]

[0436] The potency of these compounds was tested as described in methods 1 and 2. The results are provided in Table 4a. Detailed information about the compounds, such as IUPAC nomenclature, can be found in Example 1 and the sequence listing. [surface] [4a] [:] [GLP-1] [Receptor] [-] [Amyloid receptor co-activators in vitro in humans] [AmyR3] [and] [GLP-1R] [Its valence.] [Compound Number] [Human] [GLP-1R] [Valence] [[EC50 (pM)]] [Human] [AmyR3] [Valence] [[EC50 (pM)]] 0007 13.3 9.4 0009 7.9 49.5 0010 5.4 37.0 0019 13.7 26.5 0026 8.8 14.0 0035 16.7 16.0 0039 34.8 59.5 0040 20.7 7.7 0042 16.2 10.8 0044 16.0 9.1 0045 19.4 25.9 0051 14.3 19.5 0052 17.0 19.4 0056 41.4 120.0 0057 59.0 164.8 0071 69.4 158.9 0072 55.9 95.1 0073 1.6 34.7 0074 0.8 60.9 0075 84.5 43.9 0076 1.7 46.4 0077 2.1 25.7 0083 5.4 46.2 0084 2.5 14.0 0085 2.2 55.8 0086 3.9 78.3 0087 23.8 97.9 0089 5.7 65.5 0090 32.6 70.9 0092 18.5 10.9 0093 7.5 8.6 0094 7.5 11.3 0095 7.4 6.6 0097 10.0 93.1 0098 7.9 15.6 0099 9.6 44.9 0100 6.8 30.4 0101 7.1 10.2 0102 14.7 9.8 0103 28.1 11.6 0105 1.1 30.8 0106 5.5 28.4 0109 3.2 19.1 0110 2.7 40.7 0111 3.0 11.5 0114 1.0 17.5 0115 2.2 22.8 0116 1.5 21.7 0120 9.1 10.6 0124 27.9 24.4 0125 8.0 12.2 0127 7.1 63.9 0128 9.7 110.3 0129 1.2 23.5 0131 16.1 14.5 0132 3.0 34.9 0141 43.3 13.2 0142 88.2 15.4 0144 7.1 16.8 0145 11.9 16.5 0146 25.7 14.0 0147 36.8 33.7 0151 10.4 9.5 0156 22.6 22.6 0157 28.7 18.4 0159 30.3 19.3 0160 11.9 27.3 0179 8.8 35.9 0180 6.4 37.0 0191 5.9 54.8 0202 10.5 28.4 0231 5.6 68.0 0232 6.4 74.2 0233 46.4 182.5 0234 38.9 38.4 0235 10.4 24.0 0254 8.9 7.7 0255 2.5 28.6 0259 15.8 12.0 0260 11.9 41.8 0261 17.4 23.9 0263 13.8 25.2 0264 6.5 11.7 0265 6.0 8.1 0266 6.3 8.5 0267 28.5 45.3 0268 26.4 14.4 0269 7.7 7.5 0270 6.3 8.6 0271 4.6 15.2 0272 9.2 11.3 0273 24.9 18.0 0280 34.3 18.0 0281 35.2 114.5 0284 41.7 32.8 0285 19.0 78.9 0292 12.0 33.8 0294 13.7 34.3 0295 4.8 32.7 0296 4.0 29.9 0297 30.2 46.0 0299 6.0 11.5 0396 4.8 32.8 0397 3.8 18.5 0411 3.5 45.9 0414 11.2 17.7 0415 10.3 16.1 0416 104.6 18.3 0417 97.8 21.0 0431 10.9 11.9 0433 30.7 12.9 0434 11.8 13.9 0435 92.4 22.3 0436 15.2 12.3 0437 12.0 11.8 0438 11.8 27.5 0439 8.3 10.7 0440 5.7 10.4 0472 2.8 24.0 0473 3.1 16.2 0474 2.9 21.8 0475 70.4 66.8 0482 36.5 31.8 0483 33.7 36.8 0484 72.8 32.5 0502 8.4 9.0 0503 6.5 7.7 0504 8.3 6.0 0506 5.8 9.8 0509 7.1 29.9 0511 8.8 8.4 0512 7.6 10.8 0516 3.3 8.9 0518 3.4 4.4 0528 3.8 22.0 0529 6.4 14.1 0539 5.0 12.1 0552 4.7 6.9 0561 17.5 10.7 0562 19.3 4.1 0564 24.5 14.5 0565 6.4 6.2 0575 5.6 8.3 0576 2.9 10.1 0577 5.6 19.1 0578 2.5 26.9 0580 7.4 9.3 0581 17.0 26.4 0629 7.9 97.5 0630 7.1 109.7 0632 18.8 148.4 0633 28.2 5.3 0634 14.7 59.4 0635 7.3 78.9 0636 10.8 8.5 0637 1.9 14.1 0638 4.6 6.9 0639 1.5 4.6 0640 2.3 6.0 0648 17.0 9.2 0654 2.9 11.3 0655 3.0 11.4 0656 4.1 13.3 0657 9.9 10.4 0658 3.1 11.0 0659 4.7 11.5 0660 3.9 12.7 0661 2.8 14.4 0662 3.0 14.6 0663 3.2 12.6 [Example] [2b] [Compounds and comparative compounds for] [GLP-1] [and the potency of amyloid receptors] [ ]

