Co-agonists of GLP-1 and amylin receptors

Abstract

The present invention relates to compounds comprising a GLP-1 receptor agonist and an amylin receptor agonist. The invention also relates to pharmaceutical formulations suitable for, but not limited to, oral administration, comprising such compounds. The compounds and pharmaceutical formulations comprising the same are useful in the medical treatment of subjects suffering from overweight, obesity and associated co-diseases.

Description

[0001] This application is a divisional application of patent application No. 202180085551.0, filed on December 17, 2021, entitled "Co-agonist of GLP-1 and amyloid receptor". Technical Field

[0002] This invention relates to compounds comprising GLP-1 receptor agonists and amylin receptor agonists. The invention also relates to pharmaceutical formulations suitable for, but not limited to, oral administration, comprising such compounds. These compounds and pharmaceutical formulations comprising them can be used for the medical treatment of subjects suffering from: overweight or obesity with or without related comorbidities; diabetes with or without related comorbidities; cardiovascular disease; non-alcoholic steatohepatitis (NASH); and cognitive impairment, such as cognitive impairment caused by Alzheimer's disease. Background Technology

[0003] Overweight and obesity are abnormal or excessive accumulations of body fat that pose a threat to an individual's overall health. A body mass index (BMI) of over 25 is considered overweight, and 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, as well as cardiovascular diseases such as heart disease and stroke, which are leading causes of death worldwide. Obesity is now considered by the World Health Organization (WHO) to be 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 deaths each year are directly attributable to diabetes. Therefore, there is a tremendous incentive for individuals and society to try to prevent and / or treat obesity.

[0004] When diet and exercise alone are insufficient to reduce the body mass index (BMI) of obese individuals to an acceptable level, treatment with medications such as liraglutide, orlistat, and naltrexone-bupropion has been shown to result in some weight loss. Nevertheless, bariatric surgery has proven necessary in many cases. While bariatric surgery is currently the most effective treatment for achieving long-term weight loss, it is an invasive procedure associated with high risks and costs for patients. Therefore, effective and minimally invasive treatments would represent a significant improvement in the treatment of obesity.

[0005] Amylin is a long polypeptide hormone composed of 37 amino acids, produced in pancreatic beta (β) cells and co-secreted with insulin. The half-life of endogenous amylin is approximately 15–20 minutes. It acts in several different organ systems, primarily through amylin receptors 1–3 (AMYR1–3). Amylin is an important regulator of energy metabolism in both health and disease, inhibiting glucagon secretion, delaying gastric emptying, signaling satiety, and suppressing appetite. Other effects of amylin, such as those on the cardiovascular system and bones, have also been reported.

[0006] Clinical studies have shown that amylin receptor agonists can be used to treat overweight, obesity, type 1 diabetes, and / or type 2 diabetes. Currently, there is a product on the market containing an amylin receptor agonist (pramlintide acetate) as the active pharmaceutical ingredient (Symlin®). Symlin® is a liquid formulation for subcutaneous administration and is approved for patients with type 1 or type 2 diabetes who use basal and prandial insulin and have failed to achieve the desired glycemic control despite optimal insulin therapy. Pramlintide for overweight and obese patients is also under clinical investigation. Pramlintide has a short biological half-life (less than 1 hour) and needs to be administered three times daily. Therefore, there is a significant diurnal variation in pramlintide plasma levels in patients treated with it.

[0007] GLP-1 is a polypeptide hormone composed of 30 or 31 amino acids, synthesized and secreted by enteroendocrine L-cells. GLP-1 is an intestinal glucagon that lowers blood glucose levels in a glucose-dependent manner by enhancing insulin secretion. Endogenous GLP-1 is primarily rapidly degraded by dipeptidyl peptidase-4 (DPP-4), resulting in a half-life of approximately 2 minutes.

[0008] Several marketed products containing GLP-1 receptor agonists as active pharmaceutical ingredients have been approved for use in individuals with type 2 diabetes. These include dulaglutide (Trulicity®), exenatide (Byetta®, Bydureon®), liraglutide (Victoza®), lixisenatide (Lyxumia®), and semaglutide (Ozempic®).

[0009] Smegglutide is the first GLP-1 receptor agonist (Rybelsus®) approved in tablet form. It is safe and effective as a monotherapy and adjunctive therapy for the treatment of type 2 diabetes.

[0010] Two marketed products containing GLP-1 receptor agonists as the active pharmaceutical ingredient are approved for use in individuals who are overweight or obese and have 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. Amylin receptor agonist therapy is limited by tolerability in a substantially similar manner to GLP-1 receptor agonist therapy (and by similar side effects such as nausea and vomiting). There is also a desire to prolong the effects of amylin.

[0011] A fixed-dose combination of the amylin receptor agonist canagliptin and the GLP-1 receptor agonist semaglutide, used to treat overweight and obesity, is currently under investigation (Lancet 2021; 397:1736–48). The investigational drug product is a single liquid formulation for subcutaneous use. A clinical trial demonstrated that the combination of semaglutide and canagliptin induced greater weight loss in obese patients without significantly worsening side effects compared to the maximum approved dose of semaglutide monotherapy.

[0012] While current treatment options and investigational drugs offer hope, individuals suffering from overweight, obesity, and / or related comorbidities can at best rely on treatments with injectable formulations or medications of moderate efficacy. There remains a need in the field for more effective drugs that do not simultaneously cause disproportionately increased levels of side effects and are suitable for oral administration. Summary of the Invention

[0013] This article discloses a GLP-1 receptor-amylin receptor co-agonist comprising a polypeptide (R1) according to Formula I: Z1-Z2-Z3, It contains 1-3 lysine (Lys, K) residues and no disulfide bonds; wherein: • Z1 is a GLP-1 receptor agonist peptide containing 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 or SEQ ID NO: 255. • Z2 is an optional peptide linker; Z3 is an amylin receptor agonist peptide containing a C-terminal amide and up to four amino acid modifications relative to SEQ ID NO: 79, provided that Z3 (relative to SEQ ID NO: 79 or SEQ ID NO: 256) does not contain a proline (Pro, P) at position 12.

[0014] This article discloses a GLP-1 receptor-amylin receptor co-agonist comprising a polypeptide (R1) according to Formula I: Z1-Z2-Z3, It contains 1-3 lysine (Lys, K) residues and no disulfide bonds; in: • Z1 is a GLP-1 receptor agonist peptide containing up to 9 amino acid modifications relative to SEQ ID NO: 1 (human GLP-1(7-37)); • Z2 is an optional peptide linker; Z3 is an amylin receptor agonist peptide containing a C-terminal amide and up to 7 amino acid modifications relative to SEQ ID NO: 79.

[0015] This document discloses the GLP-1 receptor-amylin receptor co-agonist, which further comprises 1-3 elongated portions linked by the 1-3 lysine residues.

[0016] A preferred compound is "compound 0111", that is: H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide (see...) Figure 46 ): This article discloses a GLP-1 receptor-amylin receptor co-agonist for use as a medicine. This article discloses a GLP-1 receptor-amylin receptor co-agonist for the treatment of subjects with the following conditions: an initial body mass index (BMI) of 27 or higher, such as 30 or higher, optionally with at least one weight-related comorbidity; diabetes, optionally with at least one comorbidity; cardiovascular disease; nonsteroidal steatohepatitis; and / or cognitive impairment, such as cognitive impairment caused by Alzheimer's disease.

[0017] This article discloses a pharmaceutical formulation comprising a GLP-1 receptor-amylin receptor co-agonist and pharmaceutically acceptable excipients.

[0018] sequence list SEQ ID NO: 1 represents the amino acid sequence of human GLP-1 (7-37).

[0019] SEQ ID NO: 2-78 represents the amino acid sequence of the illustrative GLP-1 receptor agonist peptide backbone.

[0020] SEQ ID NO: 79-88 represents the amino acid sequence of the exemplified amylin receptor agonist peptide backbone.

[0021] SEQ ID NO: 89-116 represents the amino acid sequence of an illustrative alternative peptide linker.

[0022] SEQ ID NO: 117-236 represents the amino acid sequence of the illustrative GLP-1 receptor-amylin receptor co-agonist polypeptide backbone.

[0023] SEQ ID NO: 237 represents the amino acid sequence of human glucagon.

[0024] SEQ ID NO: 238 represents the amino acid sequence of the GLP-1 receptor agonist (peptide Z1) according to formula II.

[0025] SEQ ID NO: 239 represents the amino acid sequence of the optional peptide linker Z2.

[0026] SEQ ID NO: 240 represents the amino acid sequence of the amylin receptor agonist (peptide Z3) according to formula III.

[0027] SEQ ID NO: 241-245 represents the amino acid sequence of the polypeptide backbone within the illustrative comparative compounds.

[0028] SEQ ID NO: 246 represents the amino acid sequence of the polypeptide backbone within smegglutinin.

[0029] SEQ ID NO: 247 represents the amino acid sequence of the polypeptide backbone within pramlinpeptide.

[0030] SEQ ID NO: 248 represents the amino acid sequence of the polypeptide backbone within cagrillintide.

[0031] SEQ ID NO: 249 represents the amino acid sequence of salmon calcitonin.

[0032] SEQ ID NO: 250 represents the amino acid sequence of the polypeptide backbone in compound 1806.

[0033] SEQ ID NO: 251-254 represents the amino acid sequence of the polypeptide backbone in the illustrative comparative compounds.

[0034] SEQ ID NO: 255 represents the amino acid sequence of the GLP-1 receptor agonist (peptide Z1) according to formula II.

[0035] SEQ ID NO: 256 represents the amino acid sequence of the amylin receptor agonist (peptide Z3) according to formula III. Attached Figure Description

[0036] Figures 1-173 The compounds of the present invention prepared as further described in Example 1 are depicted.

[0037] Figure 1 Compound 0007 was described.

[0038] Figure 2 Compound 0009 was described.

[0039] Figure 3 Compound 0010 was described.

[0040] Figure 4 Compound 0019 was described.

[0041] Figure 5 Compound 0026 was described.

[0042] Figure 6 Compound 0035 was described.

[0043] Figure 7 Compound 0039 was described.

[0044] Figure 8 Compound 0040 was described.

[0045] Figure 9 Compound 0042 was described.

[0046] Figure 10 Compound 0044 was described.

[0047] Figure 11 Compound 0045 was described.

[0048] Figure 12 Compound 0051 was described.

[0049] Figure 13 Compound 0052 was described.

[0050] Figure 14 Compound 0056 was described.

[0051] Figure 15 Compound 0057 was described.

[0052] Figure 16 Compound 0071 was described.

[0053] Figure 17 Compound 0072 was described.

[0054] Figure 18 Compound 0073 was described.

[0055] Figure 19 Compound 0074 was described.

[0056] Figure 20 Compound 0075 was described.

[0057] Figure 21 Compound 0076 was described.

[0058] Figure 22 Compound 0077 was described.

[0059] Figure 23 Compound 0083 was described.

[0060] Figure 24 Compound 0084 was described.

[0061] Figure 25 Compound 0085 was described.

[0062] Figure 26 Compound 0086 was described.

[0063] Figure 27 Compound 0087 was described.

[0064] Figure 28 Compound 0089 was described.

[0065] Figure 29 Compound 0090 was described.

[0066] Figure 30 Compound 0092 was described.

[0067] Figure 31 Compound 0093 was described.

[0068] Figure 32 Compound 0094 was described.

[0069] Figure 33 Compound 0095 was described.

[0070] Figure 34 Compound 0096 was described.

[0071] Figure 35 Compound 0097 was described.

[0072] Figure 36 Compound 0098 was described.

[0073] Figure 37 Compound 0099 was described.

[0074] Figure 38 Compound 0100 was described.

[0075] Figure 39 Compound 0101 was described.

[0076] Figure 40 Compound 0102 was described.

[0077] Figure 41 Compound 0103 was described.

[0078] Figure 42 Compound 0105 was described.

[0079] Figure 43 Compound 0106 was described.

[0080] Figure 44 Compound 0109 was described.

[0081] Figure 45 Compound 0110 was described.

[0082] Figure 46 Compound 0111 was described.

[0083] Figure 47 Compound 0114 was described.

[0084] Figure 48 Compound 0115 was described.

[0085] Figure 49 Compound 0116 was described.

[0086] Figure 50 Compound 0120 was described.

[0087] Figure 51 Compound 0124 was described.

[0088] Figure 52 Compound 0125 was described.

[0089] Figure 53 Compound 0127 was described.

[0090] Figure 54 Compound 0128 was described.

[0091] Figure 55 Compound 0129 was described.

[0092] Figure 56 Compound 0131 was described.

[0093] Figure 57 Compound 0132 was described.

[0094] Figure 58 Compound 0141 was described.

[0095] Figure 59 Compound 0142 was described.

[0096] Figure 60 Compound 0144 was described.

[0097] Figure 61 Compound 0145 was described.

[0098] Figure 62 Compound 0146 was described.

[0099] Figure 63 Compound 0147 was described.

[0100] Figure 64 Compound 0151 was described.

[0101] Figure 65 Compound 0156 was described.

[0102] Figure 66 Compound 0157 was described.

[0103] Figure 67 Compound 0159 was described.

[0104] Figure 68 Compound 0160 was described.

[0105] Figure 69 Compound 0179 was described.

[0106] Figure 70 Compound 0180 was described.

[0107] Figure 71 Compound 0191 was described.

[0108] Figure 72 Compound 0202 was described.

[0109] Figure 73 Compound 0231 was described.

[0110] Figure 74 Compound 0232 was described.

[0111] Figure 75 Compound 0233 was described.

[0112] Figure 76 Compound 0234 was described.

[0113] Figure 77 Compound 0235 was described.

[0114] Figure 78 Compound 0254 was described.

[0115] Figure 79 Compound 0255 was described.

[0116] Figure 80 Compound 0259 was described.

[0117] Figure 81 Compound 0260 was described.

[0118] Figure 82 Compound 0261 was described.

[0119] Figure 83 Compound 0263 was described.

[0120] Figure 84 Compound 0264 was described.

[0121] Figure 85 Compound 0265 was described.

[0122] Figure 86 Compound 0266 was described.

[0123] Figure 87 Compound 0267 was described.

[0124] Figure 88 Compound 0268 was described.

[0125] Figure 89 Compound 0269 was described.

[0126] Figure 90 Compound 0270 was described.

[0127] Figure 91 Compound 0271 was described.

[0128] Figure 92 Compound 0272 was described.

[0129] Figure 93 Compound 0273 was described.

[0130] Figure 94 Compound 0280 was described.

[0131] Figure 95 Compound 0281 was described.

[0132] Figure 96 Compound 0284 was described.

[0133] Figure 97 Compound 0285 was described.

[0134] Figure 98 Compound 0292 was described.

[0135] Figure 99 Compound 0294 was described.

[0136] Figure 100 Compound 0295 was described.

[0137] Figure 101 Compound 0296 was described.

[0138] Figure 102 Compound 0297 was described.

[0139] Figure 103 Compound 0299 ​​was described.

[0140] Figure 104 Compound 0396 was described.

[0141] Figure 105 Compound 0397 was described.

[0142] Figure 106 Compound 0411 was described.

[0143] Figure 107 Compound 0414 was described.

[0144] Figure 108 Compound 0415 was described.

[0145] Figure 109 Compound 0416 was described.

[0146] Figure 110 Compound 0417 was described.

[0147] Figure 111 Compound 0431 was described.

[0148] Figure 112 Compound 0433 was described.

[0149] Figure 113 Compound 0434 was described.

[0150] Figure 114 Compound 0435 was described.

[0151] Figure 115 Compound 0436 was described.

[0152] Figure 116 Compound 0437 was described.

[0153] Figure 117 Compound 0438 was described.

[0154] Figure 118 Compound 0439 was described.

[0155] Figure 119 Compound 0440 was described.

[0156] Figure 120 Compound 0472 was described.

[0157] Figure 121 Compound 0473 was described.

[0158] Figure 122 Compound 0474 was described.

[0159] Figure 123 Compound 0475 was described.

[0160] Figure 124 Compound 0482 was described.

[0161] Figure 125 Compound 0483 was described.

[0162] Figure 126 Compound 0484 was described.

[0163] Figure 127 Compound 0502 was described.

[0164] Figure 128 Compound 0503 was described.

[0165] Figure 129 Compound 0504 was described.

[0166] Figure 130 Compound 0506 was described.

[0167] Figure 131 Compound 0509 was described.

[0168] Figure 132 Compound 0511 was described.

[0169] Figure 133 Compound 0512 was described.

[0170] Figure 134 Compound 0516 was described.

[0171] Figure 135 Compound 0518 was described.

[0172] Figure 136 Compound 0528 was described.

[0173] Figure 137 Compound 0529 was described.

[0174] Figure 138 Compound 0539 was described.

[0175] Figure 139 Compound 0552 was described.

[0176] Figure 140 Compound 0560 was described.

[0177] Figure 141 Compound 0561 was described.

[0178] Figure 142 Compound 0562 was described.

[0179] Figure 143 Compound 0564 was described.

[0180] Figure 144 Compound 0565 was described.

[0181] Figure 145 Compound 0575 was described.

[0182] Figure 146 Compound 0576 was described.

[0183] Figure 147 Compound 0577 was described.

[0184] Figure 148 Compound 0578 was described.

[0185] Figure 149 Compound 0580 was described.

[0186] Figure 150 Compound 0581 was described.

[0187] Figure 151 Compound 0629 was described.

[0188] Figure 152 Compound 0630 was described.

[0189] Figure 153 Compound 0631 was described.

[0190] Figure 154 Compound 0632 was described.

[0191] Figure 155 Compound 0633 was described.

[0192] Figure 156 Compound 0634 was described.

[0193] Figure 157 Compound 0635 was described.

[0194] Figure 158 Compound 0636 was described.

[0195] Figure 159 Compound 0637 was described.

[0196] Figure 160 Compound 0638 was described.

[0197] Figure 161 Compound 0639 was described.

[0198] Figure 162 Compound 0640 was described.

[0199] Figure 163 Compound 0648 was described.

[0200] Figure 164 Compound 0654 was described.

[0201] Figure 165 Compound 0655 was described.

[0202] Figure 166 Compound 0656 was described.

[0203] Figure 167 Compound 0657 was described.

[0204] Figure 168 Compound 0658 was described.

[0205] Figure 169 Compound 0659 was described.

[0206] Figure 170 Compound 0660 was described.

[0207] Figure 171 Compound 0661 was described.

[0208] Figure 172 Compound 0662 was described.

[0209] Figure 173 Compound 0663 was described.

[0210] Figures 174-182 The comparative compounds prepared as further described in Example 1 are depicted.

[0211] Figure 174 The comparison compound 0164 is described.

[0212] Figure 175The comparative compound 0185 was described.

[0213] Figure 176 The comparative compound 0015 was described.

[0214] Figure 177 The comparison compound 0016 is described.

[0215] Figure 178 The comparative compound 0668 was described.

[0216] Figure 179 The comparative compound 0671 was described.

[0217] Figure 180 The comparison compound 0672 was described.

[0218] Figure 181 The comparison compound 0167 was described.

[0219] Figure 182 The comparison compound 0192 was described.

[0220] Figure 183 The amylin receptor agonist 1806 was described. Detailed Implementation

[0221] This invention relates to compounds comprising an amylin receptor agonist and a GLP-1 receptor agonist. The compounds disclosed herein are capable of activating or “activating” both the GLP-1 receptor and the amylin receptor system: they are “GLP-1 receptor-amylin receptor co-agonists.” The compounds may further comprise one, two, or three extended moieties.

[0222] The compounds disclosed herein can be effective GLP-1 receptor agonists.

[0223] The compounds disclosed in this article can be effective amylin receptor agonists.

[0224] The compounds disclosed herein can provide similar levels of activation for both receptor systems; that is, they can be “balanced.” Relatively “balanced” receptor activation is advantageous because the relative proportions of the GLP-1 and amylin receptor agonist moieties of the compounds are locked onto the molecule; it is impossible to titrate these two receptor agonists relative to each other. Ultimately, if the molecule is “balanced,” its administration can activate both hormonal systems without side effects outweighing the benefits.

[0225] Compounds that are highly effective against one receptor but much less effective against another are considered "unbalanced." For example, if a compound is highly effective against the GLP-1 receptor (e.g., EC1), it would be "unbalanced." 50 Value <50 pM), and its potency against the amyloid receptor system is quite low (e.g., EC).50 If the concentration is >200 pM, it will be "unbalanced"; that is, it is likely to act only as a GLP-1 receptor agonist. Such a compound will not achieve optimal efficacy from both hormonal systems because the side effects caused by GLP-1 receptor activation will prevent the administration of sufficiently high doses to simultaneously activate the amylin-glucan hormone system. If the compound is highly effective against amylin receptors (e.g., EC2), it will be less effective. 50 Value <50 pM), while its potency against GLP-1 receptors is quite low (e.g., EC). 50 If the value is >200 pM, the opposite may occur.

[0226] Furthermore, the compounds disclosed herein have a long half-life compared to their natural ligands. This long biological half-life, relative to the dosing interval, reduces the variability of steady-state exposure.

[0227] The compounds disclosed herein are orally bioavailable and therefore suitable for oral administration to subjects in need.

[0228] In order to obtain compounds with all the above properties, both the polypeptide backbone and the extended portion are engineered and purified.

[0229] receptor agonists A "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 full agonist can be defined as an agonist that elicits a response of the same magnitude as that of the natural ligand (see, for example, "Principles of Biochemistry", AL Lehninger, DL Nelson, MM Cox, 2nd ed., WorthPublishers, 1993, p. 763). Receptors can be activated by endogenous agonists such as endogenous hormones or exogenous agonists such as drugs.

[0230] Co-agonists In the context of this invention, a “co-agonist” is a compound comprising two distinct ligands, each of which binds to a given biological receptor to produce a biological response characteristic of the natural ligand. The co-agonists disclosed herein are referred to herein as “GLP-1-amylin co-agonists” or “GLP-1 receptor-amylin receptor co-agonists”.

[0231] GLP-1 receptor-amylin receptor co-agonists The compounds disclosed herein are “GLP-1 receptor-amylin receptor co-agonists” or “GLP-1-amylin receptor co-agonists”. A GLP-1 receptor-amylin receptor co-agonist comprises a GLP-1 receptor agonist, an optional peptide linker, and an amylin receptor agonist. The GLP-1 receptor agonist component binds to and activates the GLP-1 receptor, while the amylin receptor agonist component binds to and activates at least the human amylin 3 receptor (AMYR3).

[0232] The molecular structure can be a single-chain polypeptide backbone containing one, two, or three lysine (Lys, K) residues. The molecular structure can also be a single-chain polypeptide backbone containing one, two, or three cysteine ​​(Cys, C) residues. Furthermore, the molecular structure can be a single-chain polypeptide backbone containing one, two, or three lysine (Lys, K) and / or cysteine ​​(Cys, C) residues. The GLP-1 receptor-amyloid receptor co-agonist may further include 1-3 elongated moieties. These elongated moieties may be covalently bound to the said lysine (Lys, K) or cysteine ​​(Cys, C) residues.

[0233] To maintain maximum biological activity, the C-terminal amide moiety of the amylin receptor agonist must be free. Therefore, the C-terminal residue of the GLP-1 receptor agonist is covalently linked to either an optional peptide linker or an N-terminal residue of the amylin receptor agonist, and vice versa. When present, the peptide linker comprises 1–30 naturally occurring amino acids.

[0234] The polypeptide backbone of a GLP-1 receptor-amylin receptor co-agonist may contain 1, 2, or 3 lysine residues. The polypeptide backbone of a GLP-1 receptor-amylin receptor co-agonist may contain 1 or 2 lysine residues. The polypeptide backbone of a GLP-1 receptor-amylin receptor co-agonist may contain 1 lysine residue.

[0235] The polypeptide backbone of a GLP-1 receptor-amylin receptor co-agonist may contain 1, 2, or 3 cysteine ​​residues. The polypeptide backbone of a GLP-1 receptor-amylin receptor co-agonist may contain 1 or 2 cysteine ​​residues. The polypeptide backbone of a GLP-1 receptor-amylin receptor co-agonist may contain 1 cysteine ​​residue.

[0236] The polypeptide backbone of the GLP-1 receptor-amylin receptor co-agonist is 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 amylin receptor agonist peptide.

[0237] Compared to wild-type GLP-1 (7-37) (SEQ ID NO: 1), Z1 may contain up to 9 amino acid modifications. The C-terminus of Z1 is linked to Z2 (when Z2 is present) or to Z3 (when Z2 is absent).

[0238] 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.

[0239] Relative to SEQ ID NO: 79, Z3 may contain up to 7 amino acid modifications. The C-terminus of Z3 is modified with an amide group. The N-terminus of Z3 is connected to the C-terminus of Z2 (when Z2 is present) or to the C-terminus of Z1 (when Z2 is absent).

[0240] Z1-Z2-Z3 contains 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 herein as “R2-R3”, where “R2” is an optional linker and “R3” is an elongation portion.

[0241] As described in this article, GLP-1 receptor-amylin receptor co-agonists can exhibit a variety of properties that make them suitable for use as drugs.

[0242] GLP-1 receptor-amylin receptor co-agonists may be effective against both GLP-1 and amylin receptors. The in vitro potency of GLP-1 receptor-amylin receptor co-agonists against GLP-1 and amylin-3 receptors can be measured as described in assays 1 and 2, respectively. The potency of the compound can be determined by its EC50. 50 Described by value. EC 50 This indicates the compound concentration at which 50% of its maximum effect is observed. (EC) 50 The lower the value, the more effective the compound.

[0243] When tested as described in assay 1, the EC of the GLP-1 receptor-amylin receptor co-agonist disclosed herein 50 The value can 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.

[0244] When tested as described in assay 2, the EC of the GLP-1 receptor-amylin receptor co-agonist disclosed herein 50The value can 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.

[0245] The in vivo pharmacology of the GLP-1 receptor-amylin receptor co-agonists described herein, including their half-life, can be evaluated as described in Examples 4 and 5.

[0246] The half-life of GLP-1 receptor-amylin receptor co-agonists in animal subjects can be as long as 125 hours or longer. The half-life of GLP-1 receptor-amylin receptor co-agonists in animal subjects can be at least 4 hours. The half-life of GLP-1 receptor-amylin receptor co-agonists can exceed 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, and 120 hours. The half-life of GLP-1 receptor-amylin receptor co-agonists can be 15-60 hours, such as 20-55 hours, or 25-50 hours.

[0247] GLP-1 receptor-amylin receptor co-agonists can be orally bioavailable; that is, they are present in the bloodstream after each oral administration.

[0248] The GLP-1 receptor-amylin receptor co-agonist disclosed herein reduces food intake in subjects. Administration of the GLP-1 receptor-amylin receptor co-agonist disclosed herein results in a sharp reduction in food intake. The in vivo effect of the GLP-1 receptor-amylin receptor co-agonist on food intake in rats can be assessed as described in Example 5. Administration of the GLP-1 receptor-amylin receptor co-agonist disclosed herein results in a food intake of 0-90%, such as 0-80%, such as 0-70%, such as 0-60%, preferably 0-50%, and even more preferably 0-40% in rats within 0-24 hours following a single subcutaneous injection of 10 nmol / kg of the co-agonist, relative to the medium. A food intake of 0% relative to the medium means that the rats do not eat. Administration of the GLP-1 receptor-amylin receptor co-agonist disclosed herein results in a food intake of 0-90%, such as 0-80%, such as 0-70%, such as 0-60%, preferably 0-50%, and even more preferably 0-40%, in rats within 24-48 hours following a single subcutaneous injection of 10 nmol / kg of the co-agonist, where a food intake of 0% relative to the medium means that the rats do not eat.

[0249] GLP-1 The term “GLP-1” or “natural GLP-1” in this document refers to human glucagon-like peptide-1 (GLP-1(7-37)), shown in the sequence listing as SEQ ID NO: 1. In the sequence listing, amino acid residues are numbered consecutively from 1 to 31. Therefore, the first amino acid in wild-type human GLP-1(7-37) – namely the N-terminal histidine – is number “1” in SEQ ID NO: 1. GLP-1 receptor agonists 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 “full” GLP-1 receptor agonist can be defined as a GLP-1 receptor agonist capable of eliciting a biological response of the same magnitude as that of GLP-1.

[0251] Smegglutinin, disclosed in Example 4 of WO2006 / 097537, is an example of an exogenous GLP-1 receptor agonist.

[0252] GLP-1 receptor agonists must have a free N-terminus. Therefore, the compounds disclosed herein comprise GLP-1 receptor agonists whose C-terminus is linked to an optional peptide or amylin receptor agonist.

[0253] GLP-1 receptor agonists contain the peptide "Z1".

[0254] The compounds disclosed herein may comprise GLP-1 receptor agonists as 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).

[0255] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0256] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0257] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0258] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0259] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0260] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0261] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0262] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0263] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 9 amino acid modifications relative to wild-type human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 9 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0264] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 8 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0265] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 7 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0266] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 6 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0267] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 5 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0268] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 4 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0269] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 3 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0270] GLP-1 receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1). GLP-1 receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 2 amino acid modifications relative to human GLP-1 (SEQ ID NO: 1).

[0271] Relative to the amino acid sequence and numbering of human GLP-1 (7-37), GLP-1 receptor agonists may contain a phenylalanine residue (Phe, F), tryptophan (Trp, W), or tyrosine (Tyr, Y) residue at position 28. The numbering shifts by -6 relative to SEQ ID NO: 1, as shown in Formula II, SEQ ID NO: 238, and SEQ ID NO: 255. Therefore, relative to SEQ ID NO: 1, SEQ ID NO: 238, or SEQ ID NO: 255, GLP-1 receptor agonists may contain a phenylalanine residue (Phe, F), tryptophan (Trp, W), or tyrosine (Tyr, Y) residue at position 22. Relative to SEQ ID NO: 1, SEQ ID NO: 238, or SEQ ID NO: 255, GLP-1 receptor agonists may not contain isoleucine (Ile, I) at position 22.

[0272] Relative to the amino acid sequence and numbering of human GLP-1 (7-37), GLP-1 receptor agonists may contain an isoleucine (Ile, I), leucine (Leu, L), or valine (Val, V) residue at position 29. The numbering shifts by -6 relative to SEQ ID NO: 1, as shown in Formula II and SEQ ID NO: 238. Therefore, relative to SEQ ID NO: 1, SEQ ID NO: 238, or SEQ ID NO: 255, GLP-1 receptor agonists may contain an isoleucine (Ile, I), leucine (Leu, L), or valine (Val, V) residue at position 23.

[0273] Relative to the amino acid sequence and numbering of human GLP-1 (7-37), GLP-1 receptor agonists may contain Imp (imidazolium propionyl or deaminohistidine) of Formula 1 at position 7. The numbering shifts by -6 relative to SEQ ID NO: 1, as shown in Formula II and SEQ ID NO: 238.

[0274] Chemical Formula 1: Relative to the amino acid sequence and numbering of human GLP-1 (7-37), GLP-1 receptor agonists may contain Aib (alpha(α)-aminoisobutyryl, α-aminoisobutyric acid, or α-methylalanine) of Formula 2 at position 8. The numbering shifts by 6 relative to SEQ ID NO: 1, as shown in Formula II and SEQ ID NO: 238.

[0275] Chemical formula 2: Relative to SEQ ID NO: 238 or SEQ ID NO: 255, the GLP-1 receptor agonist peptide may contain a lysine (Lys, K) residue at any of the following positions: 9, 10, 12, 16, 17, 20, 21, 24, 25, 28, 29, 30 or 31.

[0276] The GLP-1 receptor agonist disclosed herein may have Formula II, as shown in the sequence listing below (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, in Xaa1 is His(H) or Imp. Xaa2 can be Aib, Ala (A), Gly (G), or Trp (W). Xaa9 can be Cys(C), Asp(D), or Lys(K). Xaa10 is Cys (C), Lys (K), or Val (V). Xaa12 can be Cys (C), Lys (K), Arg (R), or Ser (S). Xaa16 can be Cys (C), Glu (E), Gly (G), or Lys (K). Xaa17 can be Cys(C), Gln(Q), or Lys(K). Xaa19 is either Ala (A) or Val (V). Xaa20 can be Cys(C), Lys(K), or Arg(R). Xaa21 can be Cys (C), Glu (E), or Lys (K). Xaa22 can be Phe (F), Trp (W), or Tyr (Y). Xaa23 can be Ile (I), Leu (L), or Val (V). Xaa24 can be Ala (A), Cys (C), Glu (E), or Lys (K). Xaa25 can be Cys (C), Lys (K), or Trp (W). Xaa28 can be Cys(C), Lys(K), or Arg(R). Xaa29 can be 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.

[0277] Skilled technicians typically refer to the standard human wild-type GLP-1 (7-37) nomenclature to refer to 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, terminating at glycine, number 37.

[0278] Therefore, a skilled technician can 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 can be Cys(C), Lys(K), or Val(V). Xaa18 can be Cys (C), Lys (K), Arg (R), or Ser (S). Xaa22 can be Cys (C), Glu (E), Gly (G), or Lys (K). Xaa23 can be 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 can be 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 can be Cys (C), Lys (K), or Trp (W). Xaa34 can be 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.

[0279] The GLP-1 receptor agonist disclosed herein may have Formula II, as shown in the sequence listing below (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, in Xaa1 is His(H) or Imp. Xaa2 can be Aib, Ala (A), Gly (G), or Trp (W). Xaa9 is either Asp(D) or Lys(K). Xaa10 is either Lys(K) or Val(V). Xaa12 can be 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.

[0280] The GLP-1 receptor agonist peptide (Z1) can be described with reference to the sequences in the sequence listing. The GLP-1 receptor co-agonists disclosed herein may comprise a GLP-1 receptor agonist peptide (Z1) selected from any of the sequences described in SEQ ID NO: 2-78.

[0281] The GLP-1 receptor agonists disclosed herein activate or arouse GLP-1 receptors. This term refers to the ability to bind to the GLP-1 receptor and initiate signal transduction pathways, thereby resulting in insulinotropic effects or other physiological effects known in the art. GLP-1 receptor activation by the GLP-1 receptor agonists disclosed herein can be tested as described in Examples 2 (in vitro), 4, and 5 (in vivo).

[0282] The more effective the compound, the higher its EC value. 50 The lower the value, the better. When the compound's EC value... 50 When the value is below approximately 50 pM, this compound is considered a very potent GLP-1 receptor agonist. When the compound's EC50... 50 At a value of 50-250 pM, this compound is considered to have moderate potency. When the compound's EC50... 50 The compound is considered to have poor potency when its EC value is between 250 and 1000 pM. 50 When the value is higher than 1000 pM, the compound is considered inactive.

[0283] GLP-1 receptor agonists may have an EC50 of approximately 300 pM or lower in human GLP-1 receptor function assays (see Assay 1). 50 GLP-1 receptor agonists may have an EC50 of approximately 200 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 150 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 100 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 90 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 80 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 70 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 60 pM or lower in human GLP-1 receptor function assays. 50 Preferably, the GLP-1 receptor agonist has an EC50 of about 50 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 40 pM or lower in human GLP-1 receptor function assays. 50GLP-1 receptor agonists may have an EC50 of approximately 30 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 25 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 20 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 19 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 18 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 17 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 16 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 15 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 14 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 13 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 12 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 11 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 10 pM or lower in human GLP-1 receptor function assays. 50 GLP-1 receptor agonists may have an EC50 of approximately 5 pM or lower in human GLP-1 receptor function assays. 50 .

[0284] GLP-1 receptor agonists may have similar potency to smegglutinin.

[0285] amylin The term "amylin" in this article refers to a polypeptide that has the same amino acid sequence as endogenous amylin, such as human amylin.

[0286] amylin receptor Amylin receptor agonists can activate or invigorate the calcitonin receptor (CTR) and / or the amylin receptor (AMYR). The amylin receptor consists of a two-component heterodimer: the calcitonin receptor (CTR) and one of three receptor activity-altering proteins (RAMP1–3), resulting in three possible complexes, AMYR1–3. Unless otherwise stated herein, “amylin receptor” refers at least to amylin receptor 3 (AMYR3). Nevertheless, some degree of cross-reactivity is expected.

[0287] amylin receptor agonists The compounds disclosed herein include amylin receptor agonists. An "amylin receptor agonist" can be defined as a chemical entity capable of binding to and activating an amylin receptor. In the context of this invention, an "amylin receptor agonist" is at least capable of binding to and activating the AMYR3 complex. The amylin receptor agonist may also be capable of agonizing calcitonin receptors and AMYR1-2.

[0288] Examples of endogenous amylin receptor agonists are human amylin and human calcitonin. Examples of exogenous amylin receptor agonists are pramlintide and canagliflozin (disclosed in WO2012 / 168432).

[0289] The amylin receptor agonists disclosed herein contain the peptide "Z3". These amylin receptor agonists also contain a C-terminal amide, which is essential for biological activity.

[0290] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 7 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 7 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 7 amino acid modifications relative to SEQ ID NO: 79.

[0291] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 6 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 6 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 6 amino acid modifications relative to SEQ ID NO: 79.

[0292] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 5 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 5 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 5 amino acid modifications relative to SEQ ID NO: 79.

[0293] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 4 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 4 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 4 amino acid modifications relative to SEQ ID NO: 79.

[0294] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 3 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 3 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 3 amino acid modifications relative to SEQ ID NO: 79.

[0295] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a maximum of 2 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a maximum of 2 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 lysine residue and a maximum of 2 amino acid modifications relative to SEQ ID NO: 79.

[0296] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 lysine residues and a modification of 1 amino acid relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 lysine residues and a modification of 1 amino acid relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 lysine residue and a modification of 1 amino acid relative to SEQ ID NO: 79.

[0297] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 7 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 7 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 7 amino acid modifications relative to SEQ ID NO: 79.

[0298] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 6 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 6 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 6 amino acid modifications relative to SEQ ID NO: 79.

[0299] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 5 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 5 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 5 amino acid modifications relative to SEQ ID NO: 79.

[0300] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 4 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 4 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 4 amino acid modifications relative to SEQ ID NO: 79.

[0301] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 3 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 3 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 3 amino acid modifications relative to SEQ ID NO: 79.

[0302] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a maximum of 2 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a maximum of 2 amino acid modifications relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a maximum of 2 amino acid modifications relative to SEQ ID NO: 79.

[0303] Amylin receptor agonists may comprise a polypeptide containing 0, 1, 2, or 3 cysteine ​​residues and a 1-amino acid modification relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 or 2 cysteine ​​residues and a 1-amino acid modification relative to SEQ ID NO: 79. Amylin receptor agonists may comprise a polypeptide containing 1 cysteine ​​residue and a 1-modified amino acid relative to SEQ ID NO: 79.

[0304] Compared to SEQ ID NO: 240 or SEQ ID NO: 256, amylin receptor agonists may not contain proline at position 12.

[0305] Relative to SEQ ID NO: 240 or SEQ ID NO: 256, the amylin receptor agonist peptide may contain a lysine (Lys, K) residue at any of positions 1, 2, 3, 7, 14, 18, 20, 23 or 29.

[0306] The GLP-1 receptor-amylin receptor co-agonists disclosed herein may comprise amylin receptor agonists 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 can be 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).

[0307] The GLP-1 receptor-amylin receptor co-agonists disclosed herein may include amylin receptor agonists 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 is either 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). The amylin receptor agonist may comprise a polypeptide (Z3) represented by any one of SEQ ID NO: 79-88. Therefore, the polypeptide backbone of the amylin receptor agonist (Z3) described herein can be described with reference to the sequences in the sequence listing.

[0309] The amylin receptor agonists disclosed herein activate or stimulate the amylin receptor. The amylin activity of the disclosed amylin agonists can be tested as described in Examples 2 (in vitro), 4, and 5 (in vivo).

[0310] The more effective the compound, the higher its EC value. 50 The lower the value, the better. When the compound's EC value... 50 When the value is below 50 pM, this compound is considered a very potent amylin receptor agonist. When the compound's EC50... 50 At a value of 50-250 pM, this compound is considered to have moderate potency. When the compound's EC50... 50 The compound is considered to have poor potency when its EC value is between 250 and 1000 pM. 50 When the value is higher than 1000 pM, the compound is considered ineffective.

[0311] Amylin receptor agonists may have an EC50 of approximately 300 pM or lower in human amylin receptor function assays (see assay 2). 50 Amylin receptor agonists can have an EC50 of approximately 250 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 200 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 150 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 100 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 90 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 80 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 70 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 60 pM or lower in human amylin receptor function assays. 50 Preferably, the amylin receptor agonist has an EC50 of about 50 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 40 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 30 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 25 pM or lower in human amylin receptor function assays. 50Amylin receptor agonists can have an EC50 of approximately 20 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 19 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 18 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 17 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 16 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 15 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 14 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 13 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 12 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 11 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists can have an EC50 of approximately 10 pM or lower in human amylin receptor function assays. 50 Amylin receptor agonists may have an EC50 of approximately 5 pM or lower in human amylin receptor function assays. 50 .

[0312] The amylin receptor agonists disclosed herein may have similar potency to canagliflozin, pramlintide, or amylin receptor agonist 1806. peptide linkers The GLP-1 receptor-amylin receptor co-agonist polypeptide backbone R1 disclosed herein may include an optional peptide linker Z2, which may be 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 are either absent or independently selected from any 7 naturally occurring or standard amino acid residues.

[0314] Therefore, the optional peptide linker may contain 1-30 canonical amino acid residues. Alternatively, the optional peptide linker may contain 1-25 canonical amino acid residues. Another option is to include 1-20 canonical amino acid residues, such as 1-15, 1-10, or 1-5 canonical amino acid residues.

[0315] In the case 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.

[0316] Xaa can be selected from alanine (Ala, A), cysteine ​​(Cys, C), glutamic acid (E), glycine (G), isoleucine (Ile, I), lysine (Lys, K), glutamine (Q), serine (S) and / or proline (Pro, P).

[0317] Xaa can be selected from alanine (A), glutamic acid (E), glycine (G), isoleucine (I), lysine (K), glutamine (Q), serine (S) and / or proline (P).

[0318] The optional peptide linker (Z2) can be any peptide linker represented by SEQ ID NO: 89-116. The optional peptide linker (Z2) can be any peptide linker listed in Table 1. The optional peptide linker can be GGGGE.

[0319] Table 1: Optional peptide linkers (Z2)

[0320] polypeptide As used herein, the term “polypeptide” or “peptide” refers to a compound consisting of a series of amino acid residues linked together by amide (or peptide) bonds.

[0321] The polypeptide backbone (R1) of the GLP-1 receptor-amylin receptor co-agonist disclosed herein typically comprises 60-85 amino acid residues linked together by peptide bonds. R1 comprises peptides Z1-Z2-Z3, which are GLP-1 receptor agonists (Z1), optional peptide linkers (Z2), and peptides that act as amylin receptor agonists (Z3).

[0322] amino acids Amino acids are molecules that contain amine and carboxylic acid groups and optionally one or more additional groups commonly referred to as side chains.

[0323] The term "amino acid" includes both regulated amino acids (genetically encoded) and non-natural amino acids.

[0324] Non-limiting examples of non-natural amino acids are Aib (α-aminoisobutyric acid), deaminohistidine (also known as 3-(imidazol-4-yl)propionic acid, abbreviated as Imp (imidazolyl propionyl)), and the D-isomers of the canonical amino acid.

[0325] Unless otherwise stated, all amino acid residues in a polypeptide whose optical isomer is not specified shall be understood herein to refer to the L-isomer.

[0326] The GLP-1 receptor agonist peptide (Z1) disclosed herein may have up to 9 amino acid modifications compared to human GLP-1 (SEQ ID NO: 1). The amylin receptor agonist peptide (Z3) disclosed herein may have up to 7 amino acid modifications compared to SEQ ID NO: 79. Here, "amino acid modification" refers to the substitution, addition, or deletion of an amino acid at a given position in the reference sequence.

[0327] Extension The GLP-1 receptor-amylin receptor co-agonists disclosed herein may further comprise one, two, or three "extension moieties." The extension moieties may be represented by the general formula "R2-R3," where R2 is an optional linker and R3 is an extension moiety. Each extension moiety is linked to a lysine or cysteine ​​residue in the polypeptide backbone (R1) of the compound.

[0328] The extension portion may consist of a single extension body.

[0329] The extension may include a connector and an extension.

[0330] The extension may include one connector and two extensions.

[0331] When the linker (R2) is present, the elongated portion is connected to the polypeptide backbone (R1) via R2. When the linker (R2) is absent, R3 is connected to the polypeptide backbone.

[0332] The extended portions (R2-R3) can be linked to lysine residues in the GLP-1 receptor agonist portion ("Z1" in Z1-Z2-Z3) of the polypeptide backbone. The extended portions can also be linked to lysine residues in an optional peptide linker portion ("Z2" in Z1-Z2-Z3) of the polypeptide backbone. The extended portions can also be linked to lysine residues in the amylin receptor agonist portion ("Z3" in Z1-Z2-Z3) of the polypeptide backbone. When the extended portions are linked to lysine residues via amide bonds, the GLP-1 receptor-amylin receptor co-agonist is considered "acylated".

[0333] The GLP-1 receptor-amylin receptor co-agonist disclosed herein may contain a single lysine residue with a single elongated portion attached to that residue.

[0334] The GLP-1 receptor-amylin receptor co-agonists disclosed herein may comprise two lysine residues and two elongated moieties. The compounds disclosed herein may comprise two lysine residues and two identical elongated moieties.

[0335] The GLP-1 receptor-amylin receptor co-agonists disclosed herein may comprise three lysine residues and three elongated moieties. The compounds disclosed herein may comprise three lysine residues and three identical elongated moieties.

[0336] The extended portion can be linked to a cysteine ​​residue in the GLP-1 receptor agonist portion of the polypeptide backbone (“Z1” in Z1-Z2-Z3). The extended portion can also be linked to a cysteine ​​residue in an optional peptide linker portion of the polypeptide backbone (“Z2” in Z1-Z2-Z3). The extended portion can also be linked to a cysteine ​​residue in the amylin receptor agonist portion of the polypeptide backbone (“Z3” in Z1-Z2-Z3). When the extended portion is linked to a cysteine ​​residue via a thioether bond, the GLP-1 receptor-amylin receptor co-agonist is considered “alkylated.”

[0337] The GLP-1 receptor-amylin receptor co-agonist disclosed herein may contain a single cysteine ​​residue with a single elongated portion attached to that residue.

[0338] The GLP-1 receptor-amylin receptor co-agonist disclosed herein may contain two cysteine ​​residues and two identical elongated moieties.

[0339] The compounds disclosed herein may contain three cysteine ​​residues and three identical elongated moieties.

[0340] When a GLP-1 receptor-amylin receptor co-agonist comprises two or three extended moieties, these extended moieties are similar, preferably substantially identical, or most preferably identical.

[0341] In the case of the chemical part, as disclosed in the extended portion herein, any suitable computer program and / or algorithm known in the art may be used to determine similarity and / or identity.

[0342] A skilled technician may refer to a compound containing an extended portion as a "derivative". For example, "amylin derivative" is understood to be an amylin receptor agonist containing an extended portion.

[0343] In this paper, the term "extended moiety" refers to a synthetic moiety containing an "extended body" (R3) and an optional "side chain linker" or "linker" (R2) for an extended half-life. R2 may link R3 to a side chain of a lysine or cysteine ​​residue in R1, which is the polypeptide backbone of a GLP-1 receptor-amylin receptor co-agonist.

[0344] The extended portion may be able to non-covalently bind to albumin, thereby promoting the circulation of GLP-1 receptor-amylin receptor co-agonists in the bloodstream and prolonging their half-life. Therefore, skilled technicians may also refer to the extended portion as the "albumin-binding portion".

[0345] The elongated body (R3) may contain an acyl group. This acyl group may be branched or unbranched. The acyl group may be saturated or unsaturated. The elongated body (R3) may contain an aliphatic acyl group. This acyl group may be branched or unbranched. The acyl group may be saturated or unsaturated.

[0346] The elongated body (R3) may contain a distal carboxylic acid group.

[0347] The elongated body (R3) may contain fatty acid groups.

[0348] The elongated body (“R3”) may contain fatty acid groups and amide groups.

[0349] The elongated body (R3) may contain distal carboxylic acid groups and amide groups.

[0350] The elongated body (R3) may contain alkyl groups.

[0351] The elongated body (R3) may contain an aryl group.

[0352] The elongated body (R3) may contain a tetrazolium group.

[0353] The elongated body (R3) may contain sulfonic acid groups.

[0354] The elongated body (R3) may contain phenoxy groups.

[0355] The elongated body (R3) may contain benzoic acid groups.

[0356] The extended body (R3) may contain groups defined by the following formula: 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 expressed as Chemical formula 3b: , where n is an integer in the range of 8-30.

[0357] The elongated body (R3) can contain 8-30 carbon atoms. The elongated body can contain 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.

[0358] The elongated body (R3) may contain 6 to 30 consecutive -CH2- groups. The elongated body (R3) may contain a carbon chain containing 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.

[0359] The extension (R3) can contain 12-26 carbon atoms. The "extension" or "side chain" can contain 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 carbon atoms.

[0360] The elongated body (R3) may contain 10-26 consecutive -CH2- groups. The elongated body (R3) may contain a carbon chain containing 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 consecutive -CH2- groups.

[0361] The extended body (R3) may contain 16-22 carbon atoms. The compound may contain a single extended portion containing a side chain containing 16, 17, 18, 19, 20, 21 or 22 carbon atoms.

[0362] The elongated body (R3) may contain 14-20 consecutive -CH2- groups. The elongated body (R3) may contain a carbon chain containing 14, 15, 16, 17, 18, 19 or 20 consecutive -CH2- groups.

[0363] The extended body (R3) may contain 16-22 consecutive carbon atoms and 14-20 consecutive -CH2- groups.

[0364] The extended body (R3) may contain 16 consecutive carbon atoms and 14 consecutive -CH2- groups.

[0365] The extended body (R3) may contain 18 consecutive carbon atoms and 16 consecutive -CH2- groups.

[0366] The extended body (R3) may contain 20 consecutive carbon atoms and 18 consecutive -CH2- groups.

[0367] The extended body (R3) may contain 22 consecutive carbon atoms and 20 consecutive -CH2- groups.

[0368] GLP-1 receptor-amylin receptor co-agonists may comprise two extended moieties, each containing 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Each extended moiety (R3) may contain 12, 13, 14, 15, 16, 17, or 18 consecutive -CH2- groups.

[0369] GLP-1 receptor-amylin receptor co-agonists may contain two C14 diacids, two C16 diacids, or two C18 diacids.

[0370] GLP-1 receptor-amylin receptor co-agonists may comprise three elongated moieties, each containing an elongated body with 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The elongated body (R3) may contain 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive -CH2- groups.

[0371] The elongated portions (R2-R3) can be covalently linked to lysine residues in the polypeptide backbone (R1). The elongated portions can be linked via an amide bond formed between the carboxylic acid group in the elongated portion and the ε-amino group of the lysine residue.

[0372] The elongated portions (R2-R3) can be covalently linked to cysteine ​​residues in the polypeptide backbone (R1). The elongated portions can be connected via thioether bonds formed between the elongated portions and the sulfur atoms of the cysteine ​​residues in the polypeptide.

[0373] As described above, the compounds disclosed herein may contain one, two, or three lysine or cysteine ​​residues, and thus may contain one, two, or three elongated portions (R2-R3), wherein each elongated portion is attached to a side chain of a single lysine or cysteine ​​residue.

[0374] The extended portion can be linked to the polypeptide backbone described herein (R1) 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 (Z1) of the polypeptide backbone relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0375] The extended portion can be linked to the polypeptide backbone (R1) via a lysine (K) residue in an optional linker (Z2).

[0376] The extended portion can be linked 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 amylin receptor agonist portion (Z3) of the polypeptide backbone relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0377] The extended portion can be linked 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 of the GLP-1 receptor agonist portion (Z1) of the polypeptide backbone relative to SEQ ID NO: 238.

[0378] The extended portion can be linked to the polypeptide backbone (R1) via a cysteine ​​(C) residue in an optional linker portion (Z2) of the polypeptide backbone.

[0379] The extended portion can be linked to the polypeptide described herein via a cysteine ​​(C) residue in the amylin receptor agonist moiety (Z3) of the polypeptide backbone. This 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.

[0380] The GLP-1 receptor-amylin receptor co-agonists disclosed herein may comprise an elongation (R3) selected from any of those described in Table 2. In Table 2, R2 represents an optional linker that links the shown elongation (R3) to the polypeptide backbone (R1). R1 ​​is not shown in the table. Table 2: Elongated Body (R3)

[0382] As described above, the extension portion (“R2-R3”) may include an optional side chain connector “R2”.

[0383] Optional side-chain linkers (R2) may include Ado, Aeep or Aeeep, sulfonamide, Trx, ε-Lys, Ahx, Glu, γGlu, Gly, Ser, Ala, Thr and / or bonds.

[0384] Optional side-chain linkers may contain at least a portion that can be represented by the following chemical formula: Chemical formula 4a: -NH-(CH2)2-(O-(CH2)] k -O-(CH2) n -CO- .

[0385] 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, the linker element can be called Ado, or 8-amino-3,6-dioxanoyl, which can be represented by the following chemical formula: Chemical formula 5a: -NH-(CH2)2-O-(CH2)2-O-CH2-CO- .

[0386] or Chemical formula 5b: .

[0387] When k=1 and n=2, the 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, the 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: Optional side-chain linkers may include a sulfonamide-C4 moiety. The sulfonamide-C4 group is a sulfonamide group linked 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: Optional side-chain linkers 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: .

[0388] Optional side chain linkers may include ε-lysine (ε-Lys).

[0389] Optional side chain linkers may include lysine (Lys).

[0390] Optional side-chain linkers may include Ahx. Ahx is also known as aminohexanoic acid or 6-aminohexanoic acid, and is defined as... Chemical formula 11a: -NH-(CH2)5-CO- or Chemical formula 11b: Optional side-chain linkers may contain a di-radical Glu group, such as in formula 12: The Glu divalent group can be included p times, where p is an integer in the range of 1-3.

[0391] 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 lysine. As mentioned above, the other linker element can be, for example, another Glu residue or an Ado molecule. The amino group of Glu then forms an 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).

[0392] The GLP-1 receptor-amylin receptor co-agonists disclosed herein may include a side-chain linker (R2) selected from any of those described in Table 3. In Table 3, “R1” represents the polypeptide backbone (Z1-Z2-Z3), R2 (depicted) represents the side-chain linker, and “R3” represents the elongation. Table 3: Optional Connectors ("R2") Co-agonists can exist as different stereoisomers having the same molecular formula and bonded atomic order, but differing only in the three-dimensional orientation of their atoms in space. The stereoisomerism of example co-agonists is described in the experimental section using standard nomenclature, by name and structure. Unless otherwise stated, this invention relates to all stereoisomers of specific derivatives.

[0395] Production methods For example, the compounds disclosed herein can be produced by classical peptide synthesis, such as solid-phase peptide synthesis using t-Boc or Fmoc chemistry, or other established 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 WCChan and PD White, Oxford University Press, 2000.

[0396] Alternatively, the compound can be produced through recombinant methods, for example, by culturing host cells containing DNA sequences encoding peptide sequences and capable of expressing those peptides in a suitable nutrient medium under conditions that allow for peptide expression. A non-limiting example of a suitable host cell for expressing these peptides is *Escherichia coli* (E. coli). Escherichia coli ), brewer's yeast ( Saccharomyces cerevisiae ) and mammalian BHK or CHO cell lines.

[0397] Co-agonists containing non-natural amino acids and / or covalently linked substituents can be produced as described in the experimental section.

[0398] The examples include specific instances of methods for preparing various disclosed compounds.

[0399] Another aspect of the present invention relates to a method for preparing the peptides described herein.

[0400] Another aspect of the present invention relates to a method for preparing the receptor co-agonist described herein.

[0401] In one embodiment, a method for preparing the compounds described herein includes a solid-phase peptide synthesis step. Substituents may be constructed as part of the solid-phase peptide synthesis sequence, or may be generated independently and linked via lysine residues after peptide synthesis.

[0402] In one embodiment, the compound is produced through a two-step process, whereby two peptide fragments are linked after a substituent is attached to one of the peptide fragments. Pharmaceutical Composition This document also discloses pharmaceutical compositions comprising the GLP-1 receptor-amylin receptor co-agonist disclosed herein. Pharmaceutical compositions comprising the GLP-1 receptor-amylin receptor co-agonist 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.

[0404] The term "pharmaceuticalally acceptable excipient" refers to any component in a 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, mediators, fillers, binders, lubricants, flow aids, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, etc. The amount of each excipient used can vary within the conventional range in the art.

[0405] The pharmaceutical composition is suitable for oral administration. Techniques and excipients that can be used to formulate oral pharmaceutical compositions are described in the following literature: Handbook of Pharmaceutical Excipients (e.g., 8th edition, edited by Sheskey et al., American Pharmaceuticals Association and Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain Publishing House (2017), and subsequent editions); and Remington: The Science and Practice of Pharmacy (e.g., 22nd edition, edited by Remington and Allen, Pharmaceutical Press (2013), and subsequent editions).

[0406] Pharmaceutical formulations can be solid pharmaceutical formulations (e.g., compressed tablets or capsules) containing active pharmaceutical ingredients, such as as freeze-dried or spray-dried compositions, and can be used as is, dissolved before use, or combined with excipients in the formulation.

[0407] The pharmaceutical composition may contain compounds disclosed herein. N-[8-(2-hydroxybenzoyl)amino]octanoate and one or more other excipients as described in the art. For example, solid dosage forms may be as described in WO 2012 / 080471, WO2013 / 139694, WO 2013 / 189988, WO 2019 / 149880, WO2019 / 215063 or WO2021 / 219710.

[0408] Alternatively, the pharmaceutical composition may be a liquid formulation, such as an aqueous formulation. Such liquid compositions may be suitable for oral or parenteral administration. Liquid compositions suitable for injection can be prepared using conventional techniques of the pharmaceutical industry, which include, as appropriate, dissolving and mixing the components to obtain the desired end product. Thus, the compounds described herein are dissolved in a suitable buffer solution of appropriate pH according to a procedure. For example, the composition can be sterilized by sterile filtration. Techniques and excipients that can be used to prepare liquid formulations are described in the following literature: Handbook of Pharmaceutical Excipients (e.g., 8th edition, edited by Sheskey et al., American Pharmaceuticals Association and Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain (2017), and subsequent editions); and Remington: The Science and Practice of Pharmacy (e.g., 22nd edition, edited by Remington and Allen, Pharmaceutical Press (2013), and subsequent editions).

[0409] Drug indications The GLP-1 receptor-amylin receptor co-agonist disclosed in this article can be used as a drug.

[0410] The GLP-1 receptor-amylin receptor co-agonists disclosed in this article can be used for the following medical treatments: (i) Prevention and / or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (mature-onset diabetes mellitus), gestational diabetes, and / or for reducing HbA1c. (ii) Delay or prevent the progression of diabetes, such as the progression of type 2 diabetes, delay the progression of impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delay the progression of insulin-free type 2 diabetes to insulin-requiring type 2 diabetes. (iii) For example, by reducing food intake, reducing weight, suppressing appetite, inducing satiety to prevent and / or treat eating disorders such as obesity; treat or prevent bulimia, irritable eating disorder, bulimia nervosa and / or obesity induced by antipsychotic drugs or steroid administration; reduce gastric motility; and / or delay gastric emptying; (iv) Weight maintenance after successful weight loss (whether induced by medication or by diet and exercise) – that is, preventing weight gain after successful weight loss. (v) Prevention and / or treatment of cardiovascular diseases, such as delaying or reducing the development of major adverse cardiovascular events (MACEs) selected from cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, hospitalization due to unstable angina, and hospitalization due to heart failure.

[0411] (vi) Prevention and / or treatment of nonalcoholic steatohepatitis (NASH); (vii) Prevention and / or treatment of cognitive impairment, such as cognitive impairment caused by Alzheimer's disease.

[0412] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In yet another particular aspect, 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.

[0413] As used herein, the term "treatment" refers to medical treatment of any human or other vertebrate subject in need. The subject is expected to have undergone a physical examination by a licensed veterinarian who has provided a preliminary or definitive diagnosis indicating that the use of the specific treatment will be beneficial to the health of the human or other vertebrate. The timing and purpose of the treatment may vary from individual to individual, depending on the subject's current health condition. Therefore, the treatment may be preventative (avoidant), palliative, symptomatic, and / or curative.

[0414] In some embodiments, the indications are (i) and (iii). In some embodiments, the indications are (ii) and (iii).

[0415] In some implementation schemes, the subjects suffering from obesity are people, such as adults or pediatric patients (including infants, children and adolescents).

[0416] Body Mass Index (BMI) is a measure of body fat based on height and weight. The formula is BMI = weight in kilograms / height in meters. 2 Human subjects suffering from obesity may have a BMI ≥30; such subjects may also be described as obese. In some embodiments, human subjects suffering from obesity may have a BMI ≥35 or a BMI in the range of ≥30 to <40. In some embodiments, the obesity is severe obesity or morbid obesity, wherein the human subject may have a BMI ≥40.

[0417] In some embodiments, the present invention relates to methods for treating or preventing overweight in the presence of at least one weight-related comorbidity. In some embodiments, the present invention relates to the use of the said preparation for treating or preventing overweight in the presence of at least one weight-related comorbidity. In some embodiments, the overweight subject is a person, such as an adult or a pediatric patient (including infants, children, and adolescents). In some embodiments, the overweight human subject 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 subject has a BMI in the range of 25 to <30 or a BMI in the range of 27 to <30. In some embodiments, the weight-related comorbidity is selected from hypertension, diabetes (such as type 2 diabetes), dyslipidemia, high cholesterol, and obstructive sleep apnea.

[0418] The term "weight loss" can include the treatment or prevention of obesity and / or overweight.

[0419] The compounds disclosed herein can be administered at an initial body mass index (BMI) of 30 kg / m². 2 Or higher (obese) or 27 kg / m 2 In adult or pediatric patients who are overweight or higher and have at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, or dyslipidemia), it is used as an adjunct to a low-calorie diet and increased physical activity for long-term weight management.

[0420] Dosage frequency The GLP-1 receptor-amylin receptor co-agonist disclosed herein can be administered approximately once daily, such as every 12-36 hours, every 18-30 hours, or approximately every 24 hours.

[0421] The GLP-1 amyloid receptor co-agonist disclosed in this article can be administered approximately every other day, such as every 36-60 hours, every 42-54 hours, or approximately every 48 hours.

[0422] The GLP-1 amyloid receptor co-agonist 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.

[0423] The following is a non-limiting list of embodiments of the present invention.

[0424] Implementation Plan 1. A GLP-1 receptor-amylin receptor co-agonist comprising a polypeptide (R1) according to formula I: Z1-Z2-Z3, It contains 1-3 lysine (Lys, K) residues and optionally contains no disulfide bonds; wherein: • Z1 is a GLP-1 receptor agonist peptide containing up to 9 amino acid modifications relative to SEQ ID NO: 1 (human GLP-1(7-37)); • Z2 is an optional peptide linker; Z3 is an amylin receptor agonist peptide containing a C-terminal amide and up to 7 amino acid modifications relative to SEQ ID NO: 79.

[0425] 2. A GLP-1 receptor-amylin receptor co-agonist comprising a polypeptide (R1) according to formula I: Z1-Z2-Z3, It contains 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 containing up to 9 amino acid modifications relative to SEQ ID NO: 1 (human GLP-1(7-37)); • Z2 is an optional peptide linker; Z3 is an amylin receptor agonist peptide containing a C-terminal amide and up to 7 amino acid modifications relative to SEQ ID NO: 79.

[0426] 3. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, further comprising 1-3 elongated portions (R2-R3) linked to the polypeptide (R1) via the 1-3 lysine residues.

[0427] 4. The GLP-1 receptor-amylin receptor co-agonist according to the aforementioned implementation scheme, which contains 1-3 lysine residues.

[0428] 5. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising 1-2 lysine residues.

[0429] 6. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising one lysine residue.

[0430] 7. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising 1-3 cysteine ​​residues.

[0431] 8. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising 1-2 cysteine ​​residues.

[0432] 9. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising one cysteine ​​residue.

[0433] 10. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist 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.

[0434] 11. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist 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 any one of 21, 30 or 31, or • 21 and 30 or 31.

[0435] 12. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist 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 30, or • 21 and 31.

[0436] 13. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) contains one lysine residue (Lys, K) at any one of positions 12, 17, 20, 21, 28, 30 or 31.

[0437] 14. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) contains one lysine residue (Lys, K) at position 31.

[0438] 15. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the peptide linker (Z2) comprises 0-3 lysine (K) residues.

[0439] 16. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the peptide linker (Z2) comprises 1-2 lysine (Lys, K) residues.

[0440] 17. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the peptide linker (Z2) comprises one lysine (Lys, K) residue.

[0441] 18. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the peptide linker (Z2) comprises 0-3 cysteine ​​(Cys, C) residues.

[0442] 19. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the peptide linker (Z2) comprises 1-2 cysteine ​​(Cys, C) residues.

[0443] 20. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the peptide linker (Z2) comprises one cysteine ​​(Cys, C) residue.

[0444] 21. The GLP-1 receptor-amylin receptor agonist according to any one of the preceding claims, wherein the amylin receptor agonist peptide (Z3) comprises 0-3 lysine (Lys, K) residues.

[0445] 22. The GLP-1 receptor-amylin receptor agonist according to any one of the preceding claims, wherein the amylin receptor agonist peptide (Z3) comprises 0-3 cysteine ​​(Cys, C) residues.

[0446] 23. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, wherein the amylin receptor agonist 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.

[0447] 24. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, wherein the amylin receptor agonist peptide (Z3) comprises one lysine (Lys, K) residue at any one of positions 14, 18, 20, 23, 29 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0448] 25. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, wherein the amylin receptor agonist peptide (Z3) comprises a lysine (Lys, K) residue at position 18 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0449] 26. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising the GLP-1 receptor agonist (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 can be Cys(C), Asp(D), or Lys(K). Xaa10 is Cys (C), Lys (K), or Val (V). Xaa12 can be Cys (C), Lys (K), Arg (R), or Ser (S). Xaa16 can be Cys (C), Glu (E), Gly (G), or Lys (K). Xaa17 can be Cys(C), Gln(Q), or Lys(K). Xaa19 is either Ala (A) or Val (V). Xaa20 can be Cys(C), Lys(K), or Arg(R). Xaa21 can be Cys (C), Glu (E), or Lys (K). Xaa22 can be Phe (F), Trp (W), or Tyr (Y). Xaa23 can be Ile (I), Leu (L), or Val (V). Xaa24 can be Ala (A), Cys (C), Glu (E), or Lys (K). Xaa25 can be Cys (C), Lys (K), or Trp (W). Xaa28 can be Cys(C), Lys(K), or Arg(R). Xaa29 can be 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.

[0450] 27. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising the GLP-1 receptor agonist (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 is either Asp(D) or Lys(K). Xaa10 is either Lys(K) or Val(V). Xaa12 can be 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 can be Phe (F), Trp (W), or Tyr (Y). Xaa23 can be 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.

[0451] 28. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) does not contain isoleucine (Ile, I) at position 22 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0452] 29. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist 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.

[0453] 30. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) comprises phenylalanine (Phe, F) at position 22 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0454] 31. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist 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.

[0455] 32. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) comprises isoleucine (Ile, I) at position 23 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0456] 33. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising the GLP-1 receptor agonist (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-Xaa 17-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 is either Asp(D) or Lys(K). Xaa10 is either Lys(K) or Val(V). Xaa12 can be 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.

[0457] 34. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, Where Z1 is Xaa1-Xaa2-Glu-Gly-Thr-Phe-Thr-Ser-Xaa9-Xaa10-S-Xaa12-Tyr-Leu-Glu-Xaa16-Xaa1 7-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 can be Cys(C), Arg(R), or Ser(S). Xaa16 can be 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.

[0458] 35. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) does not contain proline (Pro, P) at position 12 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0459] 36. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) contains leucine (Leu, L) at position 12 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0460] 37. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) comprises leucine (Leu12) at position 12 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0461] 38. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the optional linker Z2 is absent or contains 1-30, 1-25 or 1-20 naturally occurring amino acid residues (SEQ ID NO:239).

[0462] 39. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the optional linker Z2 comprises 0-20 amino acid residues selected from Ala (A), Glu (E), Gly (G), Lys (K), Pro (P) and Gln (Q).

[0463] 40. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the optional linker Z2 is any one of those listed in Table 1.

[0464] 41. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising an amylin receptor agonist 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 can be 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).

[0465] 42. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising an amylin receptor agonist (Z3) according to Formula III (SEQ ID NO: 256): Xaa1-Xaa2-Xaa3-Leu-Ser-Thr-Xaa7-Ala-Leu-Gly-Arg-Leu-Ser-Xaa 14 -Glu-Leu-His-Xaa 18 -Leu-Xaa 20 -Thr-Leu-Xaa 23 -Arg-Thr-Glu-Thr-Gly-Xaa 29 -Gly-Ser-Xaa 32 , 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 is either 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).

[0466] 43. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) comprises 2, 3, 4, 5, 6, 7, 8 or 9 amino acid modifications relative to human GLP-1 (7-37).

[0467] 44. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) comprises one or two substitutions of naturally occurring amino acid residues with one or two non-natural amino acids.

[0468] 45. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) comprises an imidazole propionyl group (Imp) 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.

[0469] 46. ​​The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) comprises an α-aminoisobutyryl group (Aib) 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.

[0470] 47. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist peptide (Z1) comprises alanine (Ala, A) at any one of positions 8, 25, 30 or 37 relative to human GLP-1 (7-37), or at any one of positions 2, 19, 24 or 31 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0471] 48. The GLP-1 receptor-amylin receptor co-agonist according to any of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) comprises an arginine residue (Arg, R) at any position 26 or 34 relative to human GLP-1 (7-37), or at any position 18 or 26 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0472] 49. The GLP-1 receptor-amylin receptor co-agonist according to any of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) contains 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.

[0473] 50. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) comprises a glutamate residue (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.

[0474] 51. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) comprises a glycine residue (Gly, G) at any position 8 or 36 relative to human GLP-1 (7-37), or at any position 2 or 30 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0475] 52. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) contains 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.

[0476] 53. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) contains 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.

[0477] 54. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) comprises a tryptophan residue (Trp, W) at any position 8 or 31 relative to human GLP-1 (7-37), or at any position 2 or 25 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0478] 55. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the GLP-1 receptor agonist (Z1) comprises a valine residue (Val, V) at any position 16 or 25 relative to human GLP-1 (7-37), or at any position 10 or 19 relative to SEQ ID NO: 238 or SEQ ID NO: 255.

[0479] 56. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) comprises 0, 1, 2, 3 or 4 amino acid modifications relative to SEQ ID NO: 79.

[0480] 57. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) comprises 0, 1, 2 or 3 amino acid modifications relative to SEQ ID NO: 79.

[0481] 58. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) comprises 0, 1 or 2 amino acid modifications relative to SEQ ID NO: 79.

[0482] 59. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) comprises 0 or 1 amino acid modification relative to SEQ ID NO: 79.

[0483] 60. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) comprises 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.

[0484] 61. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) comprises 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.

[0485] 62. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) contains an arginine (Arg, R) residue at position 3 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0486] 63. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) contains a Glu (E) residue at position 7 relative to SEQ ID NO: 240 or SEQ ID NO: 256.

[0487] 64. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the amylin receptor agonist peptide (Z3) contains Leu (L) at position 12 relative to SEQ ID NO: 79.

[0488] 65. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein Z1 is a GLP-1 receptor agonist selected from SEQ ID NO: 2-78.

[0489] 66. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein Z2 is any amino acid residue or peptide presented in Table 1.

[0490] 67. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein Z3 is an amylin receptor agonist peptide (Z3) selected from SEQ ID NO: 79-88.

[0491] 68. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, further comprising an extension portion linked to each lysine residue.

[0492] 69. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein each lysine residue is acylated.

[0493] 70. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the extended portion comprises a C14-C20 diacid.

[0494] 71. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the extended portion comprises C14 diacid, C16 diacid, C18 diacid, C20 diacid, C18-tetrazole, C14-sulfonic acid, 4-(9-carboxynonyloxy)benzoic acid, 4-(10-carboxydecyloxy)benzoic acid or 3-(9-carboxynonyloxy)benzoic acid.

[0495] 72. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising two C14 diacids, C16 diacids, or C18 diacids.

[0496] 73. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, comprising three C14 diacids.

[0497] 74. The GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments, wherein the lysine is linked to any one of the optional linkers (“R2”) presented in Table 3.

[0498] 75. A GLP-1 receptor-amylin receptor co-agonist comprising a polypeptide selected from any one of SEQ ID NO: 117-236.

[0499] 76. A GLP-1 receptor-amylin receptor co-agonist selected from any of those identified in Example 1a.

[0500] 77. A pharmaceutically acceptable salt of the GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments.

[0501] 78. A pharmaceutical formulation comprising a GLP-1 receptor-amylin receptor co-agonist according to any one of the foregoing embodiments.

[0502] 79. The pharmaceutical preparation according to any one of the foregoing embodiments, for oral administration.

[0503] 80. The pharmaceutical preparation according to any one of the foregoing embodiments is a solid pharmaceutical preparation.

[0504] 81. The solid pharmaceutical preparation according to any one of the foregoing embodiments is a tablet.

[0505] 82. The tablet according to the aforementioned embodiment comprises sodium N-(8-(2-hydroxybenzoyl)amino)octanoate and magnesium stearate.

[0506] 83. The tablet according to the aforementioned embodiment comprises 75-600 mg of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate and 7-8.5 mg of magnesium stearate.

[0507] 84. The pharmaceutical preparation according to any one of embodiments 78-83, which is used for administration approximately once a day, for example every 12-36 hours, for example every 18-30 hours, for example approximately every 24 hours.

[0508] 85. The GLP-1 receptor-amylin receptor co-agonist according to any one of embodiments 1-77 or the formulation according to any one of embodiments 78-84, used as a medicine.

[0509] 86. A GLP-1 receptor-amylin receptor co-agonist according to any one of embodiments 1-77 or a formulation according to any one of embodiments 78-84, for the treatment of subjects with an initial body mass index (BMI) of 27 or higher, such as 30 or higher.

[0510] 87. A GLP-1 receptor-amylin receptor co-agonist according to any one of embodiments 1-77 or a formulation according to any one of embodiments 78-84, for the treatment of a subject with an initial body mass index (BMI) of 27 or higher and suffering from at least one weight-related comorbidity.

[0511] 88. A GLP-1 receptor-amylin receptor co-agonist according to any one of embodiments 1-77 or a formulation according to any one of embodiments 78-84, wherein the initial body mass index (BMI) is 30 kg / m². 2 Or higher (obese) or 27 kg / m 2 In adult subjects who are overweight or higher and have at least one weight-related comorbidity, it is used as an adjunct to low-calorie diets and increased physical activity for long-term weight management.

[0512] 89. The use according to the foregoing embodiments, wherein the comorbidity is diabetes and / or cardiovascular disease.

[0513] 90. A GLP-1 receptor-amylin receptor co-agonist according to any one of embodiments 1-77 or a formulation according to any one of embodiments 78-84, for the treatment of a subject with diabetes such as type 2 diabetes.

[0514] 91. A GLP-1 receptor-amylin receptor co-agonist according to any one of embodiments 1-77 or a formulation according to any one of embodiments 78-84, for the treatment and / or prevention of cardiovascular disease.

[0515] 92. A GLP-1 receptor-amylin receptor co-agonist according to any one of embodiments 1-77 or a formulation according to any one of embodiments 78-84, for the treatment of NASH.

[0516] 93. A GLP-1 receptor-amylin receptor co-agonist according to any one of embodiments 1-77 or a formulation according to any one of embodiments 78-84, for the treatment and / or prevention of cognitive impairment, such as cognitive impairment caused by Alzheimer's disease.

[0517] Example Example 1: Synthesis of GLP-1 receptor-amylin receptor co-agonists and comparative compounds This embodiment provides the identity, preparation materials, and synthesis methods of many compounds according to the present invention.

[0518] The identification, preparation materials, and synthesis methods of the comparative compounds described herein are also provided.

[0519] Materials and Methods List of abbreviations The following abbreviations, listed in alphabetical order, will be used in the following text: Ac: Acetyl group Aib: α-Aminoisobutyric acid AUC: Area under the curve Boc: tert-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-linked immunosorbent assay Fmoc: 9-fluorenylmethoxycarbonyl HFIP: 1,1,1,3,3,3-Hexafluoro-2-propanol or hexafluoroisopropanol HOBt: 1-Hydroxybenzotriazole HPLC: High Performance Liquid Chromatography HSA: Human serum albumin Imp: Imidazole propionyl iv: Intravenous LCMS or LC-MS: Liquid Chromatography-Mass Spectrometry 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: Standard error of the mean tBu: tert-butyl TFA: Trifluoroacetic acid TIS: Triisopropylsilane Trt: Triphenylmethyl or Triphenylmethyl Trx: Tranexamic acid UPLC: Ultra-high performance liquid chromatography General preparation method This section covers general methods for solid-phase peptide synthesis (SPPS method, including methods for cleaving peptides from resin and removing protecting groups and their purification). It also includes LCMS methods for detecting and characterizing the resulting peptides.

[0520] The resins used to prepare C-terminal peptide amides are PAL Amide AM resin (e.g., loaded with 0.6 mmol / g), H-Rink Amide-ChemMatrix resin (e.g., loaded with 0.5 mmol / g), Rink Amide AM polystyrene resin (e.g., loaded with 0.3–0.7 mmol / g), Tentagel® rink amide resin (e.g., loaded with 0.2–0.3 mmol / g), or similar resins suitable for SPPS.

[0521] The Fmoc-protected amino acid derivatives used specifically include those conforming to recommended standards: such as 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, and Fmoc-Protein Technologies, or Novabiochem, provided by AAPPTEC, Anaspec, Bachem, ChemImpex, Iris Biotech, Midwest Biotech, Gyros Protein Technologies, or Novabiochem. 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. Other structural units, such as Fmoc-pseudoproline and similar derivatives, were used in some difficult sequences. Natural L-type amino acids were used unless otherwise specified. Boc protection of the N-terminal amino acid at the α-amino group is achieved by using a reagent pre-loaded with a Boc group (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 loading an amino acid at the N-terminus of the peptide. In cases involving side-chain loading, Fmoc-Lys(Mtt)-OH and similar derivatives, such as, but not limited to, Fmoc-Lys(ivDDE) with an orthogonal protecting group at the ε-amino position, are used. The ε-amino derivative is released using a suitable orthogonal deprotecting agent such as HFIP in DCM, and the side chain is loaded stepwise by SPPS or by directly coupling the ε-amino functional group to the side-chain structural unit of an activated ester (e.g., an NHS ester).

[0522] When using SPPS for stepwise side-chain linkage, the following appropriately protected structural units are 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, tert-butyl octadecanoate, tert-butyl nonadecanoate, tert-butyl eicosanoate, tert-butyl hexadecanoate, tert-butyl tetradecanoate, or tert-butyl 4-(9-carboxynonyloxy)benzoate. All the following operations are performed on a synthetic scale of 50–450 μmol.

[0523] SPPS of the peptide backbone: SPPS was performed using a Fmoc-based chemical method on a SymphonyX Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714U.SA). Fmoc deprotection was achieved using 20% ​​piperidine in DMF containing 0 to 0.2 M Oxyma. Peptide coupling was performed using DIC / Oxyma Pure®. An amino acid / Oxyma Pure® solution (0.3 M / 0.3 M in DMF, 3–12 times molar excess) was added to the resin, followed by the same molar equivalents of DIC (as a 0.6–1.5 M solution in DMF) and collidine (1.5 M in DMF). The stepwise assembly is performed using the following steps: 1) Pre-swell the resin with DMF; 2) Deprotect the Fmoc by treating it 1-5 times with 20% piperidine in DMF containing 0 to 0.2 M Oxyma Pure®, each time for 5-30 min; 3) Wash with DMF to remove trace amounts of piperidine; 4) Couple the Fmoc-amino acid by mixing 3-12 equivalents of a 0.3 M solution of the Fmoc-amino acid (in DMF containing 0.3 M Oxyma Pure®) with an equimolar volume of DIC and chlorpheniramine for 1-12 hours. For sterically hindered amino acids, this coupling step is repeated once or twice; 5) Wash with DMF to remove excess reagent; 6) Perform a final wash with DCM at the end of assembly, which prepares the resin for attaching modifying groups to the lysine side chain.

[0524] Alternatively, SPPS can be performed using a Fmoc-based chemical method on the SymphonyX Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714U.SA). Fmoc deprotection is achieved using 20% ​​piperidine in DMF containing 0 to 0.2 MOxyma. 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 (as a 0.6 M solution in DMF). The stepwise assembly is performed using the following steps: 1) Pre-swell the resin with DMF; 2) Deprotect the Fmoc by treating it 1-5 times with 20% piperidine in DMF containing 0 to 0.2 M Oxyma Pure®, each time for 5-30 min; 3) Wash with DMF to remove trace amounts of piperidine; 4) Couple the Fmoc-amino acid by mixing 3-12 equivalents of a 0.3 M solution of the Fmoc-amino acid (in DMF containing 0.3 M Oxyma Pure®) with an equimolar volume of DIC for 1-12 hours. For sterically hindered amino acids, this coupling step is repeated once or twice; 5) Wash with DMF to remove excess reagent; 6) Perform a final wash with DCM at the end of assembly, which prepares the resin for attaching modifying groups to the lysine side chain.

[0525] Alternatively, protected peptide resins can be synthesized on a Prelude solid-phase peptide synthesizer (Protein Technologies, Tucson, USA) using a manufacturer-supplied machine program according to the Fmoc strategy. Coupling is accomplished using DIC (dicyclohexylcarbodiimide) and Oxyma Pure (ethyl 2-cyano-2-(hydroxyimino)-ethyl acetate, Merck, Novabiochem, Switzerland) mediated in DMF. Fmoc-amino acid coupling is performed as described above, with an amino acid substitution of 4-8 times (4-8 equivalents) relative to the resin. Coupling times range from 1 hour to 6 hours. Fmoc-Arg(pbf)-OH is coupled using a double coupling program (1 hour + 1 hour). Stepwise solid-phase assembly was performed on Prelude using the following steps: 1) Deprotection (removal of Fmoc) with 20-25% piperidine in DMF for 2 x 4-10 min; 2) Washing with DMF and DCM (removal of piperidine); 3) Initiation by adding 1 / 10 volume of 3M DIC in DMF and 1 / 10 volume of cyproheptadine in DMF, coupling with 3-10 equivalents of excess Fmoc-amino acids (0.3M Fmoc-amino acids in 0.3M Oxyma Pure in DMF) for 1-4 h. Mixing was performed from time to time by bubbling with nitrogen; 4) Washing (removal of excess amino acids and reagents using DMF and DCM). The final step included washing with DCM, which prepared the resin for attachment of modifying groups to the lysine side chains.

[0526] Linkage between the side chain and the protected peptide backbone bound to the resin: The N-ε-lysine Mtt protecting group is removed by washing the resin for multiple cycles (e.g., 1 x 5 min and 2 x 20 min) with a suitable orthogonal deprotection mixture, such as, but not limited to, 20-30% HFIP in DCM containing 0-5% TIS, followed by washing with piperidine, DMF and DCM.

[0527] Acylation is performed manually or on a solid-phase peptide synthesizer, as described in the "SPPS of Peptide Backbone" section of this method. This solid-phase peptide synthesizer is, for example, but not limited to, the SymphonyX Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 USA), employing a stepwise addition of structural units, such as, but not limited to, Fmoc-8-amino-3,6-dioxanoic acid (Fmoc-OEG-OH), Fmoc-Glu-OtBu, and Fmoc-tranexamic acid (Fmoc-Trx-OH). The fatty acid moiety is introduced using suitable structural units, such as, but not limited to, tert-butyl octadecanoate, tert-butyl eicosanoate, tert-butyl hexadecanoate, tert-butyl tetradecanoate, and tert-butyl 4-(9-carboxynonyloxy)benzoate.

[0528] Alternatively, suitable side-chain structural units equipped with activated esters such as NHS can be used, as described in Part I of this section, to directly install the side-chain portion in a single step after the removal of the Mtt group.

[0529] Cleavage and purification of resin-bound peptides After synthesis, the resin is washed with DCM and treated with a mixture of TFAs in the presence of 1-20% (v / v) of a scavenger, such as, but not limited to, water, TIS, DTT, and DODT. The cleavage reaction is typically carried out at room temperature for 1-3 hours. Alternatively, cleavage can be performed for a shorter period (15-60 minutes) at an elevated temperature (e.g., 50°C). Following the cleavage reaction, the crude peptide is precipitated with cold (e.g., 5°C) diethyl ether. The precipitate is washed with diethyl ether and dissolved in a suitable mixture of water and MeCN. Optionally, a suitable water-miscible co-solvent, such as acetic acid, is used.

[0530] The crude peptide solution was purified by reversed-phase preparative HPLC (Waters Deltaprep 4000) on a C18 silica column. Elution was performed with a gradient of gradually increasing MeCN aqueous solution containing 0.1% TFA. The fractions were analyzed by analytical UPLC. Fractions containing the purified target peptide were combined and lyophilized.

[0531] Alternatively, or when further purification is required, the crude peptide or lyophilized peptide TFA salt isolated as described above is dissolved in a neutral (e.g., pH 7-8) aqueous buffer based on a common buffer salt (e.g., but not limited to sodium hydrogen phosphate or ammonium bicarbonate) and purified on a column containing C18 silica gel using a reversed-phase preparative HPLC (Waters Deltaprep 4000). Elution was performed using a gradually increasing gradient of MeCN in an aqueous buffer (e.g., but not limited to sodium phosphate (5-100 mM, pH 7-8, or 2-40 g / L ammonium bicarbonate)). Fractions were analyzed by analytical UPLC. Fractions containing the purified target peptide were combined, acidified to pH 2 with TFA, and diluted with water until the total MeCN concentration was <20%. Optionally, the resulting mixture was degassed by vacuum filtration. The solution was then purified by reversed-phase preparative HPLC (Waters Deltaprep 4000) on a C18 silica column. Elution was performed using a gradually increasing gradient of aqueous MeCN containing 0.1% TFA. Fractions were analyzed by analytical UPLC. Fractions containing the purified target peptide were combined and lyophilized.

[0532] LCMS characterization method: LCMS34: LCMS34 was performed on a device consisting of a Waters Acquity UPLC H Class system and a Waters Xevo G2-XS QTof. Eluents: A: 0.1% formic acid in MQ aqueous solution; B: 0.1% formic acid in MeCN solution.

[0533] The analysis was performed at RT (column temperature 40 °C) by injecting an appropriate volume of sample onto the column and eluting with gradients of A and B. UPLC conditions, detector settings, and mass spectrometer settings were as follows: Column: Waters Acquity BEH, C-18, 1.7 µm, 2.1 mm x 50 mm. Gradient: Linear 5%–95% B over 4.0 min, flow rate 0.4 ml / min. Detection: MS resolution mode; Ionization method: ES. Scan: 50–4000 amu.

[0534] LCMS36: LCMS36 was performed on a device consisting of a Waters Acquity UPLC H Class system and a Waters Xevo G2-XS QTof. Eluents: A: 0.1% formic acid in MQ aqueous solution; B: 0.1% formic acid in MeCN solution.

[0535] The analysis was performed at RT (column temperature 60 °C) by injecting an appropriate volume of sample onto the column and eluting with gradients of A and B. UPLC conditions, detector settings, and mass spectrometer settings were as follows: Column: Phenomenex Aeris, C-4, 3.6 µm wide well, 2.1 mm x 50 mm. Gradient: Stepwise elution over 8 min; 5%–25% B over 1.0 min, 25%–65% B over 6 min, 65%–95% B over 0.5 min, isocratic elution with 95% B for 0.5 min, flow rate 0.4 ml / min. Detection: MS resolution mode; ionization method: ES. Scan: 50–4000 amu.

[0536] LCMS_ZQ: LCMS_ZQ was performed on an LCMS instrument consisting of a Waters Acquity UPLC system coupled with a Waters Acquity TUV detector and a Waters Micromass ZQ 2000 detector. Eluents: A – 0.05% TFA in MQ aqueous solution; B – 0.05% TFA in acetonitrile solution.

[0537] The analysis was performed at RT (column temperature 40 °C) by injecting an appropriate volume (0.2–10 µl) of sample onto the column and eluting with gradients of A and B. Column: Waters Acquity UPLC BEH, C-18, 1.7 µm, 2.1 mm x 50 mm. Gradient run time: linear 5–95% B over 4.5 min, followed by 95% B for 0.5 min, 95–5% B for 0.5 min, and 5% B for 0.5 min, at a flow rate of 0.45 ml / min. Detection: Ionization method: positive electrospray ionization; 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 method: quadrupole. LCMS01: LCMS_01 was performed on a setup consisting of a Waters Acquity UPLC system and an LCT Premier XE mass spectrometer from Micromass. Eluents: A: 0.1% formic acid in MQ aqueous solution; B: 0.1% formic acid in MeCN solution. The analysis was performed at RT (column temperature 40°C) by injecting an appropriate volume of sample onto the column and eluting with a gradient of 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 over 4.0 min at a flow rate of 0.4 ml / min. Detection: 214 nm (analog output from TUV (tunable UV detector)). MS ionization mode: API-ES. Scan: 500-2000 atomic mass units (amu).

[0539] Prepared compounds Example 1a: Compounds according to the present invention Compound 0007 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 332 H 531 N 89 O 112 Calculated molecular weight (average): 7561.3 g / mol Monoisotope mass: 7556.9 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1513.3 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 117 Compound 0009 H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGEGEEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 347 H 552 N 92 O 121 Calculated molecular weight (average): 7948.6 g / mol Monoisotope mass: 7944.0 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1591 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAREFIAWLVRGKGEGEGEEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 118 Compound 0010 H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGEGEGE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 353 H 564 N 96 O 122 Calculated molecular weight (average): 8104.8 g / mol Monoisotope mass: 8100.1 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1622 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGEGEGEKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 119 Compound 0019 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 362 H 575 N 97 O 124 Calculated molecular weight (average): 8270.0144 g / mol Monoisotope mass: 8265.1670 g / mol LCMS36: Actual Measurement (M + 5H) 5+ 1654.85 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGQEPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 120 Compound 0026 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 358 H 570 N 96 O 121 Calculated molecular weight (average): 8154.9270 g / mol Monoisotope mass: 8150.1400 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1631.04 (Most Abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 121 Compound 0035 Imp-AEGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 344 H 552 N 90 O 113 Calculated molecular weight (average): 7756.5989 g / mol Monoisotope mass: 7752.0214 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1552 (the most abundant) The amino acid sequence of XAEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 122. Compound 0039 HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxy-tetrazylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxy-tetrazylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 359 H577 N 91 O 124 Calculated molecular weight (average): 8151.9580 g / mol Monoisotope mass: 8147.1642 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1631.6 (the most abundant) The amino acid sequence of HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 123. Compound 0040 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 334 H 534 N 90 O 113 Calculated molecular weight (average): 7618.3490 g / mol Monoisotope mass: 7613.8806 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1524.92 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 124. Compound 0042 H-Aib-EGTFTSDVSSYLEGQAAKEFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 336 H 540 N 90 O 112 Calculated molecular weight (average): 7632.4186 g / mol Monoisotope mass: 7627.9326 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1527.76 (the most abundant) The amino acid sequence of 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]hexanoyl])-EFIAWLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 338 H 543 N 91 O 113 Calculated molecular weight (average): 7689.4699 g / mol Monoisotope mass: 7684.9541 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1538.8 (Most abundant) The amino acid sequence of 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]hexanoyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 342 H 552 N 92 O 113 Calculated molecular weight (average): 7760.5909 g / mol Monoisotope mass: 7756.0276 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1553.22 (the most abundant) The amino acid sequence of 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-amide C 334 H 535 N 89 O 112 Calculated molecular weight (average): 7589.3508 g / mol Monoisotope mass: 7584.8904 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1519.1 (Most abundant) The amino acid sequence of XAEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 122. Compound 0052 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 344 H 549 N 95 O 118 Calculated molecular weight (average): 7903.6056 g / mol Monoisotope mass: 7898.9879 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1581.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 126. Compound 0056 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-QEPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 401 H 645 N 101 O 136 Calculated molecular weight (average): 9057.0071 g / mol Monoisotope mass: 9051.6660 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1812.4 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGKQEPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 127 Compound 0057 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 398 H 641 N 101 O 136 Calculated molecular weight (average): 9016.9432 g / mol Monoisotope mass: 9011.6347 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1804.1 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGQEKGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 128 Compound 0071 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 403 H 648 N 102 O 137 Calculated molecular weight (average): 9114.0584 g / mol Monoisotope mass: 9108.6874 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1823.7 (The most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGQEPGQEPKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 129. Compound 0072 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 367 H 593 N 93 O 124 Calculated molecular weight (average): 8292.1840 g / mol Monoisotope mass: 8287.2955 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1659.27 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 130. Compound 0073 H-Aib-EGTFTSDVSSYLEGQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 368 H 598 N 96 O 122 Calculated molecular weight (average): 8319.2557 g / mol Monoisotope mass: 8314.3540 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1664.69 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAARKFIAWLVRGRGGKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 131 Compound 0074 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 371 H 602 N 96 O 124 Calculated molecular weight (average): 8391.3184 g / mol Monoisotope mass: 8386.3752 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1679.1 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 132. Compound 0075 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 363 H 584 N 90 O 124 Calculated molecular weight (average): 8193.0497 g / mol Monoisotope mass: 8188.2159 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1639.45 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGKGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 133. Compound 0076 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 367 H 593 N 93 O 124 Calculated molecular weight (average): 8292.1840 g / mol Monoisotope mass: 8287.2955 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1659.48 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGKGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 134. Compound 0077 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLV-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 367 H 593 N 93 O 124 Calculated molecular weight (average): 8292.1840 g / mol Monoisotope mass: 8287.2955 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1659.48 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVKGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 135 Compound 0083 H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 364 H 582 N 100 O 122 Calculated molecular weight (average): 8311.1127 g / mol Monoisotope mass: 8306.2411 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1662.34 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEGQAAREFIAWLVRGRKGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 136. Compound 0084 H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEP-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 364 H 582 N 100 O 122 Calculated molecular weight (average): 8311.1127 g / mol Monoisotope mass: 8306.2411 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1663 (the most abundant) The amino acid sequence of 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-amide C 364 H 582 N 100 O 122 Calculated molecular weight (average): 8311.1127 g / mol Monoisotope mass: 8306.2411 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1662.24 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPGQAPKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 138. Compound 0086 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 374 H 602 N 94 O 129 Calculated molecular weight (average): 8479.3341 g / mol Monoisotope mass: 8474.3436 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1696.69 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 139. Compound 0087 HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 372 H 598 N 94 O 129 Calculated molecular weight (average): 8451.2809 g / mol Monoisotope mass: 8446.3123 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1691.08 (Most Abundant) The amino acid sequence of HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 140. Compound 0089 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 378 H 610 N 94 O 129 Calculated molecular weight (average): 8535.4404 g / mol Monoisotope mass: 8530.4062 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1707.9 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 139. Compound 0090 HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 376 H 606 N 94 O 129 Calculated molecular weight (average): 8507.3872 g / mol Monoisotope mass: 8502.3749 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1702.49 (Most abundant) The amino acid sequence of HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 140. Compound 0092 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 352 H561 N 99 O 122 Calculated molecular weight (average): 8131.8108 g / mol Monoisotope mass: 8127.0737 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1627.5 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 141 Compound 0093 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 360 H 573 N 103 O 126 Calculated molecular weight (average): 8360.0161 g / mol Monoisotope mass: 8355.1596 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1672.8 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 142 Compound 0094 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 346 H 553 N 95 O 118 Calculated molecular weight (average): 7931.6587 g / mol Monoisotope mass: 7927.0192 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1587.2 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 126. Compound 0095 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 354 H 566 N 96 O 119 Calculated molecular weight (average): 8070.8536 g / mol Monoisotope mass: 8066.1189 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1615.0 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 126. Compound 0096 HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 372 H 583 N 93 O 130 Calculated molecular weight (average): 8438.1545 g / mol Monoisotope mass: 8433.1868 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1688.65 (the most abundant) The amino acid sequence of HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 143. Compound 0097 HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 380 H 595 N 97 O 134 Calculated molecular weight (average): 8666.3598 g / mol Monoisotope mass: 8661.2726 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1734.26 (the most abundant) The amino acid sequence of HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 144 Compound 0098 HGEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 388 H 607 N 101 O 138 Calculated molecular weight (average): 8894.5651 g / mol Monoisotope mass: 8889.3585 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1779.88 (the most abundant) The amino acid sequence of HGEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 145 Compound 0099 HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 381 H 590 N 94 O 130 Calculated molecular weight (average): 8567.3131 g / mol Monoisotope mass: 8562.2446 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1714.46 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 146. Compound 0100 HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 389 H 602 N 98 O 134 Calculated molecular weight (average): 8795.5184 g / mol Monoisotope mass: 8790.3305 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1760.08 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 147 Compound 0101 HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 397 H 614 N 102 O 138 Calculated molecular weight (average): 9023.7237 g / mol Monoisotope mass: 9018.4163 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1805.49 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 148 Compound 0102 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(4-[17-(1H-tetrazo-5-yl)heptadecanoylaminosulfonyl]butyryl)-ELSTAALGRLSAELHELATLPRTETGSGSP-amide C 311 H 499 N 89 O 98 S Calculated molecular weight (average): 7084.8923 g / mol Monoisotope mass: 7080.6520 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1418 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 149. Compound 0103 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(4-[17-(1H-tetrazo-5-yl)heptadecanoylaminosulfonyl]butyryl)-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 322 H 516 N 92 O 104 S Calculated molecular weight (average): 7372.1614 g / mol Monoisotope mass: 7367.7637 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1475 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 150. Compound 0105 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGQEPGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 386 H 620 N 98 O 133 Calculated molecular weight (average): 8761.6298 g / mol Monoisotope mass: 8756.4764 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1753.31 (the richest) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGQEPGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 151. Compound 0106 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGQEPGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 390 H 628 N 98 O 133 Calculated molecular weight (average): 8817.7361 g / mol Monoisotope mass: 8812.5390 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1764.33 (the richest) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGEGQEPGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 151. Compound 0109 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 383 H 619 N 99 O 130 Calculated molecular weight (average): 8690.5983 g / mol Monoisotope mass: 8685.4869 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1738.9 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGKGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 152. Compound 0110 H-Aib-EGTFTSDVSSYLEEQAAR-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]hexanoyl])-FIAWLVRG-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]hexanoyl])-GGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 395 H 643 N 103 O 132 Calculated molecular weight (average): 8946.9428 g / mol Monoisotope mass: 8941.6768 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1790.3 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGKGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 152. Compound 0111 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-amide C 343 H 550 N 94 O 116 Calculated molecular weight (average): 7846.5973 g / mol Monoisotope mass: 7842.0028 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1570.22 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. Compound 0114 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])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 339 H 544 N 92 O 114 Calculated molecular weight (average): 7732.4947 g / mol Monoisotope mass: 7727.9599 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1547.4 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 154. Compound 0115 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])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 335 H 538 N 90 O 112 Calculated molecular weight (average): 7618.3920 g / mol Monoisotope mass: 7613.9169 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1524.6 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 150. Compound 0116 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 375 H 610 N 96 O 124 Calculated molecular weight (average): 8447.4247 g / mol Monoisotope mass: 8442.4378 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1690.3 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 155. Compound 0120 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 353 H 567 N 95 O 117 Calculated molecular weight (average): 8013.8454 g / mol Monoisotope mass: 8009.1338 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1603.63 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153. Compound 0124 Imp-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(4-[17-(1H-tetrazo-5-yl)heptadecanoylaminosulfonyl]butyryl)-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 322 H 515 N 91 O 104 S Calculated molecular weight (average): 7357.1468 g / mol Monoisotope mass: 7352.7528 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1472 (the most abundant) The amino acid sequence of XXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 156. Compound 0125 H-Aib-EGTFTSDVSSYLEEQAAR-K(4-[17-(1H-tetrazo-5-yl)heptadecanoylaminosulfonyl]butyryl)-FIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 319 H 512 N 92 O 102 S Calculated molecular weight (average): 7300.0988 g / mol Monoisotope mass: 7295.7426 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1461 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 157. Compound 0127 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 369 H 598 N 92 O 123 Calculated molecular weight (average): 8291.2390 g / mol Monoisotope mass: 8286.3367 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1659.1 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 158. Compound 0128 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 371 H 600 N 92 O 125 Calculated molecular weight (average): 8349.2751 g / mol Monoisotope mass: 8344.3421 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1670.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 159. Compound 0129 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 377H 612 N 96 O 126 Calculated molecular weight (average): 8505.4608 g / mol Monoisotope mass: 8500.4432 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1702.0 (Most comprehensive) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 160. Compound 0131 H-Aib-EGTFTSDVSSYLEEQAAR-K([(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyryl])-FIAWLVRGR-K([(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyryl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 347 H 560 N 90 O 110 Calculated molecular weight (average): 7752.6963 g / mol Monoisotope mass: 7748.0993 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1551.6 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 161. Compound 0132 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 333 H 532 N 88 O 113 Calculated molecular weight (average): 7576.3090 g / mol Monoisotope mass: 7571.8588 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1516.11 (Most Abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 162. Compound 0141 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 325 H 520 N 88 O 106 Calculated molecular weight (average): 7356.1323 g / mol Monoisotope mass: 7351.8005 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1472 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 150. Compound 0142 Imp-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 325 H 519 N 87 O 106 Calculated molecular weight (average): 7341.1177 g / mol Monoisotope mass: 7336.7896 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1469 (the most abundant) The amino acid sequence of XXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 156.

[0540] Compound 0144 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLV-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 339 H 541 N 91 O 116 Calculated molecular weight (average): 7747.4629 g / mol Monoisotope mass: 7742.9232 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1550.39 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVKGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 163. Compound 0145 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGRG-K(4-[17-(1H-tetrazo-5-yl)heptadecanoylaminosulfonyl]butyryl)-GGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 325 H 521 N 95 O 105 S Calculated molecular weight (average): 7471.2527 g / mol Monoisotope mass: 7466.8070 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1495 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRGKGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 164. Compound 0146 H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRG-K(4-[17-(1H-tetrazo-5-yl)heptadecanoylaminosulfonyl]butyryl)-GGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 319 H 508 N 90 O 105 S Calculated molecular weight (average): 7316.0518 g / mol Monoisotope mass: 7311.6899 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1464 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIEWLVRGKGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 165 Compound 0147 H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRG-K(4-[17-(1H-tetrazo-5-yl)heptadecanoylaminosulfonyl]butyryl)-ASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 313 H 499 N 87 O 102 S Calculated molecular weight (average): 7144.8979 g / mol Monoisotope mass: 7140.6255 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1430 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIEWLVRGKASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 166.

[0541] Compound 0151 H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 340 H 546 N 94 O 114 Calculated molecular weight (average): 7774.5346 g / mol Monoisotope mass: 7769.9817 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1555.81 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 167.

[0542] Compound 0156 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGQAPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 358 H 570 N 96 O 121 Calculated molecular weight (average): 8154.9270 g / mol Monoisotope mass: 8150.1400 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1631.04 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGQAPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 168. Compound 0157 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGQAPGQEPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 360 H 574 N 96 O 121 Calculated molecular weight (average): 8182.9802 g / mol Monoisotope mass: 8178.1713 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1636.65 (single isotope) The amino acid sequence of 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-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-EFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 350 H 561 N 97 O 119 Calculated molecular weight (average): 8031.7778 g / mol Monoisotope mass: 8027.0828 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1607.2 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGGGGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 126. Compound 0160 H-Aib-EGTFTSDVSSYLEEQAAR-K([(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl])-FIAWLVRGRGGGGGGGGG-K([(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 363 H 584 N 98 O 118 Calculated molecular weight (average): 8209.1069 g / mol Monoisotope mass: 8204.2710 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1642.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGGGGKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 169. Compound 0179 H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EAEAEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 363 H 581 N 95 O 123 Calculated molecular weight (average): 8244.0599 g / mol Monoisotope mass: 8239.2129 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1648.86 (single isotope) The amino acid sequence of 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-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-EAEAEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 369 H 593 N 97 O 124 Calculated molecular weight (average): 8372.2322 g / mol Monoisotope mass: 8367.3078 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1674.46 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIEWLVRGRKEAEAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 170. Compound 0191 H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEP-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQAPASRLSTEALGRLSAELHELATLPRTETGSGSP-amide C 362 H 582 N 102 O 119 Calculated molecular weight (average): 8267.1065 g / mol Monoisotope mass: 8262.2625 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1653.45 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPKGQAPASRLSTEALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 171. Compound 0202 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 360 H 574 N 96 O 121 Calculated molecular weight (average): 8182.9802 g / mol Monoisotope mass: 8178.1713 g / mol LCMS34: Actual Measurement (M + 5H)5+ 1636.67 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGQEPGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 121.

[0543] Compound 0231 HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-amide C 387 H 602 N 100 O 131 Calculated molecular weight (average): 8751.5122 g / mol Monoisotope mass: 8746.3519 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1751.09 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 172.

[0544] Compound 0232 HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-amide C 387 H 602 N 100 O 131 Calculated molecular weight (average): 8751.5122 g / mol Monoisotope mass: 8746.3519 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1751.17 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 173.

[0545] Compound 0233 HWEGTFTSDVSSYLEEQAAREFIEWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-amide C 386 H 597 N 97 O 133 Calculated molecular weight (average): 8724.4405 g / mol Monoisotope mass: 8719.2933 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1745.54 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAAREFIEWLVRGKGEGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 174. Compound 0234 HWEGTFTSDVSSYLEEQAAREFIEWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEGGGGGASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-amide C 386 H 597 N 97 O 133 Calculated molecular weight (average): 8724.4405 g / mol Monoisotope mass: 8719.2933 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1745.73 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAAREFIEWLVRGKGEGGGGGASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 175.

[0546] Compound 0235 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(3-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])--K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[10-(3-carboxyphenoxy)decanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 371 H 584 N 94 O 127 Calculated molecular weight (average): 8393.1603 g / mol Monoisotope mass: 8388.2129 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1678.65 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGKKGGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 176.

[0547] Compound 0254 HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 361 H 571 N 97 O 118 Calculated molecular weight (average): 8157.9755 g / mol Monoisotope mass: 8153.1662 g / mol LCMS34: Actual Measurement (M + 5H) 5+1632.55 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 177.

[0548] Compound 0255 HWEGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[11-(4-carboxyphenoxy)undecanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[11-(4-carboxyphenoxy)undecanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-amide C 389 H 606 N 100 O 131 Calculated molecular weight (average): 8779.5653 g / mol Monoisotope mass: 8774.3832 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1756.92 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 172.

[0549] Compound 0259 H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGGGGGGEASELSTAALGRLSAELH-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LATLPRTETGSGSP-amide C 372 H 602 N 98 O 126 Calculated molecular weight (average): 8463.3413 g / mol Monoisotope mass: 8458.3711 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1693.6 (the most abundant) The amino acid sequence of HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHKLATLPRTETGSGSP has SEQ ID NO: 178.

[0550] Compound 0260 H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGGGGGGEASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-amide C 374 H 604 N 98 O 128 Calculated molecular weight (average): 8521.3774 g / mol Monoisotope mass: 8516.3766 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1705.3 (Most abundant) The amino acid sequence of HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 179.

[0551] Compound 0261 H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGRGGGGGEASELSTAALGRLSAELHELATL-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-RTETGSGSP-amide C 372 H 602 N 98 O 128 Calculated molecular weight (average): 8495.3401 g / mol Monoisotope mass: 8490.3610 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1699.9 (Most abundant) The amino acid sequence of HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLKRTETGSGSP has SEQ ID NO: 180.

[0552] Compound 0263 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 345 H 555 N 91 O 113 Calculated molecular weight (average): 7785.6401 g / mol Monoisotope mass: 7781.0480 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1558.2 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 150.

[0553] Compound 0264 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 347 H 555 N 91 O 116 Calculated molecular weight (average): 7857.6597 g / mol Monoisotope mass: 7853.0327 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1572.5 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 181.

[0554] Compound 0265 H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 348 H 559 N 93 O 115 Calculated molecular weight (average): 7885.7162 g / mol Monoisotope mass: 7881.0752 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1577.9 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 182.

[0555] Compound 0266 H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 348 H 558 N 94 O 116 Calculated molecular weight (average): 7914.7143 g / mol Monoisotope mass: 7910.0654 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1583.9 (the most abundant) The amino acid sequence of HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 183.

[0556] Compound 0267 HWEGTFTSDVSSYLEEQAAREFIEWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 350 H 551 N 89 O 115 Calculated molecular weight (average): 7845.6472 g / mol Monoisotope mass: 7841.0003 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1570.1 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAAREFIEWLVRGKGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 184.

[0557] Compound 0268 HWEGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C360 H 570 N 96 O 117 Calculated molecular weight (average): 8114.9508 g / mol Monoisotope mass: 8110.1604 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1624.0 (Most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 185.

[0558] Compound 0269 HWEGTFTSDVSSYLEEQAAREFIEWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 362 H 572 N 96 O 119 Calculated molecular weight (average): 8172.9869 g / mol Monoisotope mass: 8168.1658 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1634.5 (single isotope) The amino acid sequence of HWEGTFTSDVSSYLEEQAAREFIEWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 186.

[0559] Compound 0270 HWEGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 351 H 555 N 91 O 114 Calculated molecular weight (average): 7873.7037 g / mol Monoisotope mass: 7869.0429 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1575.4 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 187.

[0560] Compound 0271 HWEGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 341 H 538 N 90 O 113 Calculated molecular weight (average): 7706.4556 g / mol Monoisotope mass: 7701.9119 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1542.27 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 187.

[0561] Compound 0272 HWEGTFTSD-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 351 H 554 N 92 O 115 Calculated molecular weight (average): 7902.7019 g / mol Monoisotope mass: 7898.0330 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1581.4 (the most abundant) The amino acid sequence of HWEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 188.

[0562] 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-amide C 341 H 537 N 91 O 114 Calculated molecular weight (average): 7735.4538 g / mol Monoisotope mass: 7730.9020 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1547.9 (the most abundant) The amino acid sequence of HWEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 188.

[0563] Compound 0280 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGGEASELSTAALGRLSAELH-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LATLPRTETGSGSP-amide C 371 H 599 N 95 O 126 Calculated molecular weight (average): 8406.2867 g / mol Monoisotope mass: 8401.3384 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1682.1 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGGEASELSTAALGRLSAELHKLATLPRTETGSGSP has SEQ ID NO: 189.

[0564] Compound 0281 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGGEASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-amide C 373 H 601 N 95 O 128 Calculated molecular weight (average): 8464.3227 g / mol Monoisotope mass: 8459.3439 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1693.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGGEASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 190.

[0565] Compound 0284 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGGEASELSTAALGRLSAELHELATL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-RTETGSGSP-amide C 371 H 599 N 95 O 128 Calculated molecular weight (average): 8438.2855 g / mol Monoisotope mass: 8433.3283 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1688.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGGEASELSTAALGRLSAELHELATLKRTETGSGSP has SEQ ID NO: 191.

[0566] Compound 0285 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGGEASELSTAALGRLSAELHELATLPRTETG-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GSP-amide C 373 H 601 N 95 O 127 Calculated molecular weight (average): 8448.3233 g / mol Monoisotope mass: 8443.3490 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1690.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGKGGGGGEASELSTAALGRLSAELHELATLPRTETGKGSP has SEQ ID NO: 192.

[0567] Compound 0292 H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIAWLVRGRGRGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-amide C 369 H 597 N 97 O 125 Calculated molecular weight (average): 8392.2634 g / mol Monoisotope mass: 8387.3340 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1679.24 (the most abundant) The amino acid sequence of HXEGTFTSDKSSYLEEQAAREFIAWLVRGRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 193.

[0568] Compound 0294 H-Aib-EGTFTSDVSSYLE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-QAAREFIAWLVRGRGRGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-amide C 369 H 599 N 97 O 123 Calculated molecular weight (average): 8362.2805 g / mol Monoisotope mass: 8357.3598 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1673.26 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEKQAAREFIAWLVRGRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 194.

[0569] Compound 0295 H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-amide C 369 H 598 N 96 O 124 Calculated molecular weight (average): 8363.2652 g / mol Monoisotope mass: 8358.3439 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1673.65 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 195.

[0570] Compound 0296 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-amide C 369 H 599 N 97 O 123 Calculated molecular weight (average): 8362.2805 g / mol Monoisotope mass: 8357.3598 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1673.46 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 196.

[0571] Compound 0297 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-RGGGGGASELSTAALGRLS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-ELHELATLPRTETGSGSP-amide C 372 H 603 N 97 O 125 Calculated molecular weight (average): 8434.3431 g / mol Monoisotope mass: 8429.3810 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1687.87 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRKRGGGGGASELSTAALGRLSKELHELATLPRTETGSGSP has SEQ ID NO: 197.

[0572] Compound 0299 H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGGEASELSTAALGRLSAELH-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LATLPRTETGSGSP-amide C 372 H 603 N 97 O 125 Calculated molecular weight (average): 8434.3431 g / mol Monoisotope mass: 8429.3810 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1688 (the most comprehensive) The amino acid sequence of HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHKLATLPRTETGSGSP has SEQ ID NO: 198.

[0573] Compound 0396 H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGGEASELSTAALGRLSAELHEL-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-TLPRTETGSGSP-amide C 374 H 605 N 97 O 127 Calculated molecular weight (average): 8492.3792 g / mol Monoisotope mass: 8487.3865 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1699 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELKTLPRTETGSGSP has SEQ ID NO: 199.

[0574] Compound 0397 H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGGEASELSTAALGRLSAELHELATL-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-RTETGSGSP-amide C 372 H 603 N 97 O 127 Calculated molecular weight (average): 8466.3419 g / mol Monoisotope mass: 8461.3708 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1694 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLKRTETGSGSP has SEQ ID NO: 200.

[0575] Compound 0411 H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIAWLVRGRGGGGGGEASELSTAALGRLSAELHELATLPRTETG-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GSP-amide C 374 H 605 N 97 O 126 Calculated molecular weight (average): 8476.3798 g / mol Monoisotope mass: 8471.3915 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1696 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEKAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGKGSP has SEQ ID NO: 201.

[0576] Compound 0414 HAEGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 343 H 550 N 90 O 114 Calculated molecular weight (average): 7758.5717 g / mol Monoisotope mass: 7754.0007 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1551.88 (single isotope) The amino acid sequence of HAEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 202.

[0577] Compound 0415 H-Aib-EGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 344 H 552 N 90 O 114 Calculated molecular weight (average): 7772.5983 g / mol Monoisotope mass: 7768.0163 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1554.67 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 203.

[0578] Compound 0416 HAEGTFTS-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-VSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 344 H 553 N 91 O 113 Calculated molecular weight (average): 7771.6135 g / mol Monoisotope mass: 7767.0323 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1555.3 (Most abundant) The amino acid sequence of HAEGTFTSKVSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 204.

[0579] Compound 0417 H-Aib-EGTFTS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-VSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 345 H 555 N 91 O 113 Calculated molecular weight (average): 7785.6401 g / mol Monoisotope mass: 7781.0480 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1558.1 (the most abundant) The amino acid sequence of HXEGTFTSKVSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 205.

[0580] Compound 0431 HAEGTFTSD-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 343 H 549 N 91 O 115 Calculated molecular weight (average): 7787.5699 g / mol Monoisotope mass: 7782.9908 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1558.67 (the most abundant) The amino acid sequence of HAEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 206.

[0581] Compound 0433 HWEGTFTSD-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 357 H 566 N 94 O 116 Calculated molecular weight (average): 8030.8741 g / mol Monoisotope mass: 8026.1280 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1607.09 (Most Abundant) The amino acid sequence of HWEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 188.

[0582] Compound 0434 HWEGTFTSDVSSYLEE-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 357 H 567 N 93 O 115 Calculated molecular weight (average): 8001.8760 g / mol Monoisotope mass: 7997.1378 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1601.19 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 187.

[0583] Compound 0435 HWEGTFTSDVSSYLEEQAA-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-EFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 356 H 563 N 91 O 116 Calculated molecular weight (average): 7973.8195 g / mol Monoisotope mass: 7969.0953 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1595.67 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAAKEFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 207.

[0584] Compound 0436 H-Aib-EGTFTSDVSSYLEEQAA-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-EFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 349 H 560 N 90 O 116 Calculated molecular weight (average): 7872.7141 g / mol Monoisotope mass: 7868.0688 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1575.47 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAKEFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 208.

[0585] Compound 0437 HWEGTFTSDVSSYLEEQAAR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-FIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 357 H 568 N 94 O 114 Calculated molecular weight (average): 8000.8912 g / mol Monoisotope mass: 7996.1538 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1601.06 (Most Abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAARKFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 209.

[0586] Compound 0438 H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 353 H 569 N 93 O 116 Calculated molecular weight (average): 7971.8485 g / mol Monoisotope mass: 7967.1484 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1595.27 (the most abundant) The amino acid sequence of 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-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-FIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 350 H 565 N 93 O 114 Calculated molecular weight (average): 7899.7858 g / mol Monoisotope mass: 7895.1273 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1580.88 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 211.

[0587] Compound 0440 H-Aib-EGTFTSD-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 344 H 551 N 91 O 115 Calculated molecular weight (average): 7801.5964 g / mol Monoisotope mass: 7797.0065 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1560.48 (single isotope) The amino acid sequence of HXEGTFTSDKSSYLEEQAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 212.

[0588] 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-amide C 333 H 533 N 89 O 113 Calculated molecular weight (average): 7591.3236 g / mol Monoisotope mass: 7586.8697 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1519.18 (the most abundant) The amino acid sequence of HAEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 202.

[0589] Compound 0473 HWEGTFTSDVSSYLEE-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 343 H 542 N 90 O 113 Calculated molecular weight (average): 7734.5088 g / mol Monoisotope mass: 7729.9432 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1547.82 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 187.

[0590] Compound 0474 HAEGTFTSDVSSYLEE-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 335 H 537 N 89 O 113 Calculated molecular weight (average): 7619.3768 g / mol Monoisotope mass: 7614.9010 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1524.8 (the most abundant) The amino acid sequence of HAEGTFTSDVSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 202.

[0591] Compound 0475 HAEGTFTSD-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-SSYLEE-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-AAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 365 H 589 N 93 O 125 Calculated molecular weight (average): 8280.1303 g / mol Monoisotope mass: 8275.2591 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1656.86 (the most abundant) The amino acid sequence of HAEGTFTSDKSSYLEEKAAREFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 213.

[0592] Compound 0482 HAEGTFTSDVS-K([2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAVREFIA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 365 H 599 N 95 O 125 Calculated molecular weight (average): 8318.2231 g / mol Monoisotope mass: 8313.3435 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1664.64 (the most abundant) The amino acid sequence of HAEGTFTSDVSKYLEEQAVREFIAKLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 214.

[0593] Compound 0483 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAVREFIA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 366 H 601 N 95 O 125 Calculated molecular weight (average): 8332.2496 g / mol Monoisotope mass: 8327.3592 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1667.47 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAVREFIAKLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 215.

[0594] Compound 0484 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxy-tetrazylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAVREFIA-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxy-tetrazylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 362 H 593 N 95 O 125 Calculated molecular weight (average): 8276.1433 g / mol Monoisotope mass: 8271.2966 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1656.1 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAVREFIAKLVRGRGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 215.

[0595] Compound 0502 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 345 H 554 N 94 O 116 Calculated molecular weight (average): 7874.6505 g / mol Monoisotope mass: 7870.0341 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1575.09 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0596] Compound 0503 H-Aib-EGTFTSDVSSYLEEQAAREFIEWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 355 H 569 N 95 O 119 Calculated molecular weight (average): 8071.8815 g / mol Monoisotope mass: 8067.1393 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1614.52 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIEWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 216.

[0597] Compound 0504 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGRP-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 358 H 574 N 96 O 118 Calculated molecular weight (average): 8110.9606 g / mol Monoisotope mass: 8106.1866 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1622.34 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRPKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 217.

[0598] Compound 0506 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 359 H 579 N 97 O 118 Calculated molecular weight (average): 8142.0177 g / mol Monoisotope mass: 8137.2288 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1629.33 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0599] Compound 0509 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGGEASELSTAALGRLSAELH-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-LATLPRTETGSGSP-amide C 372 H 604 N 98 O 124 Calculated molecular weight (average): 8433.3584 g / mol Monoisotope mass: 8428.3970 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1687.55 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHKLATLPRTETGSGSP has SEQ ID NO: 218.

[0600] Compound 0511 H-Aib-EGTFTSDVSRYLEEQAAREFIEWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 358 H 576 N 98O 118 Calculated molecular weight (average): 8140.9898 g / mol Monoisotope mass: 8136.2084 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1629.34 (the most abundant) The amino acid sequence of HXEGTFTSDVSRYLEEQAAREFIEWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 219.

[0601] Compound 0512 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 349 H 561 N 93 O 115 Calculated molecular weight (average): 7899.7427 g / mol Monoisotope mass: 7895.0909 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1580.31 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 154.

[0602] Compound 0516 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 374 H 606 N 98 O 125 Calculated molecular weight (average): 8475.3950 g / mol Monoisotope mass: 8470.4075 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1694.99 (single isotope) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 220.

[0603] Compound 0518 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 352 H 565 N 95 O 116 Calculated molecular weight (average): 7983.8194 g / mol Monoisotope mass: 7979.1232 g / mol LCMS34: Actual Measurement (M + 5H)5+ 1597.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 221.

[0604] Compound 0528 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 377 H 610 N 98 O 127 Calculated molecular weight (average): 8547.4577 g / mol Monoisotope mass: 8542.4287 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1710.41 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 222.

[0605] Compound 0529 H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEP-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 366 H586 N 100 O 122 Calculated molecular weight (average): 8339.1658 g / mol Monoisotope mass: 8334.2724 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1668.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPKGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 137.

[0606] Compound 0539 H-Aib-EGTFTSDVSSYLEGQAAREFIAWLVRGRGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GQAPEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 374 H 599 N 101 O 123 Calculated molecular weight (average): 8478.3608 g / mol Monoisotope mass: 8473.3721 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1696.5011 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEGQAAREFIAWLVRGRGQEPKGQAPEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 137.

[0607] Compound 0552 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(2S)-2-amino-6-[[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 351 H 566 N 96 O 117 Calculated molecular weight (average): 8002.8227 g / mol Monoisotope mass: 7998.1291 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1600.55 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0608] Compound 0560 HGEGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 324 H 517 N 87 O 110 Calculated molecular weight (average): 7391.0887 g / mol Monoisotope mass: 7386.7536 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1478.31 (single isotope) The amino acid sequence of HGEGTFTSDVSSYLEGQAAKEFIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 223.

[0609] Compound 0561 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 350 H 563 N 95 O 115 Calculated molecular weight (average): 7941.7827 g / mol Monoisotope mass: 7937.1127 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1589.3 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 224.

[0610] Compound 0562 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 342 H 550 N 94 O 114 Calculated molecular weight (average): 7802.5878 g / mol Monoisotope mass: 7798.0130 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1561.5 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 224.

[0611] 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-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexano]amino]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 385 H 624 N 100 O 131 Calculated molecular weight (average): 8749.6655 g / mol Monoisotope mass: 8744.5240 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1749.8 (single isotope) The amino acid sequence of HXEGTFTSDVSKYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 221.

[0612] Compound 0565 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAREFIAWLVRGRGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 344 H 552 N94 O 115 Calculated molecular weight (average): 7844.6245 g / mol Monoisotope mass: 7840.0235 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1568.89 (single isotope) The amino acid sequence of HXEGTFTSDVSKYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 221.

[0613] Compound 0575 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRQEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 379 H 614 N 100 O 127 Calculated molecular weight (average): 8603.5243 g / mol Monoisotope mass: 8598.4661 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1721.5 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIAWLVRGRQEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 225.

[0614] Compound 0576 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 378 H 611 N 99 O 128 Calculated molecular weight (average): 8590.4824 g / mol Monoisotope mass: 8585.4345 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1719.1 (The most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIEWLVRGRGEGGGGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 226.

[0615] Compound 0577 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 368 H 596 N 94 O 123 Calculated molecular weight (average): 8305.2258 g / mol Monoisotope mass: 8300.3272 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1661.9 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIEWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 227.

[0616] Compound 0578 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRQEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 369 H 599 N 95 O 122 Calculated molecular weight (average): 8318.2677 g / mol Monoisotope mass: 8313.3588 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1664.5 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIAWLVRGRQEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 228.

[0617] ©Compound0580 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 323 H 519 N 85 O 106 Calculated molecular weight (average): 7289.0829 g / mol Monoisotope mass: 7284.7834 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1458.76 (Most abundant) The amino acid sequence of H-Aib-EGTFTSDVSSYLEEQAARKFIAWLVRGGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 229.

[0618] Compound 0581 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 323 H 518 N 84 O 107 Calculated molecular weight (average): 7290.0676 g / mol Monoisotope mass: 7285.7674 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1458.96 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 230.

[0619] Compound 0629 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 366 H 591 N 91 O 123 Calculated molecular weight (average): 8234.1446 g / mol Monoisotope mass: 8229.2788 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1647.55 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 231.

[0620] Compound 0630 H-Aib-EGTFTSDVS-K(6-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]butyryl]amino]hexanoyl)-YLEEQAAR-K(6-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanoamino)butyryl]amino]butyryl]amino]hexanoyl)-FIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C364 H 583 N 91 O 119 Calculated molecular weight (average): 8138.0621 g / mol Monoisotope mass: 8133.2365 g / mol LCMS01: Actual Measurement (M + 5H) 5+ 1628.55 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 231.

[0621] Compound 0631 H-Aib-EGTFTSDVS-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanoacylamino)butyryl]amino]butyryl]amino]butyryl])-YLEEQAAR-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanoacylamino)butyryl]amino]butyryl]amino]butyryl])-FIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 372 H 589 N 93 O 129 Calculated molecular weight (average): 8428.2028 g / mol Monoisotope mass: 8423.2388 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1686.7 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 231.

[0622] Compound 0632 H-Aib-EGTFTSDVS-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]butyry]amino]butyry]amino]butyry])-YLEEQAAREFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 339 H 536 N 88 O 116 Calculated molecular weight (average): 7700.4031 g / mol Monoisotope mass: 7695.8748 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1541.1 (Most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAAREFIEWLVRGAAEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 232.

[0623] Compound 0633 H-Aib-EGTFTSDVSSYLEEQAAR-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]butyryl]amino]butyryl]amino]butyryl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 345 H 549 N 95 O 117 Calculated molecular weight (average): 7899.6169 g / mol Monoisotope mass: 7894.9930 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1580.9 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 224.

[0624] Compound 0634 H-Aib-EGTFTSDVS-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanoacylamino)butyryl]amino]butyryl]amino]butyryl])-YLEEQAAR-K([(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanoacylamino)butyryl]amino]butyryl]amino]butyryl])-FIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 372 H 592 N 96 O 127 Calculated molecular weight (average): 8441.2479 g / mol Monoisotope mass: 8436.2817 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1689.1 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIAWLVRGRGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 233.

[0625] Compound 0635 H-Aib-EGTFTSDVS-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(13-carboxy-tetrazylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-YLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4R)-4-carboxy-4-(13-carboxy-tetrazylamino)butyryl]amino] [4S]-4-carboxy-4-(13-carboxytetracetamylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 401 H 654 N 100 O 135 Calculated molecular weight (average): 9036.0725 g / mol Monoisotope mass: 9030.7384 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1807.05 (single isotope) The amino acid sequence of HXEGTFTSDVSKYLEEQAARKFIAWLVRGRKGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 234.

[0626] Compound 0636 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxyl-4-[[(4S)-4-carboxyl-4-[[(4S)-4-carboxyl-4-(19-carboxy-nonadecanoylamino)butyryl]amino]butyryl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIEWLVRGRQEAASELSTAALGRLSAELHQLATLPRTETGSGSP-amide C 352 H 565 N 95 O 119 Calculated molecular weight (average): 8031.8176 g / mol Monoisotope mass: 8027.1080 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1606.3 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIEWLVRGRQEAASELSTAALGRLSAELHQLATLPRTETGSGSP has SEQ ID NO: 235.

[0627] Compound 0637 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])-GGGGSGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 352 H 564 N 98 O 121 Calculated molecular weight (average): 8104.8286 g / mol Monoisotope mass: 8100.0992 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1621.8 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGSGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 236.

[0628] Compound 0638 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGSGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 354 H 568 N 98 O 121 Calculated molecular weight (average): 8132.8817 g / mol Monoisotope mass: 8128.1305 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1627.5 (the most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGSGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 236.

[0629] Compound 0639 H-Aib-EGTFTSDVSSYLEEQAAR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-FIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 340 H 546 N 94 O 114 Calculated molecular weight (average): 7774.5346 g / mol Monoisotope mass: 7769.9817 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1556.0 (Most abundant) The amino acid sequence of HXEGTFTSDVSSYLEEQAARKFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 224.

[0630] 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])-YLEEQAAREFIAWLVRGRGGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 342 H 548 N 94 O 115 Calculated molecular weight (average): 7816.5713 g / mol Monoisotope mass: 7811.9922 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1564.3 (the most abundant) The amino acid sequence of HXEGTFTSDVSKYLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 221.

[0631] Compound 0648 HWEGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 350 H 553 N 95 O 116 Calculated molecular weight (average): 7947.7027 g / mol Monoisotope mass: 7943.0293 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1590.5 (the most abundant) The amino acid sequence of HWEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 185.

[0632] Compound 0654 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(16-sulfohexadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 341 H 548 N 94 O 117 S Calculated molecular weight (average): 7868.6244 g / mol Monoisotope mass: 7863.9541 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1573.79 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0633] Compound 0655 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[17-(1H-tetrazo-5-yl)heptadecanoylamino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 343 H 550 N 98 O 114 Calculated molecular weight (average): 7870.6253 g / mol Monoisotope mass: 7866.0253 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1574.2 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0634] Compound 0656 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]hexanoyl]amino]hexanoyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 343 H 552 N 96 O 112 Calculated molecular weight (average): 7812.6290 g / mol Monoisotope mass: 7808.0449 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1562.61 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0635] Compound 0657 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]hexanoyl]amino]hexanoyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 345 H 556 N 96 O 112 Calculated molecular weight (average): 7840.6821 g / mol Monoisotope mass: 7836.0762 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1568.21 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0636] Compound 0658 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(6-[6-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]hexanoylamino]hexanoyl)-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 343 H 550 N 94 O 112 Calculated molecular weight (average): 7782.5997 g / mol Monoisotope mass: 7778.0231 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1556.6 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0637] Compound 0659 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K(6-[6-[[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]hexanoylamino]hexanoyl)-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 345 H 554 N 94 O 112 Calculated molecular weight (average): 7810.6529 g / mol Monoisotope mass: 7806.0544 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1562.21 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0638] Compound 0660 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 337 H 539 N 93 O 113 Calculated molecular weight (average): 7701.4409 g / mol Monoisotope mass: 7696.9289 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1540.38 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0639] 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-amide C 349 H 561 N 95 O 119 Calculated molecular weight (average): 7991.7537 g / mol Monoisotope mass: 7987.0767 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1598.41 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0640] Compound 0662 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[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]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 355 H 572 N 96 O 122 Calculated molecular weight (average): 8136.9102 g / mol Monoisotope mass: 8132.1506 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1627.42 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0641] Compound 0663 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 357 H 576 N 96 O 122 Calculated molecular weight (average): 8164.9633 g / mol Monoisotope mass: 8160.1819 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1633.03 (single isotope) The amino acid sequence of HXEGTFTSDVSSYLEEQAAREFIAWLVRGRKGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP has SEQ ID NO: 153.

[0642] Example 1b: Comparative Compounds Compare compound 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]hexanoyl])-GGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 342 H 552 N 92 O 113 Calculated molecular weight (average): 7760.5909 g / mol Monoisotope mass: 7756.0276 g / mol LCMS34: Actual Measurement (M + 5H) 5+1553.02 (the most abundant).

[0643] The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 241.

[0644] Compare 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]hexanoyl])-GGEASELSTAALGRPSAELHELATLPRTETGSGSP-amide C 341 H 548 N 92 O 113 Calculated molecular weight (average): 7744.5484 g / mol Monoisotope mass: 7739.9963 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1549.81 (Most abundant) The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 242.

[0645] Compare compound 0015 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEPCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-amide C 384 H 596 N 106 O 124 S2 Calculated molecular weight (average): 8745.6068 g / mol Monoisotope mass: 8740.3031 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+1749.9 (the most abundant) The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 243.

[0646] Compare compound 0016 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEP-K([2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxyheptadecylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-CNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-amide C 425 H 669 N 111 O 137 S2 Calculated molecular weight (average): 9589.6509 g / mol Monoisotope mass: 9583.8236 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ September 1918 (the most abundant) The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 244.

[0647] Compare compound 0668 H-Aib-EGTFTSDVSSYLEGQAA-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-EFIAWLVRGRGGQEPGQEP-K([(4S)-4-carboxy-4-[(4S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)butyryl]amino]butyryl])-CNTATCATQRLADFLRHSSPNFGAIPSSTNVGSRTY-amide C 419 H 655 N 111 O 135 S2 Calculated molecular weight (average): 9471.4767 g / mol Monoisotope mass: 9465.7242 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1895.2 (the most abundant) The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 245.

[0648] Compare compound 0671 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])-GGGGEKCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide C 378 H 588 N 104 O 120 S2 Calculated molecular weight (average): 8573.4681 g / mol Monoisotope mass: 8568.2547 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1715.4 (the most abundant) The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 251.

[0649] Compare compound 0672 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])-GGGGEKCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-amide C 376 H 590 N 106 O 120 S2 Calculated molecular weight (average): 8579.4760 g / mol Monoisotope mass: 8574.2765 g / mol LCMS_ZQ: Actual measurement (M + 5H) 5+ 1716.8 (the most abundant) The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 252.

[0650] Compare compound 0167 H-Aib-EGTFTSDVSSYLEEQAAREIFAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 353 H 567 N 95 O 117 Calculated molecular weight (average): 8013.8454 g / mol Monoisotope mass: 8009.1338 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1603.63 (Most abundant) The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 253.

[0651] Compare compound 0192 H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-[[4-[(19-carboxy-nonadecanoamino)methyl]cyclohexanecarbonyl]amino]butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRPSAELHELATLPRTETGSGSP-amide C 352 H 563 N 95 O 117 Calculated molecular weight (average): 7997.8029 g / mol Monoisotope mass: 7993.1025 g / mol LCMS34: Actual Measurement (M + 5H) 5+ 1600.63 (Most abundant) The amino acid sequence of the peptide backbone in the comparative compound has SEQ ID NO: 254.

[0652] Example 1c: Amylin receptor agonist Compound 1806 EASELSTAALGRLSAELHELATLPRTETGSGSP-amide C 141 H 236 N 42 O 52 Calculated molecular weight (average): 3351.6327 g / mol Monoisotope mass: 3349.7114 g / mol LCMS_ZQ: Actual measurement (M + 3H) 3+ 1118.4 (the most abundant).

[0653] The amino acid sequence of the peptide backbone in compound 1806 has SEQ ID NO: 250.

[0654] Example 2: The efficacy of the compound against GLP-1 and amyloid receptors The potency of the test compounds described in 1 and 2 shall be determined.

[0655] Assay 1: In vitro potency assay of human GLP-1 receptor To determine the ability of a compound to activate or stimulate the GLP-1 receptor (GLP-1R), an in vitro potency assay was performed in cells expressing the human GLP-1 receptor, as described below.

[0656] Measurement principle Activation of the GLP-1 receptor leads to an increase in cellular concentration of cyclic AMP (cAMP). Transcription is thus activated by a promoter containing multiple copies of the cAMP response element (CRE). Therefore, GLP-1 receptor activity can be measured using a CRE-luciferase reporter gene introduced into young hamster kidney (BHK) cells co-expressing the GLP-1 receptor.

[0657] Cells and assay reagents Cell stock was prepared by culturing a stably transfected cell line (BHK 467-12A KZ-10, prepared according to methods known to those skilled in the art) expressing the human GLP-1 receptor and CRE-responsive luciferase (CRE-Luc) reporter gene in growth medium. This growth medium consisted of DMEM (Gibco, 61965-026) supplemented with 10% FBS (Gibco, 16140-071), 1% penicillin / streptomycin (Gibco, 15140-122), 1 mM sodium pyruvate (Gibco, 11360-039), 1 mg / mL G418 (Gibco, 10131-027), and 240 nM MTX (Pfizer, 15936). Approximately 80-90% confluenced cells were washed once in PBS and released from the cell flask with Versene (Gibco, 15040-033). After centrifugation, the cell pellet was dissolved and diluted in culture medium to a concentration of 1.5 x 10⁶ cells / mL. This medium consisted of DMEM (Gibco, 61965-026) supplemented with 20% FBS (Gibco, 16140-071), 1% penicillin / streptomycin (Gibco, 15140-122), 1 mM sodium pyruvate (Gibco, 11360-039), 1 mg / mL G418 (Gibco, 10131-027), 240 nM MTX (Pfizer, 15936), and 10% DMSO (Sigma, D2650). Cells were aliquoted and stored at -180°C until use.

[0658] The assay buffer consisted of phenol red-free DMEM (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).

[0659] program To perform this assay, serial dilutions (10-fold dilution, 8 concentrations per compound) of the comparative compound and the GLP-1 receptor-amylin receptor co-agonist were prepared in HSA-free assay buffer, typically starting at approximately 100–200 nM in a 96-well plate. Cryopreserved stock of human GLP-1R / CRE-Luc cells were thawed in a 37°C water bath, washed once in PBS, and diluted to 100,000 cells / mL in assay buffer. For each dilution, 50 µL aliquots of the comparative compound or GLP-1 receptor-amylin receptor co-agonist were transferred to a 96-well assay plate (ThermoFisher, 237105), and 50 µL of cell suspension (5,000 cells / well) was added. The assay plate was incubated at 37°C, 5% CO2 for 3 hours, followed by 5 minutes at room temperature, after which 100 µL of SteadyLite Plus (PerkinElmer, 6066759) was added to each well. The plate was sealed and incubated at room temperature for 30 minutes with gentle shaking while protected from light. Emissions were detected using a luminescence reader such as Synergy 2 (BioTek). EC was calculated by nonlinear curve fitting using a four-parameter logical model (slope = 1) applied with GraphPad Prism or by means of TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA). 50 Value [pM].

[0660] Assay 2: In vitro potency assay of human pancreatic amylin receptor To determine the ability of a compound to activate or stimulate the amylin receptor, in vitro potency assays can be performed on cells expressing the human amylin receptor (hAmyR3) as described below.

[0661] Measurement principle Activation of hAmyR3 leads to an increase in cAMP concentration in cells. Transcription is thus activated by a promoter containing multiple copies of a cAMP response element (CRE). Therefore, hAmyR3 activity can be measured using a CRE-luciferase reporter gene introduced into young hamster kidney (BHK) cells co-expressing hAmyR3.

[0662] Cells and assay reagents BHK cell line (Hollex-1 cell line, obtained from Zymogentics, described in U.S. Patent 5,622,839) was stably transfected with a human calcitonin receptor (a) and CRE-responsive luciferase (CRE-Luc) reporter gene according to methods known to those skilled in the art. The cell line was further transfected with human receptor-modified protein 3 (RAMP3) using standard methods. This converted the human calcitonin receptor to a human amylin-3(a) receptor.

[0663] Cell stock was prepared by culturing stably transfected BHK hAmyR3 / CRE-Luc cell lines in a growth medium consisting of DMEM (Gibco, 31966-021) supplemented with 10% FBS (Gibco, 1640-071), 1% penicillin / streptomycin (Gibco, 15140-122), 0.5 mg / mL genimycin (Gibco, 10131-027), 0.4 mg / mL hygromycin (Invitrogen, 1068701), and 250 nM methotrexate (Sigma, A6770). Approximately 80-90% confluenced cells were washed once with PBS and released from the cell flasks using Versene (Gibco, 15040-033). After centrifugation, the cell pellet was collected in Recovery Cell Bank. TM Dissolve and dilute to 2.5 x 10⁶ cells / mL in cell culture freezing medium (Gibco, 12648-010). Aliquot the cells and store at -180°C until use.

[0664] The assay buffer consisted of phenol red-free DMEM (Gibco, 11880-028) supplemented with 1X GlutaMAX (Gibco, 35050-038), 10 mM HEPES (Gibco, 15630-056) and 1% (w / v) ovalbumin (Sigma, A5503).

[0665] program For this assay, BHK hAmyR3 / CRE-Luc cells were thawed the day before the experiment, washed once in PBS, and seeded at a density of 4,000 cells / well in 40 µL of growth medium in white 384-well plates (PerkinElmer, 6007688). The plates were incubated overnight at 37°C with 5% CO2. On the day of the assay, the cells were washed three times in assay buffer. Serial dilutions of the comparative compound and the GLP-1 receptor-amylin receptor co-agonist were added to the assay buffer (7-fold dilution, 7 concentrations per compound, and one well containing only assay buffer), typically starting at approximately 10–100 nM in 96-well plates, with 30 µL of each concentration added to the 384-well assay plate containing cells. The assay plate was incubated at 37°C with 5% CO2 for 3 hours, after which 30 µL of SteadyLite Plus (PerkinElmer, 6066759) was added to each well. The test plate was sealed and incubated at room temperature with gentle shaking for 5 minutes, followed by incubation in the dark without shaking for 30 minutes. Emissions were detected using a luminescence reader such as Synergy 2 (BioTek). EC was calculated using a four-parameter logical model (slope = 1.5, bottom response per plate) via nonlinear curve fitting, employing GraphPad Prism or TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA) to achieve the desired emission rate. 50 Value [pM].

[0666] Example 2a: The efficacy of GLP-1 receptor-amylin receptor co-agonists on GLP-1 and amylin receptors The potency of the compounds according to the invention was tested as described in determinations 1 and 2. The results are provided in Table 4a. Details of the compounds, such as IUPAC nomenclature, can be found in Example 1 and the sequence listing.

[0667] Table 4a: In vitro efficacy of GLP-1 receptor-amylin receptor co-agonists against human AmyR3 and GLP-1R

[0668] Example 2b: The potency of the compound and comparative compounds against GLP-1 and amyloid receptors The GLP-1 receptor (GLP-1R) and amylin receptor (AmyR3) potency of a compound (compound 0111) according to the present invention was compared with the potency of GLP-1 and amylin receptor agonists derived from the compound and with the potency of comparative compounds. The results are shown in Table 4b. For details of the compounds, such as IUPAC nomenclature, see Example 1 and the sequence listing.

[0669] Table 4b: In vitro human AmyR3 and GLP-1R potency of reference and comparative compounds.

[0670] Comparative compound 0672 contains a GLP-1RA with a similar amino acid sequence to the GLP-1RA in smegglutinin, which is linked via a short peptide linker to an amylin RA with the same amino acid sequence as the amylin RA in canagliflozin. (In smegglutinin, relative to SEQ ID NO: 1 or SEQ ID NO: 238, there is a lysine residue (Lys20) at position 20 and a glycine residue (Gly31) at position 31, and an extended portion linked to Lys20. A GLP-1 RA similar to smegglutinin contains an arginine residue (Arg20) at position 20 and a lysine residue (Lys31) at position 31 relative to SEQ ID NO: 1 or SEQ ID NO: 238, and an extended portion linked to Lys31.)

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

[0672] Compound 0111 contains the same GLP-1 sequence as used in compounds 0672 and 0671, which is linked via a short peptide linker to amylin RA having the same amino acid sequence as amylin RA in compound 1806. Example 2c: The potency of the compound and comparative compounds against GLP-1 and amyloid receptors The GLP-1 receptor (GLP-1R) and amylin receptor (AmyR3) efficacies of the two compounds (compound 0045 and compound 0120) according to the present invention are compared with the efficacies of comparative compounds having selected mutations in their GLP-1 or amylin moieties.

[0674] Except for the fact that compounds 0164 and 0167 are identical to compounds 0045 and 0120, respectively, in that their GLP-1 portions contain two sequence mutations, Phe22Ile and Ile23Phe, relative to the numbers in SEQ ID NO: 1, SEQ ID NO: 238, or SEQ ID NO: 255.

[0675] Except for the fact that compounds 0185 and 0192 are identical to compounds 0045 and 0120, respectively, with respect to the numbers in SEQ ID NO: 79, SEQ ID NO: 240, or SEQ ID NO: 256, their amylin moiety contains a single mutation in the peptide backbone: Leu12Pro.

[0676] Comparative compounds 0015, 0016, and 0668 are further examples of compounds comprising a GLP-1 receptor agonist similar to smegglutinin (as detailed in Example 2b) and an amylin receptor agonist having the amino acid sequence of canagliflozin (compounds 0015 and 0016) or an alternative to an extended amylin receptor agonist (compound 0668).

[0677] The results are shown in Table 4c. For details regarding the compounds, such as IUPAC nomenclature, see Example 1 and the sequence listing. Table 4c: In vitro human AmyR3 and GLP-1R potency of other comparative compounds.

[0679] result The data in Table 4a show that all the compounds tested are agonists of AmyR3 and GLP-1R, i.e., they are GLP-1 receptor-amylin receptor co-agonists. The compounds listed in Table 4a are all compounds according to the present invention.

[0680] In contrast, the data in Table 4b show that linking the C-terminus of an effective GLP-1 receptor agonist (similar to smegglutinin) to the N-terminus of an effective amylin receptor agonist (canagliflozin or pramlinide) via peptide linkers does not produce compounds that are equally effective against both receptors and necessarily function as GLP-1 receptor-amylin receptor co-agonists (i.e., compounds according to the invention). This is illustrated by comparing compounds 0672 and 0671 with compound 0111: compounds 0672 and 0671 retain potency against the GLP-1 receptor but have impaired potency against the amylin receptor. Only compound 0111 retains full potency against both receptors and exhibits similar potency against both GLP-1 and amylin receptors, respectively, relative to smegglutinin and canagliflozin. Compound 0111 is considered a “balanced” compound.

[0681] The data in Table 4c show that the comparative compounds exhibit impaired agonistic (activating) abilities towards GLP-1 or amylin receptors. The Phe22Ile and Ile23Phe mutations in comparative compounds 0164 and 0167 impair their ability to agonize (activate) GLP-1 receptors. The Leu12Pro mutation in comparative compounds 0185 and 0192 impairs their ability to agonize (activate) amylin receptors. Data provided in Table 6b further illustrate this impaired ability. Other data in Table 4c highlight the difficulty in linking GLP-1 receptor agonists to amylin receptor agonists. Comparative compound 0015 was found to be a poor amylin receptor agonist. Comparative compounds 0016 and 0668 did not activate amylin receptors.

[0682] Example 3: Preparation of tablets for pharmacokinetic studies in beagle dogs To assess oral exposure after tablet administration, a tablet composition comprising the test substance and SNAC (sodium N-(8-(2-hydroxybenzoyl)amino)octanoate) is prepared, for example, as described in WO 2019 / 149880, by mixing the test substance with rolled SNAC and magnesium stearate. The amount of SNAC in the tablet composition is 100-300 mg, the amount of magnesium stearate in the tablet composition is 7.7 mg, and the target amount of each test substance in the tablet composition is 3-4 mg.

[0683] Example 4: Pharmacokinetic Study in Beagle Dogs Pharmacokinetic (PK) studies were conducted in beagle dogs to determine exposure to the GLP-1 receptor-amylin receptor co-agonist following oral administration.

[0684] For pharmacokinetic studies, male Beagles aged 2–7 or 1–5 years and weighing approximately 10–15 kg (e.g., 10–12 kg) were used at the start of the study. The dogs were housed in groups in enclosures (12 hours light: 12 hours darkness) and fed individually and restrictively once daily on Royal Canin Medium Adult dog food (Royal Canin Products, China Branch, or Brogaarden A / S, Denmark). Daily exercise and group socialization were permitted whenever possible. Repeated pharmacokinetic studies were conducted using these dogs, with appropriate washout periods between consecutive administrations. An appropriate acclimatization period was given before starting the first pharmacokinetic study. All animal handling, administration, and blood sampling were performed by trained and skilled personnel. The dogs were fasted overnight prior to the study and again 0–4 hours after administration. Furthermore, water intake was restricted for 1 hour before administration until 4 hours after administration, but allowed free access to water at other times throughout the study period.

[0685] The tablets used in the oral studies described herein were SNAC-based immediate-release tablets for oral administration.

[0686] The tablets are administered as follows: 10 minutes before tablet administration, approximately 3 nmol / kg of SEQ ID NO: 237 may be administered subcutaneously to the dog, placing the tablet at the back of the dog's mouth to prevent chewing. The mouth is then closed, and 10 mL of tap water is administered via syringe or force-feed to promote swallowing of the tablet.

[0687] Blood sampling, analysis and pharmacokinetic calculations Blood samples were collected at predetermined time points and continued until 240 hours after administration, such as up to 10 hours, to fully cover the complete plasma concentration-time absorption profile of the GLP-1 agonist.

[0688] For each blood sampling time point, collect approximately 0.8 mL of whole blood in a 1.5 mL EDTA-coated tube and gently rotate the tube to mix the sample with EDTA. Transfer the blood sample (e.g., 0.8 mL) to EDTA buffer (8 mM) and centrifuge at 2000 G for 10 minutes at 4 °C. Transfer the plasma to a micronic tube on dry ice and maintain at -20 °C until analysis.

[0689] Obtain blood samples as needed, for example, from the venflon in the cephalic vein of the foreleg in the first 2 hours, and then from the jugular vein with a syringe for the remaining time points (so that the first few drops are expelled from the venflon to avoid the sample containing heparinized saline from the venflon).

[0690] Plasma concentrations of GLP-1 receptor-amylin receptor co-agonists were determined using LCMS. Individual plasma concentration-time spectra were analyzed using non-compartmental models in WinNonlin v.5.0, Phoenix v.6.2, or 6.3 (Pharsight Inc., Mountain View, CA, USA) or other relevant software for PK analysis.

[0691] Individual plasma concentration-time spectra were analyzed using non-compartmental analysis (NCA). The following PK parameters—tmax, Cmax / dose, and t½—were calculated and reported, as shown in Table 5.

[0692] Table 5: Pharmacokinetic parameters after oral administration in dogs For details regarding the compounds, such as IUPAC nomenclature, see Example 1 and the sequence listing.

[0693] Since the concentrations of the compounds in plasma were detected after oral administration (Cmax / dose > 0 and AUC / dose > 0), all the compounds tested showed oral bioavailability in this model. Furthermore, the tested compounds exhibited long half-lives (4–110 hr) compared to the half-lives of human GLP-1 and human amylin, which were measured in humans at approximately 2–4 min and 15–20 min, respectively (Meier et al., Diabetes, 2004, 53(3): 654–662).

[0694] Example 5 - Experimental protocol for testing appetite efficacy using a rat model with random feeding Acute food intake experiments were conducted using Sprague Dawley (SD) rats from Taconic Europe, Denmark, following laboratory animal care principles.

[0695] Rats weighed 200–250 g at the start of the experiment. Rats arrived at least 10–14 days prior to the start of the experiment to acclimatize to the experimental environment. During this period, the animals underwent at least two treatments. Immediately upon arrival, the rats were placed in an inverted light cycle (11:00 AM to 11:00 PM darkness) and introduced into the HM2 system, and were identified (ID chipped). Three rats were housed in each cage. During the acclimatization period, the rats had free access to food and water. Because rats are typically active during the dark period and consume the majority of their daily food intake, the administration was performed in the morning just before the lights were turned off. This setup resulted in minimal data variation and the highest test sensitivity. Each dose of the GLP-amylin receptor co-agonist was tested in a group of 5–8 rats. Each test group included a mediator group of 6–8 rats. Animals from three different treatment groups were present in each cage (if one cage was unavailable). Rats were administered a single dose of 0.01–3 mg / kg solution subcutaneously (sc) according to their body weight. The administration time for each group was recorded.

[0696] After administration, the rats were returned to their cages where they had access to food and water. Food consumption was recorded individually and continuously for up to 72 hours via an online register (HM2 system). At the end of the experimental period, the animals were euthanized.

[0697] Table 6 shows the acute food intake in lean rats. These results allow for assessment of in vivo efficacy and provide an indication of the duration of compound action. Food intake in rats was conducted for up to 48 hours.

[0698] Table 6a: Pharmacodynamic screening model: Rats after a single administration of GLP-1-amylin co-agonist (10 nmol / kg) Acute food intake.

[0699] For details regarding the compounds, such as IUPAC nomenclature, see Example 1 and the sequence listing.

[0700] Table 6b: Pharmacodynamic screening model: compared with GLP-1 impaired compound 0167 and amylin-impaired compound 0192 Compared to acute insulin resistance in rats following a single administration of a GLP-1 receptor-amylin receptor co-agonist (compound 0120, 10 nmol / kg), Food intake.

[0701] For details regarding the compounds, such as IUPAC nomenclature, see Example 1 and the sequence listing.

[0702] After administration of GLP-1 receptor-amylin receptor co-agonists to rats, many of them induced significant inhibition of food intake compared to mediator treatment, which can be inferred from the data presented in Table 6a.

[0703] The data in Table 6b highlight the importance of compounds capable of activating both the GLP-1 receptor and the amylin receptor. Three compounds were compared: a GLP-1 receptor-amylin receptor co-agonist (compound 0120), which is fully effective against both receptors; compound 0167, which exhibits impaired GLP-1 activity but full amylin potency; and compound 0192, which exhibits impaired amylin activity but full GLP-1 potency (in vitro data are shown in Table 4c). When compound 0120 (10 nmol / kg) was administered to rats, it resulted in a significant inhibition of food intake over the first 48 hours. When compound 0167 or compound 0192 (10 nmol / kg) was administered to rats, the inhibition of food intake was significantly lower in both cases than with compound 0120. This indicates that both receptor systems are activated by compound 0120, and that it is a “balanced” compound.

[0704] While certain features of the invention have been set forth and described herein, many modifications, substitutions, alterations, and equivalents will now occur to those skilled in the art. Therefore, it should be understood that all such modifications and alterations falling within the true scope of the invention are intended to be covered by the appended claims.

Claims

1. A GLP-1 receptor-amylin receptor co-agonist comprising a polypeptide (R1) according to formula I: Z1-Z2-Z3, It contains 1-3 lysine (Lys, K) residues and no disulfide bonds; wherein: • Z1 is a GLP-1 receptor agonist peptide containing up to 9 amino acid modifications relative to SEQ ID NO: 1, provided that Z1 does not contain isoleucine (Ile, I) at position 22. • Z2 is an optional peptide linker; Z3 is an amylin receptor agonist peptide containing a C-terminal amide and up to 7 amino acid modifications relative to SEQ ID NO: 79, provided that Z3 does not contain a proline (Pro, P) at position 12. It further includes 1-3 elongation portions (R2-R3) connected to the polypeptide (R1) via the 1-3 lysine (Lys, K) residues.

2. The GLP-1 receptor-amylin receptor co-agonist according to claim 1, wherein the GLP-1 receptor agonist peptide (Z1) comprises 0-3 lysine (Lys, K) residues at any of positions 9, 10, 12, 16, 19, 20, 21, 24, 25, 28, 29, 30 and / or 31 or a combination thereof relative to SEQ ID NO: 238 or 255.

3. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, wherein the GLP-1 receptor agonist peptide (Z1) comprises two lysine (Lys, K) residues at the following positions relative to SEQ ID NO: 238 or 255: • 12 and any one of 21, 30 or 31, or • 21 and 30 or 31; Preferably, at the following locations: • 12 and 21 or 30, or • 21 and 31.

4. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, wherein the GLP-1 receptor agonist peptide (Z1) contains one lysine residue (Lys, K) at any one of positions 12, 20, 21, 28, 30 or 31; preferably, it contains one lysine residue (Lys, K) at position 31.

5. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, wherein the peptide linker (Z2) comprises 0-3 lysine (Lys, K) residues; such as 1-2 lysine (Lys, K) residues; preferably, 1 lysine (Lys, K) residue.

6. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, wherein the amylin receptor agonist peptide (Z3) comprises 0-3 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; preferably, it comprises 1 lysine (Lys, K) residue at any of positions 14, 18, 20, 23, 29; and even more preferably, it comprises 1 lysine (Lys, K) residue at position 18.

7. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, comprising the GLP-1 receptor agonist peptide (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-Xaa 17-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 is either Asp(D) or Lys(K). Xaa10 is either Lys(K) or Val(V). Xaa12 can be 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 is Ala (A), Glu (E), 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.

8. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, comprising an amylin receptor agonist peptide (Z3) according to Formula III (SEQ ID NO: 256): Xaa1 - in: Xaa1 is either Ala(A) or does not exist. Xaa2 is either Lys(K) or Ser(S). Xaa3 is either Glu (E) or Arg (R). Xaa7 is either Ala (A) or Glu (E). Xaa14 is either Ala (A) or Lys (K). Xaa18 can be Glu (E), Lys (K), or Gln (Q). Xaa20 is either Ala (A) or Lys (K). Xaa23 is either Lys(K) or Pro(P). Xaa29 is either Ser(S) or Lys(K).

9. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, comprising: • One or two C14-C20 diacids; more preferably, one C16-C20 diacid or two C14-C18 diacids; even more preferably, a single C18 diacid; or • 1-2 extensions selected from those listed in Table 2.

10. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, comprising a polypeptide represented by any one of SEQ ID NO: 117-236; preferably, a polypeptide represented by SEQ ID NO:

153.

11. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims, wherein the compound is any one of the compounds listed in Example 1a; preferably, any one of the compounds listed in Table 5.

12. A GLP-1 receptor-amylin receptor co-agonist, which 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-amide: or 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-amide: or H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K([2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl])-GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide: 。 13. A pharmaceutical formulation comprising a GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims.

14. The GLP-1 receptor-amylin receptor co-agonist according to any one of claims 1-12, or the pharmaceutical formulation according to claim 13, used as a medicament.

15. The GLP-1 receptor-amylin receptor co-agonist according to any one of claims 1-12, or the formulation according to claim 13, for treating a subject with the following conditions: an initial body mass index (BMI) of 27 or higher, such as 30 or higher, optionally with at least one weight-related comorbidity; diabetes, optionally with at least one weight-related comorbidity; cardiovascular disease, nonsteroidal steatohepatitis, and / or cognitive impairment, such as cognitive impairment caused by Alzheimer's disease.

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