Tri-agonists of the GLP-1, GIP, and amylin receptors

Abstract

To provide a more effective medicament which is potent in vitro and potent against weight loss, which at the same time does not result in proportionally increased levels of side effects, which has improved pharmacokinetic properties, which has improved chemical stability, which is suitable for once weekly administration in humans, and / or which is suitable for oral administration.SOLUTION: The present invention relates to a GLP-1- / GIP- / amylin-receptor tri-agonist. This GLP-1- / GIP- / amylin-receptor tri-agonist may have improved pharmacokinetic properties and may be suitable for once weekly administration. The invention also relates to pharmaceutical compositions comprising such a GLP-1- / GIP- / amylin-receptor tri-agonist. The tri-agonist and pharmaceutical compositions comprising it may be used as a medicament for the treatment of subjects with overweight, obesity and associated co-morbidity.SELECTED DRAWING: None

Description

Technical Field

[0001] GLP-1 / GIP / Amylin receptor triple agonists for use in pharmaceuticals, and compositions comprising such compounds.

Background Art

[0002] Overweight and obesity are abnormal or excessive accumulations of body fat that pose risks to an individual's overall health. The WHO considers the body mass index (BMI) to be the most convenient population-level measure of overweight and obesity. In adults, a body mass index (BMI) of 25 or more is considered overweight, and a BMI of 30 or more is considered obese. Obesity is further subclassified into class I (BMI 30 - 34.9), class II (BMI 35 - 39.9), and class III (BMI > 40).

[0003] Obesity is a major risk factor in a number of serious medical conditions, including type 2 diabetes and its related co-morbidities, as well as cardiovascular diseases such as heart disease and stroke, which are leading causes of death worldwide. Obesity is currently recognized by the World Health Organization (WHO) as a problem that is spreading even among children, and in 2016, it was reported that 1.9 billion adults worldwide were obese, and in 2019, it was reported that 38.3 million children under the age of 5 worldwide were obese. According to the WHO, 422 million people worldwide are affected by diabetes, and 1.6 million deaths each year are directly attributable to diabetes. Therefore, there is a strong motivation, not only for individuals but also for society, to attempt to prevent and / or treat obesity.

[0004] If modifications to lifestyle, such as diet and exercise alone, are not sufficient to reduce the body mass index (BMI) of an individual living with obesity to an acceptable level, treatment with pharmaceuticals such as liraglutide, orlistat, and naltrexone-bupropion has been shown to cause some weight loss. Nevertheless, this weight loss is often not sustained and is too small for individuals with class II and class III obesity. In these cases, bariatric surgery has proven necessary. Bariatric surgery is currently the most effective treatment in terms of achieving long-term weight loss, but it is an invasive procedure that involves high risk and high cost for the patient. Thus, an effective and minimally invasive treatment would represent a significant improvement in the treatment of obesity.

[0005] GLP-1 is a 30- or 31-amino acid polypeptide synthesized and secreted from enteroendocrine L cells. GLP-1 is an incretin hormone that lowers blood glucose levels in a glucose-dependent manner by enhancing insulin secretion. Endogenous GLP-1 is rapidly degraded mainly by dipeptidyl peptidase-4 (DPP-4), resulting in a half-life of <2 minutes.

[0006] Several commercially available products containing a long-acting GLP-1 receptor agonist as the pharmaceutical active ingredient are approved for the treatment of type 2 diabetes. These include dulaglutide (Trulicity®), exenatide (Byetta®, Bydureon®), liraglutide (Victoza®), lixisenatide (Lyxumia®), and semaglutide (Ozempic®).

[0007] Two commercially available products containing a GLP-1 receptor agonist as an active pharmaceutical ingredient, liraglutide (Saxenda®) and semaglutide (Wegovy®), are approved for use in individuals living with overweight and having at least one weight-related co-morbidity, or in individuals living with obesity. The maximum effectiveness achievable with GLP-1 receptor agonists is limited by tolerance. As the dose increases, side effects such as nausea and vomiting become more prominent.

[0008] Native human GIP is a 42-amino acid polypeptide synthesized and thereby secreted by specialized enteroendocrine K cells. These cells are concentrated mainly in the duodenum and proximal jejunum but can also be found throughout the intestine. The main stimulant for GIP secretion is the ingestion of a diet rich in carbohydrates and lipids. After ingestion, circulating plasma GIP levels increase 10- to 20-fold. Similar to GLP-1, GIP is an incretin hormone and, in healthy humans, appears to actually be a more potent incretin than GLP-1. However, in individuals living with type 2 diabetes, GIP has lost its incretin effect. The half-life of intact GIP is estimated to be about 7 minutes in healthy subjects and about 5 minutes in people living with type 2 diabetes.

[0009] Long-acting (or persistent) GIP analogs have been shown to reduce body weight and improve glycemic control. With respect to weight loss, this effect is relatively less in rodent models than long-acting GLP-1 analogs (Non-Patent Document 1). Furthermore, GIP analogs induce weight loss by additive / synergistic action with long-acting GLP-1 analogs in dual administration (Non-Patent Documents 2 and 3), and thus represent suitable candidates for amplification of GLP-1-based pharmacological actions. As shown in preclinical animal models, GIPR agonistic action can also be included as a partner of GLP-1 receptor agonistic action as a single-molecule co-agonist to amplify GLP-1-driven weight loss and improvement of glycemic control (Non-Patent Documents 4 and 5). Two different peptides (MAR709 and LY3298176, the latter known as tirzepatide) with high potency against both GLP-1R and GIPR have been tested in multiple-dose clinical trials. Clinical results demonstrate improvement in glycemic control and body weight exceeding that achieved by equivalent administration of benchmark GLP-1-specific agonists (Non-Patent Documents 6 and 7), which demonstrates the translational aspect and therapeutic benefit of co-targeting of GLP-1 receptor and GIP receptor.

[0010] Since the compound tirzepatide was approved in 2022 for the treatment of diabetes, recently, this concept of co-targeting of GLP-1 receptor and GIP receptor has been proven using GLP-1 / GIP co-agonists. Furthermore, tirzepatide is also useful for the treatment of obesity because high-dose tirzepatide (15 mg) showed that patients lost 20.9% (mean) of their body weight after 72 weeks of treatment, including a 20-week dose-escalation period (Non-Patent Document 8). Tirzepatide was recently approved (trade name: Zepbound®) for weight management in people with BMI > 30 or BMI > 27, and at least one weight-related co-morbidity.

[0011] In addition to the tirzepatide described in Patent Document 1, GLP-1 / GIP co-agonists and their potential medical uses are described in several patent applications such as Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 9, Patent Document 10, Patent Document 11, Patent Document 12, Patent Document 13, and Patent Document 14.

[0012] Amylin is a 37-amino acid long polypeptide hormone produced in pancreatic beta (β) cells and co-secreted with insulin there. Amylin has a half-life of 15 - 20 minutes. It acts mainly through amylin receptors 1 - 3 (AMYR1 - 3) and produces its effects in several different organ systems. Amylin is an important regulator of energy metabolism in health and disease, inhibiting glucagon secretion, delaying gastric emptying, signaling satiety, and suppressing appetite. Other actions of amylin on the cardiovascular system and bone, etc. have also been reported.

[0013] Clinical trials have shown that amylin receptor agonists may be useful in the treatment of overweight, obesity, type 1 diabetes, and / or type 2 diabetes. Currently, one product (Symlin®) containing an amylin receptor agonist (pramlintide acetate) as a pharmaceutical active ingredient is commercially available. Symlin® is a liquid pharmaceutical composition for subcutaneous administration and is approved for use in patients with type 1 or type 2 diabetes who, despite optimal insulin therapy using basal and prandial insulin, have not been able to achieve the desired glycemic control. Pramlintide for use in people living with overweight and obesity has also been investigated. Pramlintide has a short half-life (less than 1 hour) and requires administration three times a day. As a result, there is a large diurnal variation in pramlintide plasma levels.

[0014] Amylin receptor agonist therapy is limited by a tolerance that is almost identical to that of GLP-1 receptor agonist therapy (and by similar side effects such as nausea and vomiting). There is a similar desire to be able to extend the action of amylin, and the co-targeting of the amylin receptor and the GLP-1 receptor has also been described. Amylin receptor agonists and their potential medical uses are described in several patent applications such as Patent Document 15, Patent Document 16, Patent Document 17, Patent Document 18, or Patent Document 19.

[0015] A fixed-dose combination of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide is currently under investigation for the treatment of overweight and obesity (Non-Patent Document 9). The investigational drug product is a separate liquid pharmaceutical composition for subcutaneous use. Clinical trials have demonstrated that the combination of cagrilintide and semaglutide induced greater weight loss in people living with obesity than the maximum approved dose of semaglutide monotherapy. No worsening of the side effect profile was observed. Peptide co-agonists of the GLP-1 receptor and the amylin receptor, and their potential medical uses, are described in several patent applications such as Patent Document 20. Among them, a peptide co-agonist of the human GLP-1R receptor and the amylin receptor is disclosed that is potent, balanced, i.e., has a similar level of activation of both receptor systems, and exhibits oral bioavailability. Another example is Patent Document 21, which describes a hybrid polypeptide comprising exendin covalently linked to amylin. However, there is no GLP-1 receptor and amylin receptor co-agonist that has obtained market approval to date.

[0016] Finally, Patent Documents 22 and 23 disclose multi-acting peptides useful as agents for the treatment and prevention of metabolic diseases and disorders, particularly diabetes and obesity. Patent Document 22 discloses peptides comprising two or more component peptides, including amylin, GIP, GLP-1, and / or calcitonin. The specifically disclosed peptide is a triple-acting agent for GLP-1 receptor, GIP receptor, and amylin receptor, showing activity against all three receptors in animals as well as a reduction in food intake and body weight.

[0017] Current therapeutic options and investigational drugs offer promise, but individuals living with overweight, obesity, and / or related comorbidities are, at present, at best, treated with injectable pharmaceutical formulations or medications that have some degree of efficacy. There remains a need in the art for more effective pharmaceuticals that are potent in vitro and against weight loss, do not produce proportionally increased levels of side effects, have improved pharmacokinetic properties, have improved chemical stability, are suitable for once-weekly dosing in humans, and / or are suitable for oral administration.

Prior Art Documents

Patent Documents

[0018]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

[0019] [Non-Patent Document 1] Mroz et al, Mol Metab, 2019, 20: 51 - 62 [Non-Patent Document 2] Finan et al, Sci Transl Med, 2013, 5(209):209ra151

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Summary of the Invention

[0020] The present invention relates to a GLP-1 / GIP / amylin receptor triple agonist, which is a peptide according to formula I containing one lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), · Z1 is a peptide containing up to 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein the amino acid at the X2 position represents Aib), · L1 is a peptide linker, · Z2 is a C-terminal amide and formula III (SEQ ID NO: 2): Relates to a GLP-1 / GIP / Amylin receptor triple agonist, which is a peptide containing up to 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III).

[0021] In another aspect, the present invention is a GLP-1 / GIP / Amylin receptor triple agonist, which is a peptide according to formula I containing 1 lysine (Lys, K) residue: Comprising Z1-L1-Z2 (I), ·Z1 is a peptide having up to 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 The amino acid at the position represents Aib), and And Z1 is an amino acid sequence according to formula X (SEQ ID NO: 161): X 21 X 22 X 23 GTFTSDYSX 24 LLEEX 25 AAX 26 EFIX 27 WLX 28 X 29 GGPSX 30 X 31 (X) (wherein X 21 Represents His (H) or Tyr (Y), X 22 Represents Aib, X 23 Represents Glu (E) or His (H), X 24 Represents Ile (I) or Lys (K), X 25 Represents Gln (Q) or Ile (I), X 26 Represents Arg (R) or Gln (Q), X 27 Represents Ala (A), Glu (E), or Gln (Q), X 28 represents Leu (L) or I (Ile), X 29 represents Ala (A) or Gln (Q), X 30 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 31 represents Gly (G), Glu (E), or Lys (K)), ·L1 is a peptide linker, ·Z2 contains a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions with respect to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula XII (SEQ ID NO: 164): AX 32 X 33 LSTAX 34 X 35 X 36 RLSAX 37 LHX 38 LX 39 X 40 X 41 PX 42 TETGSGX 43 P (XII) (wherein, X 32 represents Gly (G) or Ser (S), X 33 represents Gln (Q), Glu (E), His (H), or Lys (K), X 34 represents Ala (A) or Gln (Q), X 35 represents Gln (Q), Leu (L), or Thr (T), X 36 represents Ala (A), Gly (G), or Gln (Q), X 37 represents Glu (E) or Lys (K), X 38represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Lys(K), Thr(T), or Tyr(Y), X 39 represents Ala(A) or Lys(K), X 40 represents Asp(D) or Thr(T), X 41 represents Leu(L) or Glu(E), X 42 represents Arg(R) or Lys(K), X 43 (including those where X represents Ala(A) or Ser(S)) relates to a GLP-1 / GIP / amylin receptor triple agonist.

[0022] In another aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I containing 1 lysine (Lys, K) residue: Z1-L1-Z2 (I) and ·Z1 is a peptide having a maximum of 4 amino acid substitutions with respect to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 at the position represents Aib), and and Z1 is an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His(H) or Tyr(Y), X 2 represents Aib, X 3 represents Glu(E) or His(H), X 4represents Arg(R), Gly(G), Lys(K), or Ser(S), X 5 and includes (where X represents Gly(G) or Lys(K)), ·L1 is a peptide linker, ·Z2 contains a C-terminal amide, Formula III (SEQ ID NO: 2): a peptide having a maximum of 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to Formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents Gln(Q), Glu(E), His(H), or Lys(K), X 7 represents Ala(A) or Gln(Q), X 8 represents Gln(Q), Leu(L), or Thr(T), X 9 represents Ala(A), Gly(G), or Gln(Q), X 10 represents Glu(E) or Lys(K), X 11 represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Lys(K), Thr(T), or Tyr(Y), X 12 represents Ala(A) or Lys(K), X 13 represents Asp(D) or Thr(T), X 14represents Arg(R) or Lys(K), X 15 represents Ala(A) or Ser(S)), and relates to a GLP-1 / GIP / amylin receptor triple agonist.

[0023] In another aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I comprising 1 lysine (Lys, K) residue: Z1-L1-Z2 (I) ·Z1 is a peptide having an amino acid sequence according to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 the amino acid at the position represents Aib), and has a maximum of 4 amino acid substitutions, and Z1 is an amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein X 51 represents Aib, X 52 represents Ile(I) or Lys(K), X 53 represents Arg(R) or Gln(Q), X 54 represents Ala(A), Glu(E), or Gln(Q), X 55 represents Leu(L) or I(Ile), X 56 represents Ala(A) or Gln(Q), X 57 represents Gly(G) or Glu(E)), ·L1 is a peptide linker, ·Z2 contains a C-terminal amide and has the formula III (SEQ ID NO: 2): a peptide having a maximum of 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein X 58 represents Gly (G) or Ser (S), X 59 represents Gln (Q), Glu (E), or His (H), X 60 represents Ala (A) or Gln (Q), X 61 represents Leu (L) or Thr (T), X 62 represents Ala (A), Gly (G), or Gln (Q), X 63 represents Gln (Q), Glu (E), or Lys (K), X 64 represents Leu (L) or Glu (E)) and relates to a GLP-1 / GIP / Amylin receptor triple agonist.

[0024] In some embodiments, the GLP-1 / GIP / Amylin receptor triple agonist is YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 62), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPGASHLSTAQTQRLSAKLHRLATLPRTETGSGSP (SEQ ID NO: 65), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPLASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 68), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSRGEASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 78), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPLASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 87), or HXHGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPSGGGEASHLSTAQTARLSAELHQLATLPRTETGSGSP (SEQ ID NO: 111), or YXEGTFTSDYSILLEEIAAREFIEWLLAGGPSSGAGQAPGQAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 170) (wherein, in each amino acid sequence, X represents Aib), or consists of an amino acid sequence comprising the same.

[0025] The GLP-1 / GIP / amylin receptor triple agonist is an amino acid sequence according to Formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 (IV) (wherein X 1 represents Ala (A), Glu (E), Gly (G), X 2 represents Gln (Q), Glu (E), Gly (G), Leu (L), Pro (P), or is absent, X 3represents Ala (A), Gln (Q), Glu (E), Gly (G), Pro (P), or does not exist, X 4 represents Ala (A), Gln (Q), Glu (E), Gly (G), Pro (P), or does not exist, X 5 represents Glu (E), Gly (G), Pro (P), Ser (S), Thr (T), or does not exist, X 6 represents Glu (E), Gly (G), Leu (L), Gln (Q), or does not exist, X 7 represents Ala (A), Gln (Q), Glu (E), Gly (G), Phe (F), or does not exist, X 8 represents Ala (A), Gln (Q), Glu (E), Gly (G), Thr (T), Pro (P), Val (V), or does not exist, X 9 represents Glu (E), Asn (N), Pro (P), Thr (T), or does not exist, X 10 represents Alal (A), Gln (Q), Glu (E), Gly (G), Leu (L), Pro (P), Ser (S), Val (V), or does not exist, X 11 represents Ala (A), or does not exist, X 12 represents Gln (Q), or does not exist, X 13 represents Thr (T), or does not exist, X 14 contains or consists of a peptide linker L1 that includes Leu (L) (represents Leu (L) or does not exist).