[0437] The potency of the compound of the present invention (compound 0111) against the GLP-1 receptor (GLP-1R) and amyloid receptor (AmyR3) was compared with the potency of its derived GLP-1 receptor agonists and amyloid receptor agonists, and with the potency of comparative compounds. The results are provided in Table 4b. Detailed information about the compounds, such as IUPAC nomenclature, can be found in Example 1 and the sequence listing. Table 4b: In vitro potency of reference and comparative compounds against human AmyR3 and GLP-1R. [Compound number or] [INN] [name] [describe] [Human] [GLP-1R] [Valence] [[EC50 (pM)]] [Human] [AmyR3] [Valence] [[EC50 (pM)]] Semaglutide The active pharmaceutical ingredient (GLP-1 receptor agonist) in Ozempic®, Rybelsus®, and Wegovy®. 5.5 - Cagrilintide Amyloid receptor (RA) agonists under development. - 11 Pramlintide The active pharmaceutical ingredient (amylase RA) in Symlin®. - 7.8 1806 Amyloid RA without disulfide. Receptor agonist; amino acid sequence of amyloid RA in compound 0111. - 5.0 0672 Comparative compounds derived from semaglutide and caglinide. 2.2 606 0671 Comparative compounds derived from semaglutide and pramlinin. 4.5 230 0111 Compounds derived from semaglutide and compound 1806. 3.0 11.5

[0438] The amino acid sequence of GLP-1 RA in compound 0672 is similar to that in semaglutide, and is linked via a short peptide linker to an amyloid RA with the same amino acid sequence as in caglionepeptide. In semaglutide, relative to SEQ ID NO: 1 or SEQ ID NO: 238, it contains lysine (Lys20) at position 20 and glycine (Gly31) at position 31, with an extension at Lys20. Similarly, the GLP-1 RA, similar to semaglutide, includes arginine (Arg20) at position 20 and lysine (Lys31) at position 31, with an extension at Lys31.

[0439] Comparative compound 0671 includes the same GLP-1 RA as in comparative compound 0672, which is linked via a short peptide linker to the same amyloid RA as the amino acid sequence in pramlin peptide.

[0440] Compound 0111 includes the same GLP-1 peptide sequence used in compounds 0672 and 0671, which is linked via a short peptide linker to an amino acid sequence identical to that of amyloid RA in compound 1806. [Example] [2c] [Compounds and comparative compounds for] [GLP-1] [and the potency of amyloid receptors]

[0441] The potency of two compounds (compound 0045 and compound 0120) according to the present invention against the GLP-1 receptor (GLP-1R) and amyloid receptor (AmyR3) was compared with that of a comparative compound having selected mutations in the GLP-1 or amyloid moiety.

[0442] Comparative compounds 0164 and 0167 are identical to compounds 0045 and 0120, respectively, except that their GLP-1 moiety includes two sequence mutations relative to SEQ ID NO: 1 and 238: Phe22Ile and Ile23Phe.

[0443] Comparative compounds 0185 and 0192 are identical to compounds 0045 and 0120, respectively, except that their amyloid moiety includes a single mutation in the peptide backbone corresponding to SEQ ID NO: 79, SEQ ID NO: 240, or SEQ ID NO: 256: Leu12Pro.

[0444] Comparative compounds 0015, 0016, and 0668 are other examples of compounds that include GLP-1 receptor agonists similar to semaglutide (as detailed in Example 2b) and amyloid receptor agonists having the amino acid sequence of caglinide (compounds 0015 and 0016) or an extended amyloid receptor agonist (compound 0668).

[0445] The results are provided in Table 4c. Detailed information about the compounds, such as IUPAC nomenclature, can be found in Example 1 and the sequence listing. Table 4c: The in vitro potency of other comparative compounds against human AmyR3 and GLP-1R. [Name or Comparative Compound Number] [Special Features] [Human] [GLP-1R] [Valence] [[EC50 (pM)]] [Human] [AmyR3] [Valence] [[EC50 (pM)]] Semaglutide 5.5 - Human GLP-1 10.8 - Cagrilintide - 11.0 Pramlintide - 7.8 Salmon Calcitonin - 3.5 0164 Comparative compounds to compound 0045, which exhibit a weakening titer in GLP-1 receptor agonists. 852.0 29.6 0167 Comparative compounds to compound 0120, which exhibit a weakening titer in GLP-1 receptor agonists. 10000.0 10.9 0185 Comparative compounds to compound 0045, which exhibit a weakening effect on amyloid receptor agonists. 13.1 5659.0 0192 Comparative compounds to compound 0120 that exhibit a weakening effect on amyloid receptor agonists 10.8 10000 0015 Compounds including GLP-1 RA, which is similar to semaglutide, the amino acid sequence of caglinide, and a single extended moiety. 45.0 312.0 0016 This includes compounds containing GLP-1 RA, which is similar to semaglutide, the amino acid sequence of caglinide, and two extended moieties. 509.5 1550.0 0668 This includes compounds such as GLP-1 RA, which is similar to semaglutide, and acetylated amyloid agonists. 455.0 10000.0 [result] [ ]

[0446] The data in Table 4a show that all the tested compounds can promote the activity of human AmyR3 and GLP-1R, meaning they are GLP-1 receptor-amyloid receptor co-activators. All compounds listed in Table 4a are compounds according to the present invention.

[0447] In contrast, the data in Table 4b show that linking the C-terminus of an effective GLP-1 receptor agonist (similar to semaglutide) to the N-terminus of an effective amyloid receptor agonist (caglinide or pramlinide) via a peptide linker does not result in the compound being equally effective for both receptors and necessarily acting as a GLP-1 receptor-amyloid receptor co-agonist (i.e., the compound according to the invention). This is illustrated by comparing compounds 0672 and 0671 with compound 0111: compounds 0672 and 0671 retain their potency for the GLP-1 receptor but their potency for the amyloid receptor is impaired. Only compound 0111 retains full potency for both receptors and has similar potency to both GLP-1 and amyloid receptors as semaglutide and caglinide. Compound 0111 is considered a "balanced" compound.

[0448] The data in Table 4c show that the comparative compounds exhibited impaired ability to activate GLP-1 or amyloid receptors. Mutations in Phe22Ile and Ile23Phe in comparative compounds 0164 and 0167 weakened their ability to activate GLP-1 receptors. Mutations in comparative compounds 0185 and 0192 weakened their ability to activate amyloid receptors. This impaired ability is further illustrated by data provided in Table 6b. Other data in Table 4c highlight the challenges of linking GLP-1 receptor activators to amyloid receptor activators. Comparative compound 0015 was found to be a weak activator of the amyloid receptor. Compounds 0016 and 0668 did not activate the amyloid receptor. [Example] [3] [Preparation of tablets for pharmacokinetic studies in Beagle dogs] [ ]

[0449] To assess oral exposure after administration of tablets, a tablet composition comprising the test substance and SNAC (N-(8-(2-hydroxybenzoyl)amino)octanoate sodium) is prepared by mixing the test substance with rolled SNAC and magnesium stearate, as described in, for example, WO 2019 / 149880. The tablet composition contains 100-300 mg of SNAC, 7.7 mg of magnesium stearate, and a target concentration of 3-4 mg of each test substance. [Example] [4] Pharmacokinetic studies conducted in Beagle dogs [ ]

[0450] Pharmacokinetic (PK) studies were conducted in Beagle dogs to determine GLP-1 receptor-amyloid receptor co-activators exposure following oral administration.

[0451] For pharmacokinetic studies, male Beagles aged 2 to 7 years or 1 to 5 years, weighing approximately 10 to 15 kg (e.g., 10 to 12 kg) at the start of the study, were used. Dogs were grouped and housed in enclosures (12 hours light: 12 hours darkness) and fed individually and restrictively once daily with Royal Canin Medium Adult dog food (Royal Canin Products, China Branch or Brogaarden A / S, Denmark). Daily exercise and group socialization were permitted when possible. Dogs were used in repeated pharmacokinetic studies with appropriate clearance periods between consecutive administrations. An appropriate acclimatization period was given before starting the first pharmacokinetic study. All animal treatments, administration, and blood sampling were performed by trained technicians. Dogs were fasted overnight prior to the study and for 0 to 4 hours after administration. Additionally, water intake was restricted for 1 hour before administration until 4 hours after administration, but allowed free access to water throughout the entire study period.

[0452] The tablets used in the oral studies described herein are immediate-release SNAC tablets administered orally.

[0453] Administer the tablets as follows: Ten minutes before administration, administer the tablets subcutaneously to the dog at a dose of approximately 3 nmol / kg according to SEQ ID NO: 237. Place the tablet at the back of the dog's mouth to prevent chewing. Then close the mouth and administer 10 mL of tap water via syringe or tube to facilitate swallowing. [Blood sampling, analysis, and pharmacokinetic calculations] [ ]

[0454] Blood samples were taken at predetermined time points up to 240 hours after drug administration (e.g., up to 10 hours) to fully cover the complete plasma concentration-time absorption curve of the GLP-1 agonist.

[0455] At each blood sampling time point, collect approximately 0.8 mL of whole blood into a 1.5 mL EDTA-coated tube, and gently rotate the tube to mix the sample with the EDTA. Collect the blood sample (e.g., 0.8 mL) in EDTA buffer (8 mM) and then centrifuge at 4°C and 2000G for 10 minutes. Transfer the plasma to a fine tube on dry ice and maintain at -20°C until analysis.

[0456] Blood samples are collected as needed, for example, from the cephalic vein in the foreleg for the first 2 hours, and then from the jugular vein with a syringe at other times (the first few drops are allowed to drain from the venflon to avoid heparinized saline from the venflon in the sample).

[0457] Plasma concentrations of the GLP-1 receptor-amyloid receptor co-activator were determined using LCMS. Individual plasma concentration-time curves were analyzed using non-compartmental models in WinNonlin version 5.0, Phoenix version 6.2 or 6.3 (Pharsight, Mountain View, CA, USA), or other relevant software for PK analysis.

[0458] Individual plasma concentration-time absorption curves were analyzed using non-compartmental data analysis (NCA). The following PK parameters were calculated and reported as shown in Table 5: tmax, Cmax / dose, and t½. Table 5: [Pharmacokinetic parameters after oral administration in dogs] [ ] Detailed information about the compounds, such as IUPAC nomenclature, can be found in Example 1 and the sequence listing. [Compound Number] [Tmax()] [Hour] [)] [Cmax / D (kg / L)] [AUC / D (h*kg / L)] [T½ (hr)] 0045 1.3 0.27 10.90 41 0084 1.5 0.36 15.16 47 0111 1.5 2.0 0.46 0.42 15. 00 17.76 44 42 0120 2.0 2.0 0.24 0.44 7.3 14.45 24 22 0231 1.0 0.27 0.83 6 0232 0.8 0.51 2.00 4 0233 1.5 0.3 8,43 (8,43) 43 0234 1.0 0.35 8.00 31 0235 1.0 0.22 3,3 (2,25) 21 0254 1.8 0.36 19.54 40 0259 1.5 0.48 31.73 97 0265 2.0 0.16 5.68 16 0292 2.0 0.72 65.29 110 0431 1.5 0.29 9.75 34 0436 1.5 0.3 15.00 35 0439 2.0 0.21 5.36 24 0440 1.8 0.29 5.78 32 0502 2.0 2.0 4.0 0.14 0.24 0.33 9.8 13.92 22.46 66 61 74 0503 4.0 0.14 8.72 41 0504 3.0 0.12 3.25 25 0506 2.0 0.14 6.53 23 0511 2.0 0.14 3.80 25 0512 2.0 0.13 3.21 21 0516 2.0 2.0 0.67 0.39 43.92 34.57 99 103 0518 2.0 0.45 11.10 27 0528 1.5 0.5 37.01 107 0529 4.0 0.3 19.71 68 0539 3.0 0.22 8.71 30 0552 1.0 0.22 8.58 52 0575 1.5 0.34 27.60 91 0576 1.3 0.34 28.20 94 0577 1.3 0.45 37.60 93 0578 1.3 0.39 30.60 90 0580 2.0 0.38 12.77 39 0630 1.5 0.53 33.33 73 0640 1.5 0.37 7.57 (11.17) 29

[0459] When plasma concentrations of the compounds were detected after oral administration, all tested compounds showed oral bioavailability in this model (Cmax / D > 0 and AUC / D > 0). Furthermore, the half-lives of these tested compounds were longer (4-110 hours) compared to the half-lives of human GLP-1 and human amyloid (approximately 2-4 minutes and 15-20 minutes, respectively, measured in humans) (Meier et al., Diabetes, 2004, 53(3): 654-662). [Example] [5 –] [Experimental protocol for testing the efficacy of appetite using an arbitrary-fed rat model] [ ]

[0460] Acute feeding experiments were conducted using Sprague Dawley (SD) rats from Taconic Europe, Denmark, while adhering to the principles of laboratory animal care.

[0461] At the start of the experiment, the rats weighed 200-250g. Rats arrived at least 10-14 days prior to the start of the experiment to allow for acclimatization according to the experimental setup. During this period, the animals were treated at least twice. Upon arrival, the rats were immediately placed in a reversed day-night light cycle (dark period from 11 am to 11 pm) and placed in the HM2 system with ID chips. Three rats were housed in each cage. During acclimatization, rats adapted to the new photoperiod and diet (Research diet, LF 10% (D12450B), and these animals had free access to food and water. Since rats typically engage in activity and consume the majority of their daily food intake during darkness, administration was performed in the morning just before the light was turned off. This setup resulted in minimal data variation and the highest test sensitivity. Each dose of the GLP-amyloid receptor co-activator was tested in groups of 5–8 rats each. Each test group included a carrier group of 6–8 rats. Animals in each cage were drawn from three different treatment groups (assuming one cage might malfunction). Rats were administered subcutaneously (sc) once per dose, based on body weight, at a concentration of 0.01–3 mg / kg. The administration time for each group was recorded.

[0462] After administration, the rats were returned to their cages with access to food and water. Food consumption was continuously and individually recorded for 72 hours via online recording (HM2 system). At the end of the experimental period, the animals were euthanized.

[0463] Table 6 shows the acute food intake in lean rats. These results allow for assessment of in vivo potency and provide an indicator of the duration of compound action. Feeding was conducted in rats over a period of up to 48 hours. [surface] [6a] [Pharmacokinetic Screening Model: Single Dosage] [GLP-1-] [Amyloid synergist] [(10 nmol / kg)] [Subsequent acute food intake in rats.] Detailed information about the compounds, such as IUPAC nomenclature, can be found in Example 1 and the sequence listing. Compound numbering (As provided in Example 1) Intake relative to carrier (%) 0-24 hr, 10 nmol / kg Intake relative to carrier (%) 24-48 hr, 10 nmol / kg 0007 67 105 0035 76 95 0042 52 101 0044 40 82 0045 46 80 0052 42 86 0073 47 89 0084 44 50 0095 55 95 0100 85 86 0103 80 80 0111 28 75 0116 83 82 0120 53 55 0131 70 80 0151 29 70 0231 27 76 0232 61 95 0254 71 46 0411 81 88 0434 39 105 0439 43 41 0440 81 77 0502 61 72 0504 73 53 0506 47 44 0511 61 75 0516 87 82 0518 50 45 0552 56 55 0565 39 42 0640 28 66 [surface] [6b] [Pharmacokinetic Screening Models and] [GLP-1-] [Damaged compound]

[0167] [And starch] [-] [Damaged compound]

[0192] [Compared to a single throw] [GLP-1] [Receptor] [-] [Amyloid receptor co-activator] [(] [Compound] [0.120, 10 nmol / kg] [Subsequent acute food intake in rats.] Detailed information about the compounds, such as IUPAC nomenclature, can be found in Example 1 and the sequence listing. Compound or comparative compound number (As provided in Example 1) describe Intake relative to carrier (%) 0-24 hr, 10 nmol / kg Intake relative to carrier (%) 24-48 hr, 10 nmol / kg Carrier - 100 100 0120 GLP-1 receptor-amyloid receptor co-activator 53 55 0167 GLP-1 damaged comparison of compound 0120 85 73 0192 Comparative substances of compound 0120 with impaired amylase 71 67

[0464] After administration of GLP-1 receptor-amyloid receptor co-activators to rats, it was observed that they induced significant food intake inhibition in most rats compared to carrier treatment, as can be inferred from the data shown in Table 6a.

[0465] The data in Table 6b highlight the importance of compounds that can simultaneously activate both GLP-1 and amyloid receptors. Three compounds were compared: a GLP-1 receptor-amyloid receptor co-activator fully effective for both receptors (compound 0120), a comparative compound 0167 with impaired GLP-1 activity but fully effective for amyloid, and a comparative compound 0192 with impaired amyloid activity but fully effective for GLP-1 (see in vitro data in Table 4c). When compound 0120 (10 nmol / kg) was administered to rats, it caused significant feeding inhibition within the first 48 hours. When compound 0167 or compound 0192 (10 nmol / kg) was administered to rats, the feeding inhibition in these two examples was significantly less than in the case of compound 0120. This indicates that both receptor systems are activated by compound 0120 and that it is a "balanced" compound.

[0466] Although certain features of the invention have been described and set forth herein, many modifications, substitutions, variations, and equivalents will be readily apparent to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and variations falling within the true spirit of the invention.

[0467] none

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

Claims

1. Use of a GLP-1 receptor-amyloid receptor co-activator for the manufacture of a pharmaceutical product for treating individuals suffering from: overweight; obesity; diabetes; cardiovascular disease; non-alcoholic steatohepatitis and / or cognitive impairment, wherein the GLP-1 receptor-amyloid receptor co-activator is H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-acetylamine (compound 0111).

2. As requested in item 1, wherein the pharmaceutical product is intended to treat individuals with an initial body mass index (BMI) of 27 or higher.

3. As requested in item 2, wherein the individual suffers from at least one weight-related comorbidity.

4. As requested in item 2, wherein the pharmaceutical product is intended to treat individuals with an initial body mass index (BMI) of 30 or higher.

5. As requested in item 4, wherein the individual suffers from at least one weight-related comorbidity.

6. As requested in claim 1, wherein the medicine is intended to treat an individual suffering from type 2 diabetes.

7. As requested in item 6, wherein the individual suffers from at least one weight-related comorbidity.

Images