[0026] In some embodiments, the GLP-1 / GIP / amylin receptor triple agonist includes an extension that enables an extended half-life.

[0027] Preferred GLP-1 / GIP / amylin receptor triple agonists of the present invention are Compound 52, namely, [Chemical formula] Compound 55, namely, [Chemical formula] Compound 58, namely, [Chemical formula] Compound 68, namely, [Chemical formula] Compound 77, namely, [Chemical formula] Compound 101, namely, [Chemical formula] is as follows.

[0028] In a third aspect, the present invention relates to a balanced GLP-1 / GIP / amylin receptor triple agonist that can selectively activate or "operate" all three of the GLP-1 receptor, GIP receptor, and amylin receptor to a similar level.

[0029] Also, or alternatively, in a fourth aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist having improved pharmacokinetic properties.

[0030] Also, or alternatively, in a fifth aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist suitable for once-weekly administration.

[0031] Also, or alternatively, in a sixth aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist suitable for oral administration.

[0032] Also, or alternatively, in a seventh aspect, the present invention relates to GLP-1 / GIP / amylin receptor triple agonists having improved chemical stability.

[0033] In a further aspect, the present invention also relates to a pharmaceutical composition comprising such a GLP-1 / GIP / amylin receptor triple agonist and one or more pharmaceutically acceptable excipients, and for use as a medicament, in particular, optionally in the presence of at least one weight-related co-existing disease, for the treatment of a subject having an initial body mass index (BMI) of 27 or more, such as 30 or more.

[0034] The present invention can also solve further problems, which will become apparent from the disclosure of the exemplary embodiments and aspects.

Brief Description of the Drawings

[0035]

Figure 1

Figure 2

Figure 3

[0036] Sequence Listing This application is filed with a sequence listing in electronic form. The entire contents of the sequence listing are hereby incorporated by reference into this specification. SEQ ID NO: 1 represents the amino acid sequence of Formula II of Z1. SEQ ID NO: 2 represents the amino acid sequence of Formula III of Z2. SEQ ID NO: 3 represents the amino acid sequence of Formula IIa of Z1. SEQ ID NO: 4 represents the amino acid sequence of Formula IIIa of Z2. SEQ ID NO: 5 represents the most comprehensive amino acid sequence of Formula I Z1-L1-Z2. SEQ ID NO: 6 represents the amino acid sequence of Formula V of Z1. SEQ ID NO: 7 represents the amino acid sequence of Formula VI of Z1. SEQ ID NO: 8 represents the amino acid sequence of Formula VII of Z2. SEQ ID NO: 9 represents the amino acid sequence of Formula VIII of Z2. SEQ ID NO: 11 represents the amino acid sequence of the polypeptide backbone in Reference Compound 1. SEQ ID NO: 12 represents the amino acid sequence of the polypeptide backbone in Reference Compound 2. SEQ ID NO: 13 represents the amino acid sequence of the polypeptide backbone in Reference Compound 3. SEQ ID NO: 14 represents the amino acid sequence of the polypeptide backbone in Reference Compound 4. SEQ ID NO: 15 represents the amino acid sequence of the polypeptide backbone in Reference Compound 5 (Tirzepatide). SEQ ID NO: 16 represents the amino acid sequence of the polypeptide backbone in Reference Compound 6 (Cagrilintide). Sequence number 17 represents the amino acid sequence of the polypeptide backbone in reference compound 7 (semaglutide). Sequence numbers 20 to 124 represent the amino acid sequences of the peptide backbones in compounds 10 to 115 and 210. Sequence numbers 125 to 159 represent the amino acid sequence of the exemplified peptide linker L1. Sequence number 161 represents the amino acid sequence of formula X of Z1. Sequence number 162 represents the amino acid sequence of formula Xa of Z1. Sequence number 163 represents the amino acid sequence of formula XI of Z1. Sequence number 164 represents the amino acid sequence of formula XII of Z2. Sequence number 165 represents the amino acid sequence of formula XIIa of Z2. Sequence number 166 represents the amino acid sequence of formula XIII of Z2. Sequence numbers 170 to 242 represent the amino acid sequences of the peptide backbones in compounds 120 to 197 and 211 to 221. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Modes for Carrying Out the Invention]

[0037] The present invention relates to a GLP-1 / GIP / amylin receptor triple agonist, which is a peptide according to formula I containing one lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), · where Z1 is a peptide containing a maximum of 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein the amino acid at the X2 position represents Aib), · L1 is a peptide linker, · Z2 is a C-terminal amide and a peptide containing a maximum of 10 amino acid substitutions relative to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III).

[0038] In another aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist, which is a peptide according to formula I containing one lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), · where Z1 is a peptide having a maximum of 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein the amino acid at the 2 X position represents Aib), and Z1 is an amino acid sequence according to formula X (SEQ ID NO: 161): X 21 X 22 X 23 GTFTSDYSX 24 LLEEX 25 AAX 26 EFIX 27 WLX 28 X 29 GGPSX 30 X 31 (X) (wherein X 21 represents His (H) or Tyr (Y), X 22 represents Aib, X 23 represents Glu (E) or His (H), X 24 represents Ile (I) or Lys (K), X 25 represents Gln (Q) or Ile (I), X 26 represents Arg (R) or Gln (Q), X 27 represents Ala (A), Glu (E), or Gln (Q), X 28 represents Leu (L) or I (Ile), X 29 represents Ala (A) or Gln (Q), X 30 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 31 including) represents Gly (G), Glu (E), or Lys (K), ·L1 is a peptide linker, ·Z2 contains a C-terminal amide and has the formula III (SEQ ID NO: 2): a peptide having a maximum of 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula XII (SEQ ID NO: 164): AX 32 X 33 LSTAX 34 X 35 X 36 RLSAX 37 LHX 38 LX 39 X 40 X 41 PX 42 TETGSGX 43 P (XII) (wherein, X32 represents Gly (G) or Ser (S), X 33 represents Gln (Q), Glu (E), His (H), or Lys (K), X 34 represents Ala (A) or Gln (Q), X 35 represents Gln (Q), Leu (L), or Thr (T), X 36 represents Ala (A), Gly (G), or Gln (Q), X 37 represents Glu (E) or Lys (K), X 38 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 39 represents Ala (A) or Lys (K), X 40 represents Asp (D) or Thr (T), X 41 represents Leu (L) or Glu (E), X 42 represents Arg (R) or Lys (K), X 43 relates to a GLP-1 / GIP / amylin receptor triple agonist comprising (wherein represents Ala (A) or Ser (S)).

[0039] In another aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I comprising 1 lysine (Lys, K) residue: Z1-L1-Z2 (I) comprising, ·Z1 is of formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 the amino acid at position represents Aib) and has a maximum of 4 amino acid substitutions, and Z1 has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 5 represents Gly (G) or Lys (K)) and ·L1 is a peptide linker, ·Z2 contains a C-terminal amide, Formula III (SEQ ID NO: 2): a peptide having a maximum of 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Gln (Q), Glu (E), His (H), or Lys (K), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 12 represents Ala (A) or Lys (K), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R) or Lys (K), X 15 relates to a GLP-1 / GIP / amylin receptor triple agonist comprising) (wherein X represents Ala (A) or Ser (S)).

[0040] In another aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I comprising 1 lysine (Lys, K) residue: Z1-L1-Z2 (I) and ·Z1 is a peptide having a maximum of 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 the amino acid at the position represents Aib), and Z1 is an amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein, X 51 represents Aib, X 52represents Ile (I) or Lys (K), X 53 represents Arg (R) or Gln (Q), X 54 represents Ala (A), Glu (E), or Gln (Q), X 55 represents Leu (L) or I (Ile), X 56 represents Ala (A) or Gln (Q), X 57 represents Gly (G) or Glu (E)), ·L1 is a peptide linker, ·Z2 contains a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions with respect to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein, X 58 represents Gly (G) or Ser (S), X 59 represents Gln (Q), Glu (E), or His (H), X 60 represents Ala (A) or Gln (Q), X 61 represents Leu (L) or Thr (T), X 62 represents Ala (A), Gly (G), or Gln (Q), X 63 represents Gln (Q), Glu (E), or Lys (K), X 64relates to a GLP-1 / GIP / amylin receptor triple agonist comprising (wherein represents Leu (L) or Glu (E)).

[0041] The compounds disclosed herein are agonists at each of the receptors GLP-1, GIP, and amylin. Thus, the compounds of the invention are GLP-1 receptor agonists and GIP receptor agonists, as well as agonists for the amylin receptor (i.e., amylin receptor agonists). It is capable of activating or "agonizing" all three of the GLP-1 receptor, GIP receptor, and amylin receptor systems, and it is a "GLP-1 / GIP / receptor amylin receptor agonist". A GLP-1 / GIP / amylin receptor triple agonist can provide a similar level of activation of all three GLP-1, GIP, and amylin receptors, which is then referred to as a "balanced GLP-1 / GIP / amylin receptor triple agonist", or more simply a "balanced triple agonist".

[0042] An "agonist" or "agonist drug" can be defined as a ligand such as a compound that binds to a biological receptor and activates it to produce a biological response. A full agonist can be defined as one that causes a response of the same magnitude as the natural ligand (see, for example, "Principles of Biochemistry", AL Lehninger, DL Nelson, MM Cox, Second Edition, Worth Publishers, 1993, page 763). A receptor can be activated by either an endogenous agonist such as an endogenous hormone or an exogenous agonist such as a pharmaceutical agent.

[0043] In the context of the present invention, a "co-agonist" is a compound capable of binding to and activating two different biological receptors, for example, a compound comprising two different ligands, each of which binds to a given biological receptor and elicits a biological response characteristic of the native ligand. Similarly, a "triple agonist" or "tri-agonist" is a compound capable of binding to and activating three different biological receptors, for example, a compound comprising three different ligands, each of which binds to a given biological receptor and elicits a biological response characteristic of the native ligand.

[0044] A "GLP-1 receptor agonist" can be defined as a compound capable of binding to and activating the GLP-1 receptor. A "full" GLP-1 receptor agonist can be defined as a GLP-1 receptor agonist capable of eliciting a GLP-1 receptor response on a scale similar to that of native glucagon-like peptide 1 (GLP-1). Semaglutide, disclosed in Example 4 of International Publication No. WO 2006 / 097537, is an example of an exogenous GLP-1 receptor agonist.

[0045] A "GIP receptor agonist" can be defined as a compound capable of binding to and activating the GIP receptor. A "full" GIP receptor agonist can be defined as a GIP receptor agonist capable of eliciting a GIP receptor response on a scale similar to that of native glucose-dependent insulinotropic polypeptide (GIP).

[0046] A "GLP-1 / GIP receptor agonist" can be defined as a compound capable of binding to and activating both the GLP-1 receptor and the GIP receptor. An example of a GLP-1 / GIP co-agonist is tildesatide, described in International Publication No. WO 2016 / 111971.

[0047] "Amylin receptor agonist" can be defined as a compound that is capable of binding to and activating the amylin receptor (AMYR) and the calcitonin receptor (CTR). The amylin receptor consists of two components, namely, the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins (RAMP1-3), resulting in three possible complexes AMYR1-3. Unless otherwise specified herein, "amylin receptor" refers to at least amylin receptor 3 (AMYR3). Nevertheless, some co-activation of other receptors may be expected. A "full" amylin receptor agonist can be defined as an amylin receptor agonist that is capable of eliciting an amylin receptor response on a scale similar to that of native amylin. Amylin receptor agonists often also act as calcitonin receptor agonists. Examples of amylin receptor agonists are human amylin, human calcitonin, and cagrilintide (disclosed in WO 2012 / 168432). It should be noted that all headings and subheadings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0048] The use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to make the invention more clear and does not limit the scope of the invention unless otherwise claimed.

[0049] Certain terms are first defined so that the invention may be more readily understood.

[0050] Hereinafter, Greek letters may be represented by their symbols or corresponding descriptive names, for example, α = alpha, β = beta, γ = gamma, ε = epsilon, ω = omega, etc. Also, the Greek letter μ may be represented by "u", for example, μl = ul, μM = uM.

[0051] Unless otherwise indicated herein, terms presented in the singular include plural situations. The terms "a" or "an" are intended to mean "one or more".

[0052] The term "comprise" preceding a listing of steps or elements, as well as variations thereof such as "comprises" and "comprising", are intended to mean that the addition of further steps or elements is optional and not excluded. As disclosed herein, non-limiting terms such as "comprises" and "comprising" may be replaced with limiting terms such as "consists of", "consisting of".

[0053] The term "about" is used herein to mean approximately, roughly, or around. When the term "about" is used in conjunction with a numerical range, the range is modified by extending the boundaries above and below the recited numerical values. Generally, the term "about" can modify numerical values that are 10 percent above or below (higher or lower), above and below the recited value.

[0054] An amino acid is a molecule that optionally contains an amine group and a carboxylic acid group, as well as one or more additional groups often referred to as side chains.

[0055] The term "amino acid" includes standard amino acids (genetically encoded) and non-natural amino acids. Non-limiting examples of non-natural amino acids are Aib (α-aminoisobutyric acid or 2-aminoisobutyric acid), deaminohistidine (also known as 3-(imidazol-4-yl)propanoic acid, abbreviation Imp (imidazolopropionyl)), and d-isomers of standard amino acids. All amino acid residues within a peptide for which no optical isomer is described should be understood herein to mean the L-isomer, unless otherwise specified.

[0056] As used herein, the term "amino acid substitution" or "substitution" refers to one or more amino acids that are replaced with the same number of amino acids within the backbone of a peptide. The substitution may be, but is not limited to, a conservative substitution. For example, an amino acid may be substituted with an amino acid having similar biochemical properties, e.g., a basic amino acid may be substituted with another basic amino acid (e.g., from lysine to arginine), an acidic amino acid may be substituted with another acidic amino acid (e.g., from glutamic acid to aspartic acid), a neutral amino acid may be substituted with another neutral amino acid (e.g., from threonine to serine), a charged amino acid may be substituted with another charged amino acid (e.g., from glutamic acid to lysine), a hydrophilic amino acid may be substituted with another hydrophilic amino acid (e.g., from asparagine to glutamine), a hydrophobic amino acid may be substituted with another hydrophobic amino acid (e.g., from alanine to valine), a polar amino acid may be substituted with another polar amino acid (e.g., from serine to threonine), an aromatic amino acid may be substituted with another aromatic amino acid (e.g., from phenylalanine to tryptophan), and an aliphatic amino acid may be substituted with another aliphatic amino acid (e.g., from leucine to isoleucine).

[0057] As used herein, the term "excipient" broadly refers to any component other than an active pharmaceutical ingredient (API).

[0058] The terms "identity" or "sequence identity" as known in the art refer to the relationship between the sequences of two or more polypeptides determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between polypeptides determined by the number of matches between strings of two or more amino acid residues. "Identity" measures the percentage of exact matches between the shorter of two or more sequences with gap alignments (if any) handled by a particular mathematical model or computer program (i.e., "algorithm"). The identity of related polypeptides can be readily calculated by known methods, for example, using Needleman from EMBOSS - 6.6.0 (Needleman et al. J. Mol. Biol. 1970;48:443 - 453) using parameters 10 and 0.5 for gap opening and extension respectively (gapopen = 10, gapextend = 0.5), or for example, by (1) comparing two optimally aligned sequences over a comparison window (e.g., the length of the longer sequence, the length of the shorter sequence, a specified window, etc.), (2) determining the number of positions containing the same monomer (e.g., the same amino acid occurs in both sequences), which gives rise to the number of matching positions, (3) dividing the number of matching positions by the total number of positions within the comparison window (e.g., the length of the longer sequence, the length of the shorter sequence, a specified window), and (4) multiplying the result by 100 to give rise to the "sequence identity" rate. For example, if both Peptide A and Peptide B are 20 amino acids in length and have exactly the same amino acids except for one position, Peptide A and Peptide B have 95% sequence identity.

[0059] As used herein, the terms "polypeptide" or "peptide" include oligopeptides and refer to a single chain of amino acids connected by one or more amide (or peptide) bonds. The terms "polypeptide" and "peptide" shall be used interchangeably herein.

[0060] As used herein, the term "half-life" or "plasma half-life" refers to the time required for half of the amount of a substance administered to an individual to be metabolized or eliminated from the individual's serum or plasma by normal biological processes.

[0061] As used herein, the term "treatment" or variations thereof refers to medical therapy of any human subject in need thereof. The term includes administering a therapeutically effective amount of a peptide disclosed herein sufficient to reduce or eliminate at least one symptom of the disorder in question. However, "treatment" need not be a cure. The timing and purpose of such treatment may vary from individual to individual, depending on the current state of the subject's health. Accordingly, such treatment may be prophylactic, palliative, symptomatic, and / or curative. For the purposes of the present invention, prophylactic, palliative, symptomatic, and / or curative treatment may represent separate aspects of the present invention.

[0062] As used herein, the terms "prevent," "preventing," or "prevention," or variations thereof, refer to protecting a subject from the onset of at least one symptom of a disease or reducing the severity of symptoms of a disorder.

[0063] GLP-1 / GIP / Amylin receptor triple agonist The compounds disclosed herein are referred to herein as "GLP-1 / GIP / Amylin receptor tri-agonist" or "GLP-1 receptor-GIP receptor-Amylin receptor triple agonist," or "GLP-1 / GIP / Amylin receptor triple agonist" or "GLP-1 receptor-GIP receptor-Amylin receptor triple agonist."

[0064] The GLP-1 / GIP / Amylin receptor triple agonist comprises peptide Z1, which is a GLP-1 / GIP receptor co-agonist, peptide linker L1, and peptide Z2, which is an amylin receptor agonist. The GLP-1 / GIP / Amylin receptor triple agonist can bind to each of the three GLP-1, GIP, and amylin receptors and activate each receptor GLP-1R, GIPR, and the amylin receptor, and thus is a compound that elicits a response in each receptor.

[0065] Peptide Z1 disclosed herein may have up to 4 amino acid substitutions relative to formula II (SEQ ID NO: 1). Peptide Z2 disclosed herein may have up to 10 amino acid substitutions relative to formula III (SEQ ID NO: 2).

[0066] The term "compound" is used herein to refer to a molecular entity, and thus a "compound" can have different structural elements other than the minimum elements defined for each compound or group of compounds. As long as a compound contains the defined structural and / or functional elements, the compound can be a peptide or a derivative thereof. The term "compound" is also intended to encompass its pharmaceutically relevant forms, namely, the compounds defined herein, or their pharmaceutically acceptable salts, amides, or esters. As long as a compound contains the defined structural and / or functional elements, the compound can be a peptide or a derivative thereof. The term "compound" is also intended to encompass its pharmaceutically relevant forms, namely, the compounds defined herein, or their pharmaceutically acceptable salts, amides, or esters.

[0067] The compounds disclosed herein can be potent GLP-1 receptor agonists.

[0068] The compounds disclosed herein can be potent GIP receptor agonists.

[0069] The compounds disclosed herein can be potent amylin receptor agonists.

[0070] The in vitro potency of an agonist can be measured as described in the assay of Example 4. The term "potency" is used to describe the effect of a given compound in an assay where a sigmoid relationship between the log concentration and the effect of the compound has been established. Further, the response should be variable from 0 to 100%. The potency of a compound can be described using its EC (effective concentration) 50 value. EC 50 represents, for example, the concentration of a compound at which 50% of its maximal effect is observed in the assay, as described in Example 4. The lower the EC 50 value, the more potent the compound.

[0071] The compounds disclosed herein can provide a similar level of activation of all three GLP-1 receptors, GIP receptors, and amylin receptors, i.e., it can be "balanced", and is referred to as a "balanced GLP-1 / GIP / amylin receptor triple agonist", or simply a "balanced triple agonist" for short. Since the relative ratios of the GLP-1, GIP, and amylin receptor agonist activities of the compound are locked in the molecule, a relatively "balanced" receptor activation is advantageous, and it is not possible to titrate the three receptor agonists against each other. Finally, if the molecule is "balanced", it can be administered such that all three hormonal systems are activated without side effects outweighing the benefits.

[0072] A triple agonist with a potency ratio (A / B) of the potency (A) of the receptor with the lowest potency (i.e., the highest numerical EC 50 value) divided by the potency (B) of the receptor with the highest potency (i.e., the lowest numerical EC 50 value) less than 50 is a "balanced triple agonist" or a "balanced GLP-1 / GIP / amylin receptor triple agonist" (based on an assay in the absence of human serum albumin (HSA), as shown in Tables 7a and 8a of Example 4). For example, Compound 10 has an EC 50 of 13.83 pM for the GLP-1 receptor and an EC 50, and has an EC of 6.8 pM for the amylin receptor 50 Thus, this has the lowest potency against hGLP-1, and (A) corresponds to 13.83 pM and has the highest potency against the GIP receptor corresponding to 2.11 pM for (B). Thus, the potency ratio (A / B) is 13.83 pM (A) divided by 2.11 pM (B), equal to 7 (appropriately rounded), which means that Compound 10 is a "balanced triple agonist".

[0073] A compound that is potent against one receptor and much weaker against the other can be "unbalanced". Such an "unbalanced triple agonist" is defined as a compound having a potency ratio (A / B) of 50 or more. For example, Reference Compound 1 has a potency ratio (A / B) of 287 (i.e., 1516.05 pM (=A) divided by 5.29 pM (=B), appropriately rounded). For example, being potent against the GIP receptor and the amylin receptor (i.e., EC 50 value < 30 pM) and not very potent against the GLP-1 receptor (i.e., an EC 50 value of 1516 pM), this reference compound cannot achieve optimal efficacy from all three hormonal systems because the side effects resulting from the activation of the GIP receptor and the amylin receptor prevent the administration of a high enough dose to also achieve the activation of the GLP-1 hormonal system. The opposite situation can occur when a compound is potent against one receptor, e.g., the GLP-1 receptor (e.g., having an EC 50 value < 50 pM) and significantly weaker against two other receptors, e.g., the GIP receptor and the amylin receptor (e.g., each having an EC 50 value > 500 pM).

[0074] Peptide In one aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to Formula I comprising 1 lysine (Lys, K) residue: Comprising Z1-L1-Z2 (I), ·Z1 is of Formula II (SEQ ID NO: 1): YX2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein the amino acid at the X2 position represents Aib), a peptide containing up to 4 amino acid substitutions, ·L1 is a peptide linker, ·Z2 is a C-terminal amide and a peptide containing up to 10 amino acid substitutions relative to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III), relating to a GLP-1 / GIP / amylin receptor triple agonist.

[0075] The GLP-1 / GIP / amylin receptor triple agonist comprises a peptide Z1, a peptide linker L1, and a peptide Z2, and comprises a peptide Z1-L1-Z2.

[0076] Peptide Z1 is a GLP-1 / GIP receptor co-agonist that can bind to both the GLP-1 receptor and the GIP receptor and can activate both receptors. The C-terminus of peptide Z1 is bound to peptide linker L1 via a peptide bond.

[0077] L1 is a peptide linker. Its N-terminus is bound to the C-terminus of Z1 via a peptide bond, and its C-terminus is bound to the N-terminus of Z2.

[0078] Peptide Z2 is an amylin receptor agonist that can bind to at least the amylin receptor and can activate it. The N-terminus of Z2 is bound to the C-terminus of L1 via a peptide bond. The C-terminus of Z2 is modified with an amide group considered essential for biological activity. In a preferred embodiment, the amine group of the C-terminal amide is NH 2 is.

[0079] The molecular form can be a single-chain polypeptide backbone containing one lysine (Lys, K) residue. The one lysine (Lys, K) residue can be present in the peptide Z1 portion of the peptide backbone, or the one lysine (Lys, K) residue can be present in the peptide Z2 portion of the peptide backbone. The one lysine residue is herein referred to as "L P -P", can be covalently attached to an extension part called "L P ", where "L

[0080] " is an optional linker and "P" is a protractor. The peptide backbone of the GLP-1 / GIP / amylin receptor triple agonist of the present invention typically contains about 66 to about 80 amino acid residues linked together by peptide bonds.

[0081] Preferred substitutions include conservative substitutions that include similar biochemical properties or structural analogs of amino acid residues in place of the amino acid residues that appear in the sequence.

[0082] Peptide Z2 disclosed herein may have up to 10 amino acid substitutions relative to Formula III (SEQ ID NO: 2), and such substitutions can be made at any of positions 1 to 32. Preferably, such substitutions are made at positions 2, 3, 7, 8, 9, 10, 15, 18, 20, 21, 22, 24, and / or 31. The present invention encompasses variants of the GLP-1 / GIP / amylin receptor triple agonist disclosed herein, wherein peptide Z2 may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions relative to Formula III (SEQ ID NO: 2). Preferred substitutions include the conservative substitutions described above.

[0083] In some embodiments of the present invention, peptide Z1 comprises amino acids having at least 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity (i.e., sequence identity) to Formula II (SEQ ID NO: 1), and peptide Z2 comprises amino acids having at least 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity (i.e., sequence identity) to Formula III (SEQ ID NO: 2).

[0084] In some embodiments of the present invention, the GLP-1 / GIP / amylin receptor triple agonist disclosed herein does not contain cysteine (Cys, C) residues and / or does not contain disulfide bridges. The term "disulfide bridge" with respect to human amylin and its analogs refers to a functional group having the structure R-S-S-R', and may also be referred to as an "SS bond".

[0085] As described herein, the GLP-1 / GIP / amylin receptor triple agonist may exhibit various properties that make it useful as a medicament.

[0086] In another aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to Formula I, comprising one lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), ·Z1 is a peptide having a maximum of 4 amino acid substitutions with respect to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 at the position represents Aib), and Z1 is an amino acid sequence according to formula X (SEQ ID NO: 161): X 21 X 22 X 23 GTFTSDYSX 24 LLEEX 25 AAX 26 EFIX 27 WLX 28 X 29 GGPSX 30 X 31 (X) (wherein X 21 represents His (H) or Tyr (Y), X 22 represents Aib, X 23 represents Glu (E) or His (H), X 24 represents Ile (I) or Lys (K), X 25 represents Gln (Q) or Ile (I), X 26 represents Arg (R) or Gln (Q), X 27 represents Ala (A), Glu (E), or Gln (Q), X 28 represents Leu (L) or I (Ile), X 29 represents Ala (A) or Gln (Q), X 30 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 31comprises or consists of Gly (G), Glu (E), or Lys (K), ·L1 is a peptide linker, ·Z2 contains a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions relative to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III) and Z2 has an amino acid sequence according to formula XII (SEQ ID NO: 164): AX 32 X 33 LSTAX 34 X 35 X 36 RLSAX 37 LHX 38 LX 39 X 40 X 41 PX 42 TETGSGX 43 P (XII) (wherein X 32 represents Gly (G) or Ser (S), X 33 represents Gln (Q), Glu (E), His (H), or Lys (K), X 34 represents Ala (A) or Gln (Q), X 35 represents Gln (Q), Leu (L), or Thr (T), X 36 represents Ala (A), Gly (G), or Gln (Q), X 37 represents Glu (E) or Lys (K), X 38 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 39 represents Ala (A) or Lys (K), X 40 represents Asp (D) or Thr (T), X41 represents Leu (L) or Glu (E), X 42 represents Arg (R) or Lys (K), X 43 and relates to a GLP-1 / GIP / amylin receptor triple agonist comprising or consisting of ) wherein X represents Ala (A) or Ser (S).

[0087] In another aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I comprising one lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), · Z1 is a peptide having at most 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 the amino acid at the position represents Aib), and Z1 is an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 5 represents Gly (G) or Lys (K)) and comprising or consisting of, · L1 is a peptide linker, · Z2 contains a C-terminal amide, Formula III (SEQ ID NO: 2): A peptide having a maximum of 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and wherein Z2 is an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Gln (Q), Glu (E), His (H), or Lys (K), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 12 represents Ala (A) or Lys (K), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R) or Lys (K), X 15 represents Ala (A) or Ser (S)), or consisting of the foregoing, relating to a GLP-1 / GIP / amylin receptor triple agonist.

[0088] In another aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I containing 1 lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), · Z1 is a peptide having a maximum of 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 the amino acid at the position represents Aib), and Z1 is an amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein X 51 represents Aib, X 52 represents Ile (I) or Lys (K), X 53 represents Arg (R) or Gln (Q), X 54 represents Ala (A), Glu (E), or Gln (Q), X 55 represents Leu (L) or I (Ile), X 56 represents Ala (A) or Gln (Q), X 57 represents Gly (G) or Glu (E)) and contains or consists of, · L1 is a peptide linker, · Z2 contains a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions relative to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein X 58 represents Gly (G) or Ser (S), X 59 represents Gln (Q), Glu (E), or His (H), X 60 represents Ala (A) or Gln (Q), X 61 represents Leu (L) or Thr (T), X 62 represents Ala (A), Gly (G), or Gln (Q), X 63 represents Gln (Q), Glu (E), or Lys (K), X 64 represents Leu (L) or Glu (E)) and relates to a GLP-1 / GIP / amylin receptor triple agonist.

[0089] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAaREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 X 2 X 3 represents YAibE (Tyr-Aib-Glu) or HAibH (His-Aib-His), X 4 represents Arg (R), Gly (G), or Ser (S), X 5may contain, or consist of, a peptide Z1 that contains Gly (G).

[0090] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His, X 2 represents Aib, X 3 represents His (H), X 4 represents Lys (K), X 5 represents Gly (G)) may contain, or consist of, a peptide Z1.

[0091] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula V (SEQ ID NO: 6): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 G (V) (wherein X 2 represents Aib, X 4 is Arg (R) or Ser (S)) may contain, or consist of, a peptide Z1.

[0092] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula VI (SEQ ID NO: 7): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSSG (VI) (wherein X 2may contain, or consist of, a peptide Z1 that includes (representing Aib).

[0093] In some embodiments of the present invention, the peptide Z1 may include an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to SEQ ID NO: 7 (Formula VI).

[0094] In one embodiment, the GLP-1 / GIP / Amylin receptor triple agonist of the present invention has an amino acid sequence according to Formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein X 51 represents Aib, X 52 represents Ile (I) or Lys (K), X 53 represents Arg (R), X 54 represents Glu (E), X 55 represents Leu (L) or I (Ile), X 56 represents Ala (A), X 57 represents Gly (G) or Glu (E)) may contain, or consist of, a peptide Z1.

[0095] In one embodiment, the GLP-1 / GIP / Amylin receptor triple agonist of the present invention has an amino acid sequence according to Formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein, X 51 represents Aib, X 52 represents Ile (I) or Lys (K), X 53 represents Arg (R), X 54 represents Glu (E), X 55 represents Leu (L), X 56 represents Ala (A), X 57 represents Gly (G)) may contain or consist of peptide Z1.

[0096] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula XI (SEQ ID NO: 163): YX 51 EGTFTSDYSX 52 LLEEIAAREFIEWLLAGGPSSG (XI) (wherein, X 51 represents Aib, X 52 represents Ile (I) or Lys (K)) may contain or consist of peptide Z1.

[0097] In one embodiment, peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents Lys (K), X 7 represents Ala (A) or Gln (Q), X8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Thr (T), or Tyr (Y), X 12 represents Ala (A), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R), X 15 represents Ala (A) or Ser (S), or or X 6 represents Gln (Q), Glu (E), or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Lys (K), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Thr (T), or Tyr (Y), X 12 represents Ala (A), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R), X 15 represents Ala (A) or Ser (S), or or X 6represents Gln (Q), Glu (E), or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Lys (K), X 12 represents Ala (A), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R), X 15 represents Ala (A) or Ser (S), or or X 6 represents Gln (Q), Glu (E), or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Thr (T), or Tyr (Y), X 12 represents Lys (K), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R), X 15 represents Ala (A) or Ser (S), or or X 6 represents Gln (Q), Glu (E), or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Thr (T), or Tyr (Y), X 12 represents Ala (A), X 13 represents Asp (D) or Thr (T), X 14 represents Lys (K), X 15 may include or consist of).

[0098] In one embodiment, peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents His (H), X 7 represents Gln (Q), X 8 represents Thr (T), X 9 represents Gln (Q), X 10represents Glu(E), X 11 represents Arg(R) or Lys(K), X 12 represents Ala(A) or Lys(K), X 13 represents Thr(T), X 14 represents Arg(R) or Lys(K), X 15 and may comprise or consist of Ser(S)).

[0099] In one embodiment, peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents His(H), X 7 represents Ala(A) or Gln(Q), X 8 represents Leu(L) or Thr(T), X 9 represents Ala(A), Gly(G), or Gln(Q), X 10 represents Glu(E), X 11 represents Arg(R) or Gln(Q), X 12 represents Lys(K), X 13 represents Thr(T), X 14 represents Arg(R), X 15 and may comprise or consist of Ser(S)).

[0100] In one embodiment, peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Leu (L) or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R), X 12 represents Ala (A), X 13 represents Thr (T), X 14 represents Lys (K), X 15 represents Ser (S)) and may comprise or consist of the same.

[0101] In one embodiment, peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X6 represents Gln (Q), Glu (E), His (H), or Lys (K), and X 7 represents Ala (A) or Gln (Q), and X 8 represents Gln (Q), Leu (L), or Thr (T), and X 9 represents Ala (A), Gly (G), or Gln (Q), and X 10 represents Glu (E) or Lys (K), and X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), and X 12 represents Ala (A) or Lys (K), and X 13 represents Asp (D) or Thr (T), and X 14 represents Arg (R) or Lys (K), and X 15 may comprise or consist of).

[0102] In one embodiment, peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Glu (E) or His (H), and X 7 represents Ala (A) or Gln (Q), and X 8 represents Leu (L) or Thr (T), and X 9represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R), Gln (Q), or Glu (E), X 12 represents Ala (A), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R), X 15 may include or consist of Ser (S).

[0103] In one embodiment, peptide Z2 has the amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents Glu (E) or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Leu (L) or Thr (T), X 9 represents Ala (A) or Gly (G), X 10 represents Glu (E), X 11 represents Arg (R), Gln (Q), or Glu (E), X 12 represents Ala (A), X 13 represents Thr (T), X 14 represents Arg (R), X15 may contain or consist of (representing Ser(S)).

[0104] In one embodiment, peptide Z2 has an amino acid sequence according to formula VII (SEQ ID NO: 8): ASHLSTAQTQRLSAKLHRLATLPRTETGSGSP (VII) and may contain or consist of it.

[0105] In one embodiment, peptide Z2 has an amino acid sequence according to formula VIII (SEQ ID NO: 9): ASHLSTAQTQRLSAELHKLATLPRTETGSGSP (VIII) and may contain or consist of it.

[0106] In some embodiments of the present invention, peptide Z2 may contain an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to formula VII (SEQ ID NO: 8) or formula VIII (SEQ ID NO: 9).

[0107] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein X 58 represents Ser(S), X 59 represents His(H), X 60 represents Gln(Q), X 61 represents Thr(T), X 62 represents Gln(Q), X 63 represents Lys(K), X 64may contain, or consist of, a peptide Z2 containing (representing Leu (L)).

[0108] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula XIII (SEQ ID NO: 166): ASX 59 LSTAQTQRLSAELHKLATLPRTETGSGSP(XIII) (wherein X 59 represents Glu (E) or His (H)) may contain, or consist of, a peptide Z2.

[0109] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention comprises, or consists of, a peptide Z1 having an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to formula VI (SEQ ID NO: 7), and a peptide Z2 having an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to formula VII (SEQ ID NO: 8) or formula VIII (SEQ ID NO: 9).

[0110] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), or Ser (S), X5 a peptide Z1 comprising, or consisting of, Gly (G), and an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Gln (Q), Glu (E), His (H), or Lys (K), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 12 represents Ala (A) or Lys (K), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R) or Lys (K), X 15 represents Ala (A) or Ser (S)) and may comprise, or consist of, a peptide Z2.

[0111] In one embodiment, the GLP-1 / GIP / Amylin receptor triple agonist of the present invention has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), or Ser (S), X 5 represents Gly (G)) and contains or consists of peptide Z1, Amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Glu (E) or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), or Lys (K), X 12 represents Ala (A) or Lys (K), X 13 represents Thr (T), X 14represents Arg(R) or Lys(K), X 15 represents Ala(A) or Ser(S)), may include, or consist of, peptide Z2.

[0112] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist of the present invention has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein, X 1 represents His(H) or Tyr(Y), X 2 represents Aib, X 3 represents Glu(E) or His(H), X 4 represents Arg(R), Gly(G), or Ser(S), X 5 represents Gly(G)), may include, or consist of, peptide Z1. Peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents Glu(E) or His(H), X 7 represents Ala(A) or Gln(Q), X 8 represents Gln(Q), Leu(L), or Thr(T), X 9represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Lys (K), X 12 represents Ala (A), X 13 represents Thr (T), X 14 represents Arg (R), X 15 represents Ala (A) or Ser (S)) or consists of or contains the same.

[0113] In one embodiment, the GLP-1 / GIP / Amylin receptor triple agonist of the present invention has an amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein, X 51 represents Aib, X 52 represents Ile (I) or Lys (K), X 53 represents Arg (R), X 54 represents Glu (E), X 55 represents Leu (L) or I (Ile), X 56 represents Ala (A), X 57 represents Gly (G) or Glu (E)) or consists of or contains the same, peptide Z1, and an amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX63 LATX 64 PRTETGSGSP (XIIa) (wherein X 58 represents Ser(S), X 59 represents His(H), X 60 represents Gln(Q), X 61 represents Thr(T), X 62 represents Gln(Q), X 63 represents Lys(K), X 64 represents Leu(L)) may include or consist of peptide Z2.

[0114] In one embodiment, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist comprising a peptide, the peptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 20 to 124 and 170 to 242, and X represents Aib. In a particular embodiment, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist, and the amino acid sequence of the peptide is YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 62) (wherein X represents Aib), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPGASHLSTAQTQRLSAKLHRLATLPRTETGSGSP (SEQ ID NO: 65) (wherein X represents Aib), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPLASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 68) (wherein X represents Aib), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSRGEASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 78) (wherein X represents Aib), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPLASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 87) (wherein X represents Aib), or HXHGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPSGGGEASHLSTAQTARLSAELHQLATLPRTETGSGSP (SEQ ID NO: 111) (wherein X represents Aib), or comprises or consists of YXEGTFTSDYSILLEEIAAREFIEWLLAGGPSSGAGQAPGQAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 170) (wherein X represents Aib).

[0115] One aspect of the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist capable of activating human GIP receptor, GLP-1 receptor, and amylin receptor in vitro.

[0116] When tested as described in the "GLP-1 receptor assay" (preferably, Method A; in the absence of HSA), the GLP-1 / GIP / amylin receptor triple agonists disclosed herein have an EC 50 value of less than 125 pM, preferably less than 100 pM, for example, less than 75 pM, even more preferably less than 50 pM, for example, less than 40 pM, most preferably less than 30 pM, for example, less than 20 pM, for example, less than 10 pM, for example, less than 5 pM.

[0117] When tested as described in the "GIP receptor assay" (preferably, Method A; in the absence of HSA), the GLP-1 / GIP / amylin receptor triple agonist disclosed herein has an EC 50 value that can be less than 125 pM, preferably less than 100 pM, for example, less than 75 pM, even more preferably less than 50 pM, for example, less than 40 pM, most preferably less than 30 pM, for example, less than 20 pM, for example, less than 10 pM, for example, less than 5 pM.

[0118] When tested as described in the "amylin receptor assay" (preferably, Method A; in the absence of HSA), the GLP-1 / GIP / amylin receptor triple agonist disclosed herein has an EC 50 value that can be less than 125 pM, preferably less than 100 pM, for example, less than 75 pM, even more preferably less than 50 pM, for example, less than 40 pM, most preferably less than 30 pM, for example, less than 20 pM, for example, less than 10 pM, for example, less than 5 pM. The GLP-1 / GIP / amylin receptor triple agonist disclosed herein activates or activates the amylin receptor. The GLP-1 / GIP / amylin receptor triple agonist disclosed herein can be tested for amylin activity as described in Example 4.

[0119] The more potent the compound, the lower its EC 50 value. The GLP-1 / GIP / amylin receptor triple agonist can have an EC 50 of about 100 pM or less in a human GLP-1 receptor function assay (see Example 4). The GLP-1 / GIP / amylin receptor triple agonist can have an EC 50 of about 90 pM or less in a human GLP-1 receptor function assay. The GLP-1 / GIP / amylin receptor triple agonist can have an EC 50 of about 80 pM or less in a human GLP-1 receptor function assay. The GLP-1 / GIP / amylin receptor triple agonist can have an EC 50may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 70 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 60 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 50 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 40 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 30 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 25 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 20 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 15 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 10 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GLP-1 receptor function assay of about 5 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist disclosed herein may have a potency similar to that of semaglutide or tirzepatide.

[0120] The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GIP receptor function assay (see Example 4) of about 125 pM or less 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC in a human GIP receptor function assay of about 100 pM or less 50may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 90 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 80 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 75 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 70 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 60 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 50 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 40 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 30 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 25 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 20 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 15 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 10 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 9 pM or less 50 may have. The GLP-1 / GIP / Amylin receptor triple agonist has an EC in a human GIP receptor function assay of about 8 pM or less 50may have. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 in the human GIP receptor function assay of about 7 pM or less. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 in the human GIP receptor function assay of about 6 pM or less. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 in the human GIP receptor function assay of about 5 pM or less. The GLP-1 / GIP / Amylin receptor triple agonists disclosed herein may have a potency similar to that of tirzepatide.

[0121] The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 of about 125 pM or less in a human amylin receptor function assay (see Example 4). The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 of about 100 pM or less in a human amylin receptor function assay. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 of about 90 pM or less in a human amylin receptor function assay. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 of about 80 pM or less in a human amylin receptor function assay. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 of about 75 pM or less in a human amylin receptor function assay. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 of about 70 pM or less in a human amylin receptor function assay. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 of about 60 pM or less in a human amylin receptor function assay. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50 of about 50 pM or less in a human amylin receptor function assay. The GLP-1 / GIP / Amylin receptor triple agonist may have an EC 50may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist may have an EC 50 may have. The GLP-1 / GIP / amylin receptor triple agonist disclosed herein may have a potency similar to that of cagrilintide.

[0122] In another aspect, the invention relates to a balanced GLP-1 / GIP / amylin receptor triple agonist that activates the human GIP, GLP-1, and amylin receptors in vitro and has a potency ratio of less than 50 when measured without HSA in the assay described in Example 4.

[0123] Peptide linker The GLP-1 / GIP / amylin receptor triple agonist peptide backbone disclosed herein includes a peptide linker L1 that can contain from 1 to 14 amino acid residues, particularly standard amino acid residues. The peptide linker can contain from 1 to 10 amino acid residues, such as from 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 amino acid residues, particularly standard amino acid residues. Specifically, the peptide linker can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues, particularly standard amino acid residues.

[0124] Peptide linker L1 has the formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 (IV) (wherein X 1~14 is independently selected from any naturally occurring or standard amino acid residue, and any one of X 2-14 may be absent) can be represented by.

[0125] The GLP-1 / GIP / amylin receptor triple agonist peptide backbone disclosed herein includes a peptide linker L1, and the peptide linker L1 includes or consists of an amino acid sequence according to formula IV. Accordingly, the GLP-1 / GIP / amylin receptor triple agonist includes or consists of a peptide according to the amino acid sequence of SEQ ID NO: 5.

[0126] X 1~14 Any one of can be selected from any non-aromatic amino acid residue. Any one of X 1~14 can be a charged amino acid. Any one of X 1~14Any of which may be a polar amino acid. X 1~14 Any of which may be a hydrophobic amino acid.

[0127] X 1~14 Any of which may be independently selected from the group consisting of alanine (Ala, A), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), leucine (Leu, L), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), valine (Val, V), and asparagine (Asn, N). Preferably, X 1~14 Any of which may be selected from the group consisting of alanine (Ala, A), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), leucine (Leu, L), and proline (Pro, P).

[0128] In one embodiment, the peptide linker L1 may be represented by Formula IV or an amino acid sequence according to Formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 (IV) (wherein, X 1 represents Ala (A), Glu (E), Gly (G), X 2 represents Gln (Q), Glu (E), Gly (G), Leu (L), Pro (P) or does not exist, X 3 represents Ala (A), Gln (Q), Glu (E), Gly (G), Pro (P) or does not exist, X 4represents Ala (A), Gln (Q), Glu (E), Gly (G), Pro (P), or does not exist, X 5 represents Glu (E), Gly (G), Pro (P), Ser (S), Thr (T), or does not exist, X 6 represents Glu (E), Gly (G), Leu (L), Gln (Q), or does not exist, X 7 represents Ala (A), Gln (Q), Glu (E), Gly (G), Phe (F), or does not exist, X 8 represents Ala (A), Gln (Q), Glu (E), Gly (G), Thr (T), Pro (P), Val (V), or does not exist, X 9 represents Glu (E), Asn (N), Pro (P), Thr (T), or does not exist, X 10 represents Ala (A), Gln (Q), Glu (E), Gly (G), Leu (L), Pro (P), Ser (S), Val (V), or does not exist, X 11 represents Ala (A), or does not exist, X 12 represents Gln (Q), or does not exist, X 13 represents Thr (T), or does not exist, X 14 includes or consists of (representing Leu (L) or not existing).

[0129] The peptide linker L1 can be any one of the peptide linkers represented by SEQ ID NOs: 125 to 159. The peptide linker L1 can be any one of the peptide linkers listed in Table 2.

Table 2

[0130] The peptide linker L1 can be selected from the group consisting of A, E, G, AE, GE, APPE (SEQ ID NO: 125), GGGE (SEQ ID NO: 126), AGQAPG (SEQ ID NO: 127), APPPSGGG (SEQ ID NO: 128), APPPSGGGE (SEQ ID NO: 129), APPPSGGGG (SEQ ID NO: 130), ALAQTLAQTL (SEQ ID NO: 131), ALAQTLFVNQ (SEQ ID NO: 132), ALAQTLGTNE (SEQ ID NO: 133), ALQAPGQAPG (SEQ ID NO: 134), ALQAPGQAPL (SEQ ID NO: 135), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), GGGEGGGEGE (SEQ ID NO: 138), GQAPGQAPGE (SEQ ID NO: 139), GQEPGQEPGE (SEQ ID NO: 140), APPPSLAQTLAQTL (SEQ ID NO: 141), AG, AGGGG (SEQ ID NO: 142), AGEAPGQAPG (SEQ ID NO: 143), AGEAPGEAPG (SEQ ID NO: 144), AGQAPGQAPA (SEQ ID NO: 145), AGQAPGQAPE (SEQ ID NO: 146), AGQAPGQAPP (SEQ ID NO: 147), AGQAPGQAPS (SEQ ID NO: 148), AGQAPGQAPV (SEQ ID NO: 149), EGQAPGQAPG (SEQ ID NO: 150), AGQEPGQAPG (SEQ ID NO: 151), AGQAEGQAPG (SEQ ID NO: 152), AGQAPEQAPG (SEQ ID NO: 153), AGQAPGEAPG (SEQ ID NO: 154), AGQAPGQEPG (SEQ ID NO: 155), AGQAPGQAEG (SEQ ID NO: 156), AGQEPGQEPG (SEQ ID NO: 157), AGQAPGQAP (SEQ ID NO: 158), and AGQAPGEAPL (SEQ ID NO: 159).

[0131] In a preferred embodiment, the peptide linker L1 can be E, GE, APPPSGGGE (SEQ ID NO: 129), AGQAPGQAPG (SEQ ID NO: 136), or AGQAPGQAPL (SEQ ID NO: 137) or AGQAPGEAPG (SEQ ID NO: 154).

[0132] In one embodiment, the backbone of the peptide Z1-L1-Z2 contains 66 to 80 amino acid residues.

[0133] In one embodiment, the backbone of the peptide Z1-L1-Z2 comprises 67, 68, 75, or 76 amino acid residues.

[0134] In one embodiment, the backbone of the peptide Z1-L1-Z2 comprises 76 amino acid residues.

[0135] In one embodiment, the backbone of the peptide Z1-L1-Z2 comprises or consists of the amino acid sequence according to SEQ ID NO: 5.

[0136] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist comprises a peptide according to formula I: Z1-L1-Z2, the peptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 20-124, and 170-242.

[0137] Extension moiety In another aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist that may further comprise an extension moiety. In such a case, the peptide is referred to as a "peptide derivative". Thus, the addition of the term "derivative" means that an extension moiety is present and that the compound containing the extension moiety is referred to as "one derivative" or "multiple derivatives".

[0138] As used herein, the term "extension moiety" refers to a moiety having half-life extension properties and comprising a "protractor P" and an optional "linker L" P ", where L P is the optional linker and P is the protractor, and can be represented by the general formula "L P -P".

[0139] As used herein, the term "protractor" refers to a molecule capable of increasing the plasma half-life of the peptide to which it is attached. Thus, the term "extension" refers to an extension of the half-life, and thus the protractor or extension moiety serves the purpose of extending the plasma half-life of the peptides disclosed herein.

[0140] Furthermore, the GLP-1 / GIP / Amylin receptor triple agonist of the present invention has a long plasma half-life with respect to the dosing interval, and thus reduces the variability of steady-state exposure and thus enables once-weekly dosing. The compounds disclosed herein are orally bioavailable and thus may be suitable for oral administration to subjects in need thereof. Both the polypeptide backbone and the extension moiety have been engineered and purified to achieve compounds having all of the above properties.

[0141] Each extension moiety L P -P covalently binds to the epsilon amino group of a lysine residue within the peptide backbone of the GLP-1 / GIP / Amylin receptor triple agonist of the present invention. The extension moiety L P -P can bind to the epsilon position (i.e., the amino group) of one lysine (Lys, K) residue. The extension moiety L P -P can bind to the epsilon position (i.e., the amino group) of a lysine (Lys, K) residue in the X 4 position or X 5 position of Formula IIa (SEQ ID NO: 3), or at the 33rd or 34th position of Formula IIa (SEQ ID NO: 3), or at the 12th position of Formula Xa (SEQ ID NO: 162), or in the X 52 position of a lysine (Lys, K) residue in the peptide Z1 portion (the "Z1" in Z1-L1-Z2) of the peptide backbone, such as in the peptide backbone.

[0142] The extension moiety L P -P can bind to the epsilon position (i.e., the amino group) of a lysine (Lys, K) residue in the peptide linker L1 portion (the "L1" in Z1-L1-Z2) of the peptide backbone.

[0143] The extension moiety L P -P is in the X 6 position, X 10 position, X 11 position, X 12 position, or X 14at any one of the positions, or at the 3rd, 15th, 18th, 20th, or 24th position of Formula IIIa (SEQ ID NO: 4), or at the 18th position of Formula XIIa (SEQ ID NO: 165), or at the X 63 position of the lysine (Lys, K) residue in the peptide Z2 moiety (the "Z2" in Z1-L1-Z2) of the peptide backbone such as the lysine (Lys, K) residue at the epsilon position (i.e., the amino group). The point of attachment is generally referred to as R1.

[0144] Optional linker L P if present, the extension portion L P -P is covalently attached to the peptide backbone via the linker L P If the linker L P is absent, P is covalently attached to the polypeptide backbone.

[0145] The GLP-1 / GIP / Amylin receptor triple agonist of the invention disclosed herein comprises or consists of a peptide containing one lysine (Lys, K) residue to which a single extension (at the epsilon amino group) is covalently attached / conjugated. The extension may consist of one protractor P. The extension may comprise one linker L P and one protractor P. The extension may comprise one linker L P and two or more protractors (in this case, referred to as P1, P2, or P3, etc.). The two protractors (P1 and P2) may be identical or the two protractors (P1 and P2) may be non-identical. If the peptide derivative contains two or three protractors (P1, P2, P3), the protractors are preferably similar, more preferably substantially identical, or most preferably identical.

[0146] Regarding chemical moieties such as the extension disclosed herein, similarity and / or identity can be determined using any suitable computer program and / or algorithm known in the art.

[0147] The extension part can non-covalently bind to albumin, thereby promoting the circulation of the peptide derivative of the present invention in the bloodstream and possibly extending its plasma half-life. Therefore, those skilled in the art may also refer to the extension part as an "albumin-binding part".

[0148] Protractor (P) The protractor (P) may contain an acyl group. The acyl group can be branched or unbranched. The acyl group can be saturated or unsaturated. The protractor P may contain a fatty acid acyl group. The fatty acid acyl group can be branched or unbranched. The fatty acid acyl group can be saturated or unsaturated.

[0149] The protractor P may contain a distal carboxylic acid group.

[0150] The protractor P may contain a fatty acid group.

[0151] The protractor P may contain a fatty acid group and an amide group.

[0152] The protractor P may contain a distal carboxylic acid group and an amide group.

[0153] The protractor P may contain an alkyl group.

[0154] The protractor P may contain an aryl group.

[0155] The protractor P may contain a tetrazole group.

[0156] The protractor P may contain a sulfonic acid group.

[0157] The protractor P may contain a phenoxy group.

[0158] The protractor P may contain a benzoic acid group.

[0159] The protractor P may contain a phosphonic acid group.

[0160] The protractor Chemical formula 1a: HOOC-(CH 2 ) n -CO-*(wherein n is an integer in the range of 6 to 30), and may contain a group defined thereby, which is also C (n+2) dicarboxylic acid (for example, C 18 dicarboxylic acid), or Chemical formula 1b: [Chemical formula] (wherein n is an integer in the range of 6 to 30) and may be referred to as such. The asterisk (*) indicates the bonding point of the radical.

[0161] The protractor P may contain 8 to 32 carbon atoms. The protractor may contain 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 carbon atoms.

[0162] The protractor P may contain 6 to 30 consecutive -CH 2 - groups. The protractor P 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, or 30 consecutive -CH 2 - groups.

[0163] The protractor P may contain 12 to 26 carbon atoms. The protractor P may contain 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 carbon atoms.

[0164] The protractor P may contain 10 to 26 consecutive -CH 2-groups may be included. The protractor P may include a carbon chain containing 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 consecutive -CH 2 -groups.

[0165] The protractor P may contain 16 to 22 carbon atoms. The peptide derivative of the present invention may include a single extension having a protractor P that includes a carbon chain which is a side chain containing 16, 17, 18, 19, 20, 21, or 22 carbon atoms.

[0166] The protractor P may include 14 to 20 consecutive -CH 2 -groups. The protractor P may include a carbon chain containing 14, 15, 16, 17, 18, 19, or 20 consecutive -CH 2 -groups.

[0167] The protractor P may include 16 to 22 consecutive carbon atoms and 14 to 20 consecutive -CH 2 -groups.

[0168] The protractor P may include 16 consecutive carbon atoms and 14 consecutive -CH 2 -groups. The protractor P may be a C 16 dioic acid, which may be defined by the formula HOOC-(CH 2 ) 14 -CO-*.

[0169] The protractor P may include 18 consecutive carbon atoms and 16 consecutive -CH 2 -groups. The protractor P may be a C 18 dioic acid, which may be defined by the formula HOOC-(CH 2 ) 16 -CO-*.

[0170] The protractor P may include 20 consecutive carbon atoms and 18 consecutive -CH 2 -groups. The protractor P may be a C20 It may be a diacid, which may be defined by the formula HOOC-(CH 2 ) 18 -CO-*.

[0171] The protractor P may contain 22 consecutive carbon atoms and 20 consecutive -CH 2 - groups. The protractor P may be a C 22 diacid, which may be defined by the formula HOOC-(CH 2 ) 20 -CO-*.

[0172] The term "fatty acid" refers to an aliphatic mono- or dicarboxylic acid having 4 to 28 carbon atoms, which may be branched or unbranched, preferably unbranched, and may be saturated or unsaturated, preferably saturated.

[0173] As described above, the peptide derivatives disclosed herein contain 1 lysine (Lys, K) residue, and thus 1 extension (L P -P), and the extension is attached to the peptide backbone described herein via the epsilon position (i.e., the amino group) of the lysine (Lys, K) residue (via an amide bond formed between the carboxylic acid group of the extension and the epsilon amino group of the lysine residue). The extension may be attached to the epsilon position of 1 lysine (Lys, K) residue within the peptide backbone.

[0174] In one embodiment, the extension may be attached to the epsilon position of a lysine (Lys, K) residue in peptide Z1 (the "Z1" in Z1-L1-Z2) of the peptide backbone. In particular, the extension may be attached to the epsilon position of lysine (Lys, K) at the X 4 position or the X 5 position of formula IIa (SEQ ID NO: 3) of peptide Z1. In particular, the extension may be at the X 52It can bind to the epsilon position of lysine (Lys, K) at the position. In particular, the extension can bind to the epsilon position of lysine (Lys, K) at any one of positions 12, 33, or 34 of peptide Z1, preferably at position 12 or 33 of peptide Z1.

[0175] In one embodiment, the extension can bind to the epsilon position of a lysine (Lys, K) residue in the linker L1 portion of the peptide backbone (the "L1" in Z1-L1-Z2).

[0176] In one embodiment, the extension can bind to the epsilon position of a lysine (Lys, K) residue in peptide Z2 (the "Z2" in Z1-L1-Z2) of the peptide backbone. In particular, the extension is X of formula IIIa (SEQ ID NO: 4) of peptide Z2 6 position, X 10 position, X 11 position, X 12 position, or X 14 It can bind to the epsilon position of lysine (Lys, K) at any one of the positions. In particular, the extension is X of formula XIIa (SEQ ID NO: 165) of peptide Z2 63 It can bind to the epsilon position of lysine (Lys, K) at the position. In particular, the extension can bind to the epsilon position of a lysine (Lys, K) residue at any one of positions 3, 15, 18, 20, or 24 of peptide Z2. In a preferred embodiment, the extension can bind to the epsilon position of a lysine (Lys, K) residue at position 15 or at position 18 of peptide Z2.

[0177] In some embodiments, the GLP-1 / GIP / amylin receptor triple agonist comprising the peptide derivative disclosed herein may comprise a protractor P selected from any one of those depicted in Table 3. R1 is (a) the backbone of the peptide derivative, more specifically, the epsilon amino group of lysine, or (b) the optional linker L PRepresents the binding site thereto. Based on the disclosure of this specification, those skilled in the art can optionally determine other chemical moieties for use as a protractor with the specific peptide derivatives disclosed herein after some limited routine experiments.

Table 3

[0178] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist comprises a peptide derivative comprising a protractor P which is a C 12 ~C 20 dicarboxylic acid.

[0179] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist comprises a peptide derivative comprising a protractor P selected from the group consisting of C 16 dicarboxylic acid, C 18 dicarboxylic acid, and C 20 dicarboxylic acid.

[0180] In a preferred embodiment, the GLP-1 / GIP / amylin receptor triple agonist comprises a peptide derivative comprising a protractor P which is C 18 dicarboxylic acid or C 20 dicarboxylic acid.

[0181] Linker L P In one embodiment, the protractor is directly bound / conjugated onto the backbone of the peptide derivative, i.e., without using a linker L P (i.e., by a covalent bond, such as an amide bond).

[0182] In other embodiments, the protractor is covalently conjugated to the peptide derivative using a linker L P , and thus, as described above, the extension (L P -P) comprises an optional linker L P . The linker L Pmay contain several "linker elements". The linker elements can be selected such that they improve the overall properties of the molecule, for example, they improve oral bioavailability, half-life conversion, or extension effects, and thus improve the overall exposure profile upon oral administration of the compound.

[0183] Linker L P may contain Ado, Aeep, or Aeeep, Ala, ε-Lys, Glu, γGlu, Gly, Ser, sulfonamide, Thr, and / or Trx.

[0184] L P The linker has the following chemical formula (where the asterisk (*) indicates the bonding point of the radical): Chemical formula 9a: *-NH-(CH 2 ) 2 -(O-(CH 2 ) 2 ) k -O-(CH 2 ) n -CO-* Chemical formula 9b:

Chem.

[0185] When k = 1 and n = 1, the linker element can be designated as Ado, or 8-amino-3,6-dioxaoctanoyl, which has the following chemical formula: Chemical formula 10a: *-NH-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 -CO-* or Chemical 11b:

Chem.

[0186] When k = 1 and n = 2, the linker element may be designated as Aeep, which has the following chemical formula: Chemical formula 12a: *-NH-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -CO-* or Chemical formula 12b:

Chem.

[0187] When k = 2 and n = 2, the linker element may be designated as Aeeep, which has the following chemical formula: Chemical formula 13a: *-NH-(CH 2 ) 2- O-(CH 2 ) 2 O-(CH 2 ) 2 -O-(CH 2 ) 2 -CO-* or Chemical formula 13b:

Chem.

[0188] Optional linker L P may contain a sulfonamide-C4 moiety. The sulfonamide-C4 group is a sulfonamide group bonded to a 4-butanoyl group and has the following chemical formula: Chemical formula 14a: *-NH-S(O) 2 -CH 2 -CH 2 -CH 2 -CO-* or Chemical 14b:

Chem.

[0189] Linker L P may contain Trx. Trx is also referred to as tranexamic acid, trans-4-(aminomethyl)cyclohexanecarboxylic acid, and has the following chemical formula: Chemical formula 15a: *-NH-CH 2 -(C 6 H 10 )-CO-* or Chemical formula 15b:

Chem.

[0190] Linker L P may contain Ahx. Ahx is also referred to as aminocaproic acid, 6-aminohexanoic acid, and has the following chemical formula: Chemical formula 16a: *-NH-(CH 2 ) 5 -CO-* or Chemical 16b:

Chem.

[0191] Linker L P may contain epsilon-lysine (ε-Lys).

[0192] Linker L P may contain lysine (Lys).

[0193] Linker L P may contain alanine (Ala).

[0194] Linker L P may contain glycine (Gly).

[0195] Linker L P may contain serine (Ser).

[0196] Linker LP may contain glutamic acid (Glu).

[0197] Linker L P is Chemical formula 17: [Chem.] (wherein the Glu diradical may be contained p times, and p is an integer in the range of 1 to 3) and may contain a Glu diradical such as. Linker L P as, or as part of linker L P Any one of the amino acids disclosed above that is used as a part may be used as the L-isomer or the D-isomer.

[0198] Chemical formula 17 also results from the fact that it is the gamma-carboxy group of the amino acid glutamic acid used herein to connect to the epsilon-amino group of lysine, and may also be referred to as gamma-Glu, or simply γGlu. As described above, the other linker element may be, for example, another Glu residue, or an Ado molecule. Next, the amino group of Glu forms an amide bond with the carboxy group of the extension, or, if present, for example, the carboxy group of an Ado molecule, or, if present, for example, the gamma-carboxy group of another Glu.

[0199] The peptide derivatives disclosed herein may include a linker L selected from any one of those depicted in Table 4 below. R1 represents a residue within the peptide backbone to which the extension is attached, and P represents a protractor. P In some embodiments, the peptide derivative includes an extension, and the protractor chemical formula 4 or chemical formula 5 or chemical formula 6 is L in Table 4 below

[0200] In some embodiments, the peptide derivative includes an extension, and the protractor chemical formula 4 or chemical formula 5 or chemical formula 6 is L P 1, L P 2, L P 3, L P 4, L P 5, or L P 6 and is attached to the peptide backbone using the specified linker.

[0201] In some embodiments, the peptide derivative comprises an extension portion, and the protractor chemical formula 5 is L of Table 4 below P 1, L P 2, L P 3, L P 4, L P 5, or L P 6 and is attached to the peptide backbone using the specified linker, and thus the extension portion comprises chemical formula 18, chemical formula 19, chemical formula 20, chemical formula 21, chemical formula 33, or chemical formula 34 as linker L P and comprises chemical formula 5 as protractor P.

[0202] In some embodiments, the peptide derivative comprises an extension portion, and the protractor chemical formula 6 is L of Table 4 below P 1, L P 2, L P 3, L P 4, L P 5, or L P 6 and is attached to the peptide backbone using the specified linker, and thus the extension portion comprises chemical formula 18, chemical formula 19, chemical formula 20, chemical formula 21, chemical formula 33, or chemical formula 34 as linker L P and comprises chemical formula 6 as protractor P.

[0203] In a preferred embodiment, the peptide derivative comprises an extension portion, and the extension portion comprises chemical formula 20 or chemical formula 21 as linker L P and comprises chemical formula 5 or chemical formula 6 as protractor P.

[0204] In a preferred embodiment, the peptide derivative comprises an extension portion, and the protractor chemical formula 5 is attached to the peptide backbone using the linker specified as 3 in Table 4 below, and thus the extension portion comprises chemical formula 20 as linker L P and comprises chemical formula 5 as protractor P. P

[0205] In a preferred embodiment, the peptide derivative includes an extension portion, and the protractor chemical formula 6 is linked to the peptide backbone using the linker designated as L in Table 4 below. P 3 and is thus included as the extension portion includes chemical formula 20 as the linker L P and includes chemical formula 6 as the protractor P.

[0206] Based on the disclosure herein, one of ordinary skill in the art can, optionally, after some limited routine experimentation, determine the optimal L P linker for use with the specific peptide derivatives disclosed herein. [Table 4]

[0207] In some embodiments, the peptide derivative includes an extension portion selected from the group presented in Table 5. R1 represents a residue within the peptide backbone to which the extension portion is attached. [Table 5-1] [Table 5-2]

[0208] In one embodiment, the free lysine can function as a conjugation site for attaching one C 16 dioic acid gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoyl amino) butanoyl] amino] ethoxy] ethoxy] acetyl] amino] ethoxy] ethoxy] acetyl]), and thus the peptide derivative of the present invention includes an extension portion, and the extension portion is a C 16 dioic acid (S) gamma-Glu 2xAdo fatty acid moiety.

[0209] In one embodiment, the free lysine is one C 18It can function as a conjugation site for binding the diacid gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]), and thus, the peptide derivative of the present invention includes an extension portion, and the extension portion is C 18 is the diacid (S) gamma-Glu 2xAdo fatty acid moiety.

[0210] In one embodiment, the free lysine has 1 C 20 It can function as a conjugation site for binding the diacid gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]), and thus, the peptide derivative of the present invention includes an extension portion, and the extension portion is C 20 is the diacid (S) gamma-Glu 2xAdo fatty acid moiety.

[0211] In one embodiment, the free lysine has 1 C 18 It can function as a conjugation site for binding the diacid gamma-Glu fatty acid moiety (IUPAC name [(4S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butanoyl]), and thus, the peptide derivative of the present invention includes an extension portion, and the extension portion is C 18 is the diacid (S) gamma-Glu fatty acid moiety.

[0212] In one embodiment, the free lysine has 1 C 20 It can function as a conjugation site for binding the diacid gamma-Glu fatty acid moiety (IUPAC name [(4S)-4-carboxy-4-(19-carboxy-heptadecanoylamino)butanoyl]), and thus, the peptide derivative of the present invention includes an extension portion, and the extension portion is C 20The diacid (S) gamma-Glu fatty acid moiety.

[0213] In a preferred embodiment, the free lysine is a single C 18 The diacid gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]) can function as a conjugation site for binding, and thus the peptide derivative of the present invention includes an extension portion, and the extension portion is a C 18 The diacid (S) gamma-Glu 2xAdo fatty acid moiety.

[0214] In a preferred embodiment, the free lysine is a single C 20 The diacid gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]) can function as a conjugation site for binding, and thus the peptide derivative of the present invention includes an extension portion, and the extension portion is a C 20 The diacid (S) gamma-Glu 2xAdo fatty acid moiety.

[0215] In the most preferred embodiment, the free lysine is a single C 18 The diacid gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]) can function as a conjugation site for binding, and thus the peptide derivative of the present invention includes an extension portion, and the extension portion is a C 18 The diacid (S) gamma-Glu 2xAdo fatty acid moiety.

[0216] Peptide derivative As described above, the GLP-1 / GIP / amylin receptor triple agonist of the present invention may contain a peptide linker and may further contain an extension portion. Therefore, in another aspect, the present invention provides a GLP-1 / GIP / amylin receptor triple agonist, which is a peptide according to formula I containing one lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), · Z1 is a peptide having a maximum of 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 the amino acid at the position represents Aib), and Z1 is an amino acid sequence according to formula X (SEQ ID NO: 161): X 21 X 22 X 23 GTFTSDYSX 24 LLEEX 25 AAX 26 EFIX 27 WLX 28 X 29 GGPSX 30 X 31 (X) (wherein X 21 represents His (H) or Tyr (Y), X 22 represents Aib, X 23 represents Glu (E) or His (H), X 24 represents Ile (I) or Lys (K), X 25 represents Gln (Q) or Ile (I), X 26 represents Arg (R) or Gln (Q), X 27 represents Ala (A), Glu (E), or Gln (Q), X 28 represents Leu (L) or I (Ile), X29 represents Ala (A) or Gln (Q), X 30 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 31 comprises or consists of Gly (G), Glu (E), or Lys (K)), ·L1 is a peptide linker, ·Z2 contains a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions relative to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula XII (SEQ ID NO: 164): AX 32 X 33 LSTAX 34 X 35 X 36 RLSAX 37 LHX 38 LX 39 X 40 X 41 PX 42 TETGSGX 43 P (XII) (wherein, X 32 represents Gly (G) or Ser (S), X 33 represents Gln (Q), Glu (E), His (H), or Lys (K), X 34 represents Ala (A) or Gln (Q), X 35 represents Gln (Q), Leu (L), or Thr (T), X 36 represents Ala (A), Gly (G), or Gln (Q), X 37 represents Glu (E) or Lys (K), X 38represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Lys(K), Thr(T), or Tyr(Y), X 39 represents Ala(A) or Lys(K), X 40 represents Asp(D) or Thr(T), X 41 represents Leu(L) or Glu(E), X 42 represents Arg(R) or Lys(K), X 43 contains or consists of a peptide derivative containing an extension part, relates to a GLP-1 / GIP / amylin receptor triple agonist which is a peptide derivative containing an extension part.

[0217] In another aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist, which is a peptide according to formula I containing one lysine (Lys, K) residue: Z1-L1-Z2 (I) and ·Z1 is a peptide having a maximum of 4 amino acid substitutions with respect to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 the amino acid at the position represents Aib), and Z1 is an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His(H) or Tyr(Y), X 2 represents Aib, X 3represents Glu(E) or His(H), X 4 represents Arg(R), Gly(G), Lys(K), or Ser(S), X 5 contains or consists of a peptide that represents Gly(G) or Lys(K)) ·L1 is a peptide linker, ·Z2 contains a C-terminal amide, Formula III (SEQ ID NO: 2): a peptide having a maximum of 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents Gln(Q), Glu(E), His(H), or Lys(K), X 7 represents Ala(A) or Gln(Q), X 8 represents Gln(Q), Leu(L), or Thr(T), X 9 represents Ala(A), Gly(G), or Gln(Q), X 10 represents Glu(E) or Lys(K), X 11 represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Lys(K), Thr(T), or Tyr(Y), X 12 represents Ala(A) or Lys(K), X 13represents Asp(D) or Thr(T), X 14 represents Arg(R) or Lys(K), X 15 contains or consists of) Ala(A) or Ser(S), relates to a GLP-1 / GIP / amylin receptor triple agonist which is a peptide derivative containing an extension.

[0218] In another aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist which is a peptide according to formula I containing one lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), · Z1 is a peptide having a maximum of 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 at the position represents Aib), and Z1 is an amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein, X 51 represents Aib, X 52 represents Ile(I) or Lys(K), X 53 represents Arg(R) or Gln(Q), X 54 represents Ala(A), Glu(E), or Gln(Q), X 55 represents Leu(L) or I(Ile), X 56 represents Ala(A) or Gln(Q), X 57 comprises or consists of Gly (G) or Glu (E) (wherein X represents Gly (G) or Glu (E)), · L1 is a peptide linker, · Z2 contains a C-terminal amide, Formula III (SEQ ID NO: 2): a peptide having a maximum of 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to Formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein, X 58 represents Gly (G) or Ser (S), X 59 represents Gln (Q), Glu (E), or His (H), X 60 represents Ala (A) or Gln (Q), X 61 represents Leu (L) or Thr (T), X 62 represents Ala (A), Gly (G), or Gln (Q), X 63 represents Gln (Q), Glu (E), or Lys (K), X 64 represents Leu (L) or Glu (E)) and comprises or consists of a peptide derivative containing an extension part, relating to a GLP-1 / GIP / Amylin receptor triple agonist. In yet another aspect, the present invention relates to a GLP-1 / GIP / Amylin receptor triple agonist, which is a peptide according to Formula I and contains 1 lysine (Lys, K) residue:

[0219] In yet another aspect, the present invention relates to a GLP-1 / GIP / Amylin receptor triple agonist, which is a peptide according to Formula I and contains 1 lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), ·Z1 is a peptide having a maximum of 4 amino acid substitutions with respect to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 at the position represents Aib), and Z1 is an amino acid sequence according to formula X (SEQ ID NO: 161): X 21 X 22 X 23 GTFTSDYSX 24 LLEEX 25 AAX 26 EFIX 27 WLX 28 X 29 GGPSX 30 X 31 (X) (wherein X 21 represents His (H) or Tyr (Y), X 22 represents Aib, X 23 represents Glu (E) or His (H), X 24 represents Ile (I) or Lys (K), X 25 represents Gln (Q) or Ile (I), X 26 represents Arg (R) or Gln (Q), X 27 represents Ala (A), Glu (E), or Gln (Q), X 28 represents Leu (L) or I (Ile), X 29 represents Ala (A) or Gln (Q), X 30 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 31comprises or consists of Gly (G), Glu (E), or Lys (K), · L1 is a peptide linker comprising or consisting of an amino acid sequence according to formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 (IV) and is selected from the group consisting of E, GE, APPPSGGGE (SEQ ID NO: 129), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), and AGQAPGEAPG (SEQ ID NO: 154), · Z2 comprises a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions relative to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III) and Z2 is an amino acid sequence according to formula XII (SEQ ID NO: 164): AX 32 X 33 LSTAX 34 X 35 X 36 RLSAX 37 LHX 38 LX 39 X 40 X 41 PX 42 TETGSGX 43 P (XII) (wherein X 32 represents Gly (G) or Ser (S), X 33 represents Gln (Q), Glu (E), His (H), or Lys (K), X 34 represents Ala (A) or Gln (Q), X35 represents Gln (Q), Leu (L), or Thr (T), X 36 represents Ala (A), Gly (G), or Gln (Q), X 37 represents Glu (E) or Lys (K), X 38 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 39 represents Ala (A) or Lys (K), X 40 represents Asp (D) or Thr (T), X 41 represents Leu (L) or Glu (E), X 42 represents Arg (R) or Lys (K), X 43 represents Ala (A) or Ser (S)), or consists of, The present invention relates to a GLP-1 / GIP / amylin receptor triple agonist which is a peptide derivative containing an extension part.

[0220] In yet another aspect, the present invention is a GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I containing one lysine (Lys, K) residue: Z1-L1-Z2 (I), ·Z1 is of formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 The amino acid at the position represents Aib), and is a peptide having up to 4 amino acid substitutions, and Z1 is an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 5 represents Gly (G) or Lys (K)) and contains or consists of ·L1 is a peptide linker having an amino acid sequence according to formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 (IV) and contains or consists of which is selected from the group consisting of E, GE, APPPSGGGE (SEQ ID NO: 129), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), and AGQAPGEAPG (SEQ ID NO: 154), ·Z2 contains a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions with respect to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III) and Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Gln (Q), Glu (E), His (H), or Lys (K), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 12 represents Ala (A) or Lys (K), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R) or Lys (K), X 15 represents Ala (A) or Ser (S)) and comprises or consists of A GLP-1 / GIP / amylin receptor triple agonist, wherein the peptide is a peptide derivative containing an extension.

[0221] In yet another aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist, which is a peptide according to formula I containing one lysine (Lys, K) residue: Comprising Z1-L1-Z2 (I), ·Z1 is a peptide having a maximum of 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 The amino acid at the position represents Aib) and Z1 has an amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein X 51 represents Aib, X 52 represents Ile (I) or Lys (K), X 53 represents Arg (R) or Gln (Q), X 54 represents Ala (A), Glu (E), or Gln (Q), X 55 represents Leu (L) or I (Ile), X 56 represents Ala (A) or Gln (Q), X 57 represents Gly (G) or Glu (E)) and includes or consists of ·L1 has an amino acid sequence according to formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 (IV) and is a peptide linker that includes or consists of This is selected from the group consisting of E, GE, APPPSGGGE (SEQ ID NO: 129), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), and AGQAPGEAPG (SEQ ID NO: 154), ·Z2 includes a C-terminal amide and has the formula III (SEQ ID NO: 2): A peptide having up to 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 is an amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein X 58 represents Gly (G) or Ser (S), X 59 represents Gln (Q), Glu (E), or His (H), X 60 represents Ala (A) or Gln (Q), X 61 represents Leu (L) or Thr (T), X 62 represents Ala (A), Gly (G), or Gln (Q), X 63 represents Gln (Q), Glu (E), or Lys (K), X 64 represents Leu (L) or Glu (E)) and includes or consists of The peptide is a peptide derivative containing an extension part, and relates to a GLP-1 / GIP / amylin receptor triple agonist.

[0222] The GLP-1 / GIP / Amylin receptor triple agonist of the present invention is a peptide derivative comprising any one of the peptide Z1s disclosed above, any one of the peptide Z2s disclosed above, any one of the peptide linkers L1 disclosed above, and any one of the extension parts disclosed above. Based on the disclosure herein, those skilled in the art will be able to determine the optimal combination to obtain a specific peptide derivative that is a potent GLP-1 / GIP / Amylin receptor triple agonist having the specific characteristics described below.

[0223] When tested as described in the "GLP-1 Receptor Assay" (preferably, Method A; in the absence of HSA), the peptide derivatives disclosed herein have an EC value of less than 125 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, most preferably less than 30 pM, such as less than 20 pM, such as less than 10 pM, such as less than 5 pM. 50 It may have a value.

[0224] When tested as described in the "GIP Receptor Assay" (preferably, Method A; in the absence of HSA), the peptide derivatives disclosed herein have an EC value of less than 125 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, most preferably less than 30 pM, such as less than 20 pM, such as less than 10 pM, such as less than 5 pM. 50 It may have a value.

[0225] When tested as described in the "Amylin Receptor Assay" (preferably, Method A; in the absence of HSA), the peptide derivatives disclosed herein have an EC value of less than 125 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, most preferably less than 30 pM, such as less than 20 pM, such as less than 10 pM, such as less than 5 pM. 50 It may have a value.

[0226] When measured without HSA in the assay described in Example 4, a GLP-1 / GIP / amylin receptor triple agonist according to any one of the previous embodiments activates the human GIP, GLP-1, and amylin receptors in vitro and has an efficacy ratio (A / B) of less than 50.

[0227] The balanced GLP-1 / GIP / amylin receptor triple agonist of the present invention, when measured without HSA in the assay described in Example 4, activates the human GIP, GLP-1, and amylin receptors in vitro and has an efficacy ratio (A / B) of less than 50, i.e., the efficacy (A) of the receptor with the lowest efficacy divided by the efficacy (B) of the receptor with the highest efficacy. The triple agonists disclosed herein can have an efficacy ratio (A / B) of less than 50, preferably less than 20, such as less than 19, less than 18, less than 17, less than 16, even more preferably less than 15, such as less than 14, less than 13, less than 12, most preferably less than 11, such as less than 10, less than 9, and less than 8, and less than 7. Half-life is an important parameter as a long half-life can indicate that less frequent dosing of the compound may be possible. Based on the disclosure herein, one of ordinary skill in the art can, optionally, after some limited routine experimentation, determine an extension for use with the specific peptide derivatives disclosed herein. Thus, in a fourth aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist having improved pharmacokinetic properties. The GLP-1 / GIP / amylin receptor triple agonist or peptide derivative of the present invention has a long half-life relative to the dosing interval and thus reduces the variability of steady-state exposure.

[0228] The in vivo pharmacological actions, including the half-life of the GLP-1 / GIP / amylin receptor triple agonist described in this specification, can be evaluated as described in Example 6. In some embodiments, the half-life is, for example, the in vivo half-life (t1 / 2) in minipigs after intravenous administration, as described in Example 6. The half-life of the GLP-1 / GIP / amylin receptor triple agonist in an animal subject can be as long as about 100 hours or more. The half-life of the GLP-1 / GIP / amylin receptor triple agonist in an animal subject can be at least 40 hours, preferably at least 100 hours. The half-life of the GLP-1 / GIP / amylin receptor triple agonist can be more than 40, 45, 55, 60, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, or 140 hours. The half-life of the GLP-1 / GIP / amylin receptor triple agonist can be 40 to 145 hours, for example, 90 to 140 hours, for example, 85 to 125 hours.

[0229] In a fifth aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist suitable for once-weekly administration. The GLP-1 / GIP / amylin receptor triple agonist or peptide derivative of the present invention has a long half-life relative to the dosing interval, thus reducing the variability of steady-state exposure and thus enabling once-weekly administration.

[0230] In a sixth aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist suitable for oral administration. The GLP-1 / GIP / amylin receptor triple agonist is orally bioavailable, i.e., it can be present in the bloodstream after each oral administration. Thus, the compound is suitable for oral administration to a subject in need thereof.

[0231] In a seventh aspect, the present invention relates to a GLP-1 / GIP / Amylin receptor triple agonist having improved chemical stability. The term "chemical stability" refers to chemical (particularly covalent) changes in the polypeptide structure that result in the formation of chemical degradation products such as high molecular weight proteins (HMWP), deamidation, isomerization, and hydrolysis products, which potentially have reduced biological potency and / or increased immunogenic effects compared to the intact polypeptide. Chemical stability can be determined by measuring the loss of purity, for example, by SEC-HPLC and / or LCMS as described in Example 7 herein, by measuring the amount of chemical degradation products at various time points after exposure to different environmental conditions. The GLP-1 / GIP / Amylin receptor triple agonist of the present invention has a purity loss of less than 10.0 percent, preferably less than 6.0 percent, for example, 5.0 or 4.0 percent, more preferably less than 3.0 percent, and most preferably less than 1.5 percent per week when incubated at 37°C, as determined in Example 7 described herein.

[0232] In one embodiment, the GLP-1 / GIP / Amylin receptor triple agonist disclosed herein can reduce food intake in a subject, such as a normal weight rat or a DIO rat. Administration of the GLP-1 / GIP / Amylin receptor triple agonist disclosed herein can result in a rapid reduction in food intake. The in vivo effect of the GLP-1 / GIP / Amylin receptor triple agonist on food intake in rats can be evaluated as described in Example 5 or Example 8. A 100% (hypothetical value) reduction in food intake relative to or compared to the vehicle means that the rat does not eat.

[0233] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist disclosed herein can reduce the food intake on the first day (0 - 24 hours) by at least 10%, preferably at least 50%, for example, at least 70% compared to the vehicle after a single subcutaneous administration of 10 nmol / kg. The GLP-1 / GIP / amylin receptor triple agonist disclosed herein can reduce the food intake on the first day (0 - 24 hours) by 1% - 100%, for example, 15% - 95%, preferably 40% - 85% compared to the vehicle, and even more preferably 50% - 80% compared to the vehicle after a single subcutaneous administration of 10 nmol / kg.

[0234] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist disclosed herein can reduce the food intake on the second day (24 - 48 hours) by at least 15%, preferably at least 50%, for example, at least 70% compared to the vehicle after a single subcutaneous administration of 10 nmol / kg. The GLP-1 / GIP / amylin receptor triple agonist disclosed herein can reduce the food intake on the second day (24 - 48 hours) by 1% - 100%, for example, 15% - 95%, preferably 40% - 95% compared to the vehicle, and even more preferably 70% - 95% compared to the vehicle after a single subcutaneous administration of 10 nmol / kg.

[0235] In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist disclosed herein can reduce the food intake on the first day (0 - 24 hours) by at least 15%, preferably at least 35% compared to the vehicle after a single subcutaneous administration of 30 nmol / kg. The GLP-1 / GIP / amylin receptor triple agonist disclosed herein can reduce the food intake on the second day (24 - 48 hours) by at least 15%, preferably at least 35% compared to the vehicle after a single subcutaneous administration of 30 nmol / kg.

[0236] Both the polypeptide backbone and the extension are manipulated and purified to achieve peptide derivatives having all of the above characteristics.

[0237] Preferred GLP-1 / GIP / Amylin receptor triple agonists of the present invention are Compound 52, namely,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0238] Pharmaceutically acceptable salts The compounds of the present invention can be in the form of pharmaceutically acceptable salts or amides.

[0239] Salts are formed, for example, by a chemical reaction between a base and an acid, for example, 2 NH 3 +H 2 SO 4 →(NH 4 ) 2 SO 4 formed by.

[0240] The salt can be a basic salt, an acidic salt, or neither (i.e., a neutral salt). A basic salt generates hydroxide ions in water, and an acidic salt generates hydronium ions.

[0241] The salts of the compounds of the present invention can each be formed with an added cation or anion between an anionic group and a cationic group. These groups can be located in the peptide moiety and / or the extension moiety of the compounds of the present invention.

[0242] Non-limiting examples of anionic groups of the compounds of the present invention, when present, include free carboxylic acid groups in the extension moiety as well as in the peptide backbone. The peptide backbone can include free carboxylic acid groups in internal amino acid residues such as Asp (D) and Glu (E).

[0243] Non-limiting examples of cationic groups within the peptide backbone, when present, include the free amino group at the N-terminus, as well as any free amino groups of internal basic amino acid residues such as His (H), Arg (R), and Lys (K).

[0244] The amides of the compounds of the present invention can be formed, for example, during peptide synthesis (based on the resin used), or by reaction of a free carboxylic acid group with an amine or substituted amine, or by reaction of a free or substituted amino group with a carboxylic acid. Amide formation can be with any free carboxylic acid group in the extension moiety, the free amino group at the N-terminus of the peptide, and / or any free or substituted amino group within the peptide backbone.

[0245] In one aspect, the derivatives of the present invention are in the form of pharmaceutically acceptable salts, preferably in the form of trifluoroacetates.

[0246] Method of production The triple-acting agents disclosed herein can be generated by classical peptide synthesis, such as solid-phase peptide synthesis using t-Boc or Fmoc chemistry, or by other well-established techniques. See, for example, Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley & Sons, 1999, Florencio Zaragoza Dorwald, “Organic Synthesis on Solid Phase”, Wiley-VCH Verlag GmbH, 2000, and “Fmoc Solid Phase Peptide Synthesis” edited by W.C. Chan and P.O. White, Oxford University Press, 2000. In some embodiments, methods for preparing the triple-acting agents are described herein. In some embodiments, the methods for preparing the triple-acting agents described herein include the steps of solid-phase peptide synthesis.

[0247] Also, or alternatively, the compound, peptide sequence, or portion of a peptide sequence can be generated by recombinant methods, for example, by culturing a host cell that contains a DNA sequence encoding the triple-acting agent peptide sequence and is capable of expressing the peptide in a suitable nutrient medium under conditions that permit the expression of the peptide. Non-limiting examples of host cells suitable for the expression of these peptides are Escherichia coli, Saccharomyces cerevisiae, and mammalian BHK or CHO cell lines.

[0248] Triple-acting agents containing non-natural amino acids and / or covalently attached substituents (extensions) can be generated as described under "General Methods for Peptide Synthesis" in the experimental section. Or, for example, see Hodgson et al: “The synthesis of peptides and proteins containing non-natural amino acids”, Chemical Society Reviews, vol.33, no.7 (2004), p. 422-430.

[0249] The triple-acting agents described herein that contain an extension can be generated, for example, as described under "General Methods for Peptide Synthesis" in the experimental section. In some embodiments, the extension is constructed as part of solid-phase peptide synthesis or is generated separately and coupled via a single lysine residue after solid-phase peptide synthesis.

[0250] Specific examples of methods for preparing some of the triple-acting agents described herein are provided below.

[0251] A further aspect of the invention relates to a method for preparing the receptor triple-acting agents described herein.

[0252] In one embodiment, a method for preparing the compounds described herein comprises the steps of solid-phase peptide synthesis. The extension is constructed continuously as part of solid-phase peptide synthesis or is generated separately and coupled via a lysine residue after peptide synthesis.

[0253] Pharmaceutical composition In a further aspect, the present invention relates to a pharmaceutical composition comprising the GLP-1 / GIP / amylin receptor triple agonist. Disclosed herein is a pharmaceutical composition comprising the GLP-1 / GIP / amylin receptor triple agonist disclosed herein and one or more pharmaceutically acceptable excipients. The pharmaceutical composition comprising the GLP-1 / GIP / amylin receptor triple agonist disclosed herein and one or more pharmaceutically acceptable excipients can be prepared using methods known to those skilled in the art.

[0254] The term "pharmaceutically acceptable excipient" refers to any component in a pharmaceutical composition that is not an active pharmaceutical ingredient or the GLP-1 / GIP / amylin receptor triple agonist disclosed herein. The term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and acceptable for human pharmaceutical use and is useful in preparing a pharmaceutical composition. Such excipients can be, for example, solid, liquid, or semi-solid.

[0255] Excipients can be functional or inert and can serve various purposes, for example, as buffers, tonicity agents, carriers, vehicles, fillers, binders, lubricants, glidants, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavorants, surfactants, emulsifiers, or combinations thereof, and / or to improve the administration and / or absorption of the active pharmaceutical ingredient. The amount of each excipient used can vary within the conventional ranges in the art.

[0256] Techniques and excipients that can be used are described, for example, in Handbook of Pharmaceutical Excipients (e.g., 8 thedition, Sheskey et al., Eds., American Pharmaceuticals Association and Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2017) and subsequent editions), as well as Remington: The Science and Practice of Pharmacy (e.g., 23 rd edition, Remington and Allen, Eds., Pharmaceutical Press (2021) and subsequent editions).

[0257] The pharmaceutical composition containing the GLP-1 / GIP / amylin receptor triple agonist disclosed herein may be for oral administration.

[0258] The pharmaceutical composition containing the GLP-1 / GIP / amylin receptor triple agonist disclosed herein is, for example, a solid pharmaceutical composition containing a pharmaceutical active ingredient as a lyophilized or spray-dried composition (e.g., tablets or capsules), which can be used as such, dissolved before use, or combined with excipients in the formulation.

[0259] The pharmaceutical composition may be a solid pharmaceutical composition containing the compound disclosed herein, a salt of N-[8-(2-hydroxybenzoyl)amino]caprylate, preferably sodium N-(8-(2-hydroxybenzoyl)amino)caprylate, and one or more additional excipients, as described in the art. For example, the solid pharmaceutical composition may be as described in International Publication No. WO 2012 / 080471, International Publication No. WO 2013 / 139694, International Publication No. WO 2013 / 189988, International Publication No. WO 2019 / 149880, International Publication No. WO 2019 / 215063, International Publication No. WO 2021 / 219710, or International Publication No. WO 2023 / 012263 A1.

[0260] Alternatively, the pharmaceutical composition comprising the GLP-1 / GIP / amylin receptor triple agonist disclosed herein can be a liquid composition such as an aqueous composition. Such liquid compositions can be suitable for oral administration or for parenteral administration, such as intravenous, intramuscular, or subcutaneous administration.

[0261] Liquid compositions suitable for injection can be prepared using conventional techniques in the pharmaceutical industry, which involve dissolving and mixing the components as necessary to yield the desired final product. Thus, according to a certain procedure, the compounds described herein are dissolved in a suitable buffer at a suitable pH. The composition can be sterilized, for example, by sterile filtration. Techniques and excipients that can be used to prepare liquid formulations are described, for example, in Handbook of Pharmaceutical Excipients (e.g., 8 th edition, Sheskey et al., Eds., American Pharmaceuticals Association and Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2017) and subsequent editions), as well as Remington: The Science and Practice of Pharmacy (e.g., 23 rd edition, Remington and Allen, Eds., Pharmaceutical Press (2021) and subsequent editions). Preferably, in embodiments where the pharmaceutical composition is in a liquid formulation, the liquid formulation provides improved stability.

[0262] The pharmaceutical composition is typically administered in an amount sufficient to cure, alleviate, or partially prevent the disease and its complications in a subject already suffering from a disease such as the indications described below. The amount sufficient to achieve this is defined as a "therapeutically effective amount." As will be understood by those skilled in the art, the amount effective for this purpose depends on the severity of the disease, as well as the weight and general condition of the subject.

[0263] In some embodiments, the dosage of the compound delivered by subcutaneous administration can be about 0.1 mg to 500 mg of the compound per day, preferably about 0.5 mg to 150 mg per day, every other day, every two days, every three days, every four days, every five days, or once a week, depending on the severity of the condition.

[0264] Suitable dosages can also be adjusted based on the properties of the particular compound, including its in vivo half-life or mean residence time and its biological activity. For example, the compound to be delivered can be administered once a day in one embodiment, or once a week in another embodiment. Thus, the pharmaceutical composition can be used for administration approximately once a day, for example, once every 12 to 36 hours, for example, once every 18 to 30 hours, for example, approximately once every 24 hours, or for administration approximately once a week, for example, once every 6 to 8 days.

[0265] In one embodiment, the present invention relates to an injection device comprising the pharmaceutical composition.

[0266] Indications In a further aspect, the present invention relates to a GLP-1 / GIP / amylin receptor triple agonist disclosed herein for use as a medicament.

[0267] The GLP-1 / GIP / amylin receptor triple agonist disclosed herein can be used for The following medical treatments or indications: (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 (maturity-onset diabetes of the young), gestational diabetes, and / or reduction of HbA1c, (ii) Delaying or preventing the progression of diabetic diseases such as the progression of type 2 diabetes, delaying the progression from impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delaying the progression from insulin-independent type 2 diabetes to insulin-requiring type 2 diabetes, (iii) Preventing and / or treating eating disorders such as obesity, for example, by reducing food intake, reducing body weight, suppressing appetite to induce satiety, treating or preventing hyperphagia, food craving, bulimia nervosa and / or obesity induced by administration of antipsychotics or steroids, reducing gastric motility, and / or delaying gastric emptying, (iv) Maintaining body weight after successful weight loss (induced by drugs or diet and exercise), i.e., preventing weight gain after successful weight loss, (v) Preventing and / or treating cardiovascular diseases such as delaying or reducing the onset of major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, hospitalization for unstable angina, and hospitalization for heart failure, (vi) Preventing and / or treating non-alcoholic fatty liver disease (NAFLD, also known as metabolic dysfunction-associated fatty liver disease, MAFLD) and / or non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis, MASH), (vii) Preventing and / or treating cognitive impairment such as that caused by Alzheimer's disease, (viii) Preventing and / or treating chronic kidney disease, (ix) Preventing and / or treating obstructive sleep apnea.

[0268] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In yet further specific aspects, 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 (viii). In some embodiments, the indication is (ix). In some embodiments, the indication is type 2 diabetes. In some embodiments, the indication is overweight or obesity.

[0269] As used herein, the term "treatment" refers to medical therapy of any human or other vertebrate subject in need thereof. The subject is expected to have undergone a physical examination by a physician or veterinarian who has provided a provisional or definitive diagnosis indicating that the use of the particular treatment would be beneficial to the health of the human or other vertebrate. The timing and purpose of the treatment may vary from individual to individual according to the current state of the subject's health. Thus, the treatment can be prophylactic (preventive), palliative, symptomatic, and / or curative.

[0270] In some embodiments, the indication is (i) and (iii). In some embodiments, the indication is (ii) and (iii).

[0271] The World Health Organization (WHO) defines overweight and obesity as an abnormal or excessive accumulation of body fat that poses a risk to an individual's overall health. Generally, all subjects suffering from obesity are considered to be overweight as well. Subjects suffering from obesity can be humans such as adults or children, and "children" include infants, toddlers, and adolescents. As an alternative to overweight, the term pre-obesity is also used in this field. WHO regards the Body Mass Index (BMI) as the most convenient population-level measure of overweight and obesity. The Body Mass Index (BMI) is a measure of body fat based on height and weight. The formula for calculation is BMI = weight in kilograms (kg) / height in square meters (m 2 ).

[0272] For adults, WHO defines overweight and obesity as follows: Overweight means having a BMI of 25 or more, and obesity means having a BMI of 30 or more.

[0273] For children, WHO takes age into account when defining overweight and obesity. For children under 5 years old, overweight means having a weight for height that exceeds the median of the WHO child growth standards by more than 2 standard deviations, and obesity means having a weight for height that exceeds the median of the WHO child growth standards by more than 3 standard deviations. Overweight and obesity are defined for children aged 5 - 19 years as follows: Overweight means having a BMI for age that exceeds the median of the WHO child growth standards by more than 1 standard deviation, and obesity means having a BMI for age that exceeds the median of the WHO child growth standards by more than 2 standard deviations.

[0274] Nevertheless, as illustrated in Table 16 below for adults, the diagnostic criteria for underweight, normal range, pre-obesity / overweight, and obesity can vary between countries / populations.

Table 6

[0275] The guidelines for the Asian population were published by Misra A et al. J Assoc Physicians India. 2009;57:163-70.

[0276] The guidelines for the Chinese population were issued in the 2006 edition of Guidelines for Prevention and Control of Overweight and Obesity in Chinese Adults edited by the Chinese Working Group on Obesity.

[0277] The Japanese guidelines were issued in 2016 by the Japanese Society for the Study of Obesity (JASSO) as Guidelines for the management of obesity disease in the Guidelines for the Management of Obesity Diseases.

[0278] The guidelines for the Taiwanese population were issued in 2023 by the Health Promotion Administration (HPA), Ministry of Health and Welfare of the Taiwan government, in the second edition of its "Evidence-Based Guideline on Adult Obesity Prevention and Management".

[0279] In some embodiments, the subject suffering from obesity is a human such as an adult or a child (including infants, toddlers, and youths). Thus, the human subject suffering from obesity may have a BMI of 25 or more, or 27 or more, or 28 or more, or 30 or more, and this subject may also be referred to as being obese. Obesity can be class I, class II, class III, or class IV obesity (as defined in Table 16). In some embodiments, the human subject suffering from obesity may have a BMI of ≧35 or a BMI in the range of ≧30 to <40. In some embodiments, obesity is severe obesity or morbid obesity, and the human subject may have a BMI of ≧40.

[0280] In some embodiments, the present invention relates to a method for the treatment or prevention of overweight in the presence of at least one weight-related co-existing disorder, optionally. In one embodiment, the GLP-1 / GIP / amylin receptor triple agonist disclosed herein is for use in the treatment of a subject having an initial body mass index (BMI) of 25 or more, 27 or more, or 28 or more, or 30 or more, optionally in the presence of at least one weight-related co-existing disorder.

[0281] In some embodiments, the present invention relates to the use of a formulation for the treatment or prevention of overweight in the presence of at least one weight-related co-existing disorder, optionally. In some embodiments, the subject suffering from overweight is a human such as an adult or a child (including infants, toddlers, and adolescents). The adult human subject suffering from overweight may have a BMI of 23 or more, or 24 or more, or 25 or more, or 27 or more. In some embodiments, the human subject suffering from overweight has a BMI in the range of 24 to <27, 24 to <28, 25 to <30, or 27 to <30. In some embodiments, the weight-related co-existing disorder is selected from the group consisting of hypertension, glucose abnormalities (such as prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, and obstructive sleep apnea.

[0282] In some embodiments, the triple agonist disclosed herein relates to a method for weight management. In some embodiments, the triple agonist disclosed herein relates to a method for reducing appetite. In some embodiments, the triple agonist disclosed herein relates to a method for reducing food intake. In some embodiments, the triple agonist disclosed herein relates to a method for preventing or treating overweight in a subject.

[0283] The term "weight reduction" may include the treatment or prevention of obesity and / or overweight.

[0284] Administration of the compounds disclosed herein can optionally be as an adjunct to a low calorie diet and increased physical activity in an adult subject suffering from obesity, i.e., having an initial body mass index (BMI) of 25 or greater, or 27 or greater, or 28 or greater, or 30 or greater, or suffering from overweight, i.e., having an initial body mass index (BMI) of 23, or 24 or greater, or 25 or greater, or 27 or greater, optionally in the presence of at least one weight-related co-morbid condition (e.g., hypertension, glucose abnormalities (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, or obstructive sleep apnea).

[0285] Method of production The compounds disclosed herein are produced, for example, by classical peptide synthesis, e.g., solid phase peptide synthesis using t-Boc or Fmoc chemistry, or by other well-established techniques. See, for example, Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley & Sons, 1999, Florencio Zaragoza Dorwald, “Organic Synthesis on Solid Phase”, Wiley-VCH Verlag GmbH, 2000, and “Fmoc Solid Phase Peptide Synthesis” edited by W.C. Chan and P.O. White, Oxford University Press, 2000.

[0286] Alternatively, the compounds can be produced by recombinant methods, e.g., by culturing in a suitable nutrient medium, under conditions permissive for expression of the peptide, a host cell containing a DNA sequence encoding the peptide sequence and capable of expressing the peptide. Non-limiting examples of host cells suitable for expression of these peptides are Escherichia coli, Saccharomyces cerevisiae, and mammalian BHK or CHO. Specific examples of methods for preparing the disclosed compounds are included in the Examples.

[0287] A further aspect of the present invention relates to a method for preparing the peptides described herein. In one embodiment, the method for preparing the compounds described herein comprises the steps of solid-phase peptide synthesis. The extension portion may be constructed continuously as part of the solid-phase peptide synthesis or generated separately and may be linked via a lysine residue after peptide synthesis.

[0288] Specific embodiments 1. A GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I, comprising one lysine (Lys, K) residue: Comprising Z1-L1-Z2 (I), · Z1 is of formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 The amino acid at the position represents Aib), and is a peptide containing up to 4 amino acid substitutions, · L1 is a peptide linker, · Z2 is a C-terminal amide and a peptide containing up to 10 amino acid substitutions relative to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III), a GLP-1 / GIP / amylin receptor triple agonist. 2. The GLP-1 / GIP / amylin receptor triple agonist according to embodiment 1, wherein the peptide Z1 comprises an amino acid sequence having at least 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to formula II (SEQ ID NO: 1), The peptide Z2 comprises an amino acid sequence having at least 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identity to formula III (SEQ ID NO: 2). 3. A GLP-1 / GIP / amylin receptor triple agonist, a peptide according to formula I containing 1 lysine (Lys, K) residue: comprising Z1-L1-Z2 (I), · Z1 is a peptide having a maximum of 4 amino acid substitutions relative to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 the amino acid at the position represents Aib), and Z1 is an amino acid sequence according to formula X (SEQ ID NO: 161): X 21 X 22 X 23 GTFTSDYSX 24 LLEEX 25 AAX 26 EFIX 27 WLX 28 X 29 GGPSX 30 X 31 (X) (wherein X 21 represents His (H) or Tyr (Y), X 22 represents Aib, X 23 represents Glu (E) or His (H), X 24 represents Ile (I) or Lys (K), X 25 represents Gln (Q) or Ile (I), X 26 represents Arg (R) or Gln (Q), X 27 represents Ala (A), Glu (E), or Gln (Q), X 28 represents Leu (L) or I (Ile), X 29 represents Ala (A) or Gln (Q), X 30represents Arg(R), Gly(G), Lys(K), or Ser(S), X 31 contains or consists of Gly(G), Glu(E), or Lys(K)), · L1 is a peptide linker, · Z2 contains a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions with respect to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 has an amino acid sequence according to formula XII (SEQ ID NO: 164): AX 32 X 33 LSTAX 34 X 35 X 36 RLSAX 37 LHX 38 LX 39 X 40 X 41 PX 42 TETGSGX 43 P (XII) (wherein, X 32 represents Gly(G) or Ser(S), X 33 represents Gln(Q), Glu(E), His(H), or Lys(K), X 34 represents Ala(A) or Gln(Q), X 35 represents Gln(Q), Leu(L), or Thr(T), X 36 represents Ala(A), Gly(G), or Gln(Q), X 37 represents Glu(E) or Lys(K), X 38 represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Lys(K), Thr(T), or Tyr(Y), X 39 represents Ala(A) or Lys(K), X 40 represents Asp (D) or Thr (T), X 41 represents Leu (L) or Glu (E), X 42 represents Arg (R) or Lys (K), X 43 A GLP-1 / GIP / amylin receptor triple agonist comprising or consisting of) (wherein X 4. The GLP-1 / GIP / amylin receptor triple agonist according to any one of embodiments 1 to 3, wherein one lysine (Lys, K) residue is present in peptide Z1 or peptide Z2. 5. The GLP-1 / GIP / amylin receptor triple agonist according to any one of embodiments 1 to 4, wherein the GLP-1 / GIP / amylin receptor triple agonist does not contain a cysteine (Cys, C) residue. 6. The GLP-1 / GIP / amylin receptor triple agonist according to any one of embodiments 1 to 5, wherein the GLP-1 / GIP / amylin receptor triple agonist does not contain a disulfide bridge. 7. · Z1 is of formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 The amino acid at the position represents Aib), and is a peptide having a maximum of 4 amino acid substitutions relative to and Z1 has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 5 comprises or consists of) (where · L1 is a peptide linker, · Z2 contains a C-terminal amide and is a peptide having a maximum of 10 amino acid substitutions relative to formula III (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (III) and Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Gln (Q), Glu (E), His (H), or Lys (K), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 12 represents Ala (A) or Lys (K), X 13represents Asp(D) or Thr(T), X 14 represents Arg(R) or Lys(K), X 15 and contains or consists of) Ala(A) or Ser(S) (wherein X 8. · Z1 is a peptide having a maximum of 4 amino acid substitutions with respect to formula II (SEQ ID NO: 1): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X 2 represents Aib at the and Z1 is an amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein X 51 represents Aib, X 52 represents Ile(I) or Lys(K), X 53 represents Arg(R) or Gln(Q), X 54 represents Ala(A), Glu(E), or Gln(Q), X 55 represents Leu(L) or I(Ile), X 56 represents Ala(A) or Gln(Q), X 57 represents Gly(G) or Glu(E)) and contains or consists of, · L1 is a peptide linker, · Z2 contains a C-terminal amide and has the formula III (SEQ ID NO: 2): A peptide having a maximum of 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP (III), and Z2 is an amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein X 58 represents Gly (G) or Ser (S), X 59 represents Gln (Q), Glu (E), or His (H), X 60 represents Ala (A) or Gln (Q), X 61 represents Leu (L) or Thr (T), X 62 represents Ala (A), Gly (G), or Gln (Q), X 63 represents Gln (Q), Glu (E), or Lys (K), X 64 represents Leu (L) or Glu (E)), comprising or consisting of the GLP-1 / GIP / amylin receptor triple agonist according to Embodiments 1 to 6. 9. The GLP-1 / GIP / amylin receptor triple agonist according to Embodiments 1 to 8, wherein the peptide linker L1 comprises 1 to 14, 1 to 10, 4 to 10, or 9 to 10 amino acid residues. 10. The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 1 to 9, wherein the peptide linker L1 comprises 1 to 14 amino acid residues selected from the group consisting of Ala (A), Glu (E), Gln (Q), Gly (G), Leu (L), Phe (F), Pro (P), Ser (S), Thr (T), Val (V), Asn (N). 11. The peptide linker L1 has an amino acid sequence according to formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 (IV) (wherein X 1 represents Ala (A), Glu (E), Gly (G), X 2 represents Gln (Q), Glu (E), Gly (G), Leu (L), Pro (P), or is absent, X 3 represents Ala (A), Gln (Q), Glu (E), Gly (G), Pro (P), or is absent, X 4 represents Ala (A), Gln (Q), Glu (E), Gly (G), Pro (P), or is absent, X 5 represents Glu (E), Gly (G), Pro (P), Ser (S), Thr (T), or is absent, X 6 represents Glu (E), Gly (G), Leu (L), Gln (Q), or is absent, X 7 represents Ala (A), Gln (Q), Glu (E), Gly (G), Phe (F), or is absent, X 8 represents Ala (A), Gln (Q), Glu (E), Gly (G), Thr (T), Pro (P), Val (V), or is absent, X 9 represents Glu (E), Asn (N), Pro (P), Thr (T), or is absent, X 10represents Ala (A), Gln (Q), Glu (E), Gly (G), Leu (L), Pro (P), Ser (S), Val (V), or is absent, X 11 represents Ala (A), or is absent, X 12 represents Gln (Q), or is absent, X 13 represents Thr (T), or is absent, X 14 A GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 1 to 10, comprising or consisting of (wherein represents Leu (L) or is absent). 12. The peptide linker L1 has an amino acid sequence according to Formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 (IV), comprising or consisting of This is a GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 1 to 11, selected from the group consisting of A, E, G, AE, GE, APPE (SEQ ID NO: 125), GGGE (SEQ ID NO: 126), AGQAPG (SEQ ID NO: 127), APPPSGGG (SEQ ID NO: 128), APPPSGGGE (SEQ ID NO: 129), APPPSGGGG (SEQ ID NO: 130), ALAQTLAQTL (SEQ ID NO: 131), ALAQTLFVNQ (SEQ ID NO: 132), ALAQTLGTNE (SEQ ID NO: 133), ALQAPGQAPG (SEQ ID NO: 134), ALQAPGQAPL (SEQ ID NO: 135), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), GGGEGGGEGE (SEQ ID NO: 138), GQAPGQAPGE (SEQ ID NO: 139), GQEPGQEPGE (SEQ ID NO: 140), APPPSLAQTLAQTL (SEQ ID NO: 141), AG, AGGGG (SEQ ID NO: 142), AGEAPGQAPG (SEQ ID NO: 143), AGEAPGEAPG (SEQ ID NO: 144), AGQAPGQAPA (SEQ ID NO: 145), AGQAPGQAPE (SEQ ID NO: 146), AGQAPGQAPP (SEQ ID NO: 147), AGQAPGQAPS (SEQ ID NO: 148), AGQAPGQAPV (SEQ ID NO: 149), EGQAPGQAPG (SEQ ID NO: 150), AGQEPGQAPG (SEQ ID NO: 151), AGQAEGQAPG (SEQ ID NO: 152), AGQAPEQAPG (SEQ ID NO: 153), AGQAPGEAPG (SEQ ID NO: 154), AGQAPGQEPG (SEQ ID NO: 155), AGQAPGQAEG (SEQ ID NO: 156), AGQEPGQEPG (SEQ ID NO: 157), AGQAPGQAP (SEQ ID NO: 158), and AGQAPGEAPL (SEQ ID NO: 159). 13. Amino acid sequence according to Formula IV: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X14 (IV) is the GLP-1 / GIP / amylin receptor triple agonist according to Embodiment 12, selected from the group consisting of E, GE, APPPSGGGE (SEQ ID NO: 129), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), and AGQAPGEAPG (SEQ ID NO: 154). 14. The peptide Z1 has an amino acid sequence according to Formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), or Ser (S), X 5 represents Gly (G)), or consists of it, The peptide Z2 has an amino acid sequence according to Formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Gln (Q), Glu (E), His (H), or Lys (K), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 12 represents Ala (A) or Lys (K), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R) or Lys (K), X 15 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 1 to 7 and 9 to 13, comprising or consisting of) represents Ala (A) or Ser (S). 15. Peptide Z2 has an amino acid sequence according to Formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents Lys (K), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), X 12 represents Ala(A), X 13 represents Asp(D) or Thr(T), X 14 represents Arg(R), X 15 represents Ala(A) or Ser(S), or or X 6 represents Gln(Q), Glu(E), or His(H), X 7 represents Ala(A) or Gln(Q), X 8 represents Gln(Q), Leu(L), or Thr(T), X 9 represents Ala(A), Gly(G), or Gln(Q), X 10 represents Lys(K), X 11 represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), X 12 represents Ala(A), X 13 represents Asp(D) or Thr(T), X 14 represents Arg(R), X 15 represents Ala(A) or Ser(S), or or X 6 represents Gln(Q), Glu(E), or His(H), X 7 represents Ala(A) or Gln(Q), X 8 represents Gln(Q), Leu(L), or Thr(T), X 9represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Lys (K), X 12 represents Ala (A), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R), X 15 represents Ala (A) or Ser (S), or or X 6 represents Gln (Q), Glu (E), or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Thr (T), or Tyr (Y), X 12 represents Lys (K), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R), X 15 represents Ala (A) or Ser (S), or or X 6 represents Gln (Q), Glu (E), or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Thr (T), or Tyr (Y), X 12 represents Ala (A), X 13 represents Asp (D) or Thr (T), X 14 represents Lys (K), X 15 or consists of, any one of Embodiments 1 to 7 and 9 to 14 of the GLP-1 / GIP / amylin receptor triple agonist described in any one of the above. 16. Peptide Z1 has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein, X 1 X 2 X 3 represents YAibE (Tyr-Aib-Glu) or HAibH (His-Aib-His), X 4 represents Arg (R), Gly (G), or Ser (S), X 5 represents Gly (G)) or consists of, any one of Embodiments 1 to 7 and 9 to 15 of the GLP-1 / GIP / amylin receptor triple agonist described in any one of the above. 17. Peptide Z1 has an amino acid sequence according to formula V (SEQ ID NO: 6): YX 2 EGTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 G (V) (wherein X 2 represents Aib, X 4 is Arg(R) or Ser(S)) as described in Embodiment 16, or consists of, a GLP-1 / GIP / amylin receptor triple agonist. 18. Peptide Z1 has the amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His(H) or Tyr(Y), X 2 represents Aib, X 3 represents Glu(E) or His(H), X 4 represents Arg(R), Gly(G), or Ser(S), X 5 represents Gly(G)) as described in Embodiment 16, or consists of, Peptide Z2 has the amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Glu(E) or His(H), X 7 represents Ala(A) or Gln(Q), X 8 represents Gln(Q), Leu(L), or Thr(T), X 9represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), or Lys (K), X 12 represents Ala (A) or Lys (K), X 13 represents Thr (T), X 14 represents Arg (R) or Lys (K), X 15 comprising or consisting of those wherein X represents Ala (A) or Ser (S): a GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 1 to 7 and 9 to 15. 19. Peptide Z1 has an amino acid sequence according to Formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), or Ser (S), X 5 represents Gly (G)) comprising or consisting of Peptide Z2 has an amino acid sequence according to Formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX14 TETGSGX 15 P (IIIa) (wherein X 6 represents Glu (E) or His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Lys (K), X 12 represents Ala (A), X 13 represents Thr (T), X 14 represents Arg (R), X 15 represents Ala (A) or Ser (S)), and is included in or consists of any one of Embodiments 1 to 7, 9 to 15, or Embodiment 18 of the GLP-1 / GIP / Amylin receptor triple agonist. 20. Peptide Z1 has an amino acid sequence according to Formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), or Ser (S), X 5comprises or consists of Gly(G); Peptide Z2 has an amino acid sequence according to formula VIII (SEQ ID NO: 9): ASHLSTAQTQRLSAELHKLATLPRTETGSGSP (VIII), and is a GLP-1 / GIP / amylin receptor triple agonist according to any one of embodiments 9 to 15, 18, and 19. 21. The amino acid sequence of peptide Z1-L1-Z2 is YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 62), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPLASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 68), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSRGEASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 78), or YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPLASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 87), (wherein in each amino acid sequence, X represents Aib), and is a GLP-1 / GIP / amylin receptor triple agonist according to any one of embodiments 1 to 7 and 9 to 20. 22. Peptide Z2 has an amino acid sequence according to formula VII (SEQ ID NO: 8): ASHLSTAQTQRLSAKLHRLATLPRTETGSGSP (VII), and is a GLP-1 / GIP / amylin receptor triple agonist according to embodiment 16 or 17. 23. The amino acid sequence of peptide Z1-L1-Z2 is The GLP-1 / GIP / amylin receptor triple agonist according to embodiment 22, comprising or consisting of YXEGTFTSDYSILLEEQAAREFIEWLLAGGPSSGAGQAPGQAPGASHLSTAQTQRLSAKLHRLATLPRTETGSGSP (SEQ ID NO: 65). 24. The peptide Z1 has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein, X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), or Ser (S), X 5 represents Gly (G)) and comprises or consists of, The peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein, X 6 represents His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Leu (L) or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q)) X 10 represents Glu(E), X 11 represents Arg(R) or Gln(Q), X 12 represents Lys(K), X 13 represents Thr(T), X 14 represents Arg(R), X 15 A GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 1 to 7, 9 to 15, and 18, comprising or consisting of). 25. Peptide Z1 has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His(H) or Tyr(Y), X 2 represents Aib, X 3 represents Glu(E) or His(H), X 4 represents Arg(R), Gly(G), or Ser(S), X 5 represents Gly(G)) and comprises or consists of, Peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6represents His (H), X 7 represents Ala (A) or Gln (Q), X 8 represents Leu (L) or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R), X 12 represents Ala (A), X 13 represents Thr (T), X 14 represents Lys (K), X 15 contains or consists of those represented by Ser (S), and is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 1 to 7, 9 to 15, and 18. 26. Peptide Z1 has an amino acid sequence according to Formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein, X 1 represents His (H) or Tyr (Y), X 2 represents Aib, X 3 represents Glu (E) or His (H), X 4 represents Arg (R), Gly (G), or Ser (S), X 5 contains or consists of those represented by Gly (G), Peptide Z2 has an amino acid sequence according to Formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents His (H), X 7 represents Gln (Q), X 8 represents Thr (T), X 9 represents Gln (Q), X 10 represents Glu (E), X 11 represents Arg (R) or Lys (K), X 12 represents Ala (A) or Lys (K), X 13 represents Thr (T), X 14 represents Arg (R) or Lys (K), X 15 represents Ser (S)) and is included in or consists of any one of Embodiments 1 to 7, 9 to 15, and 18 of the GLP-1 / GIP / Amylin receptor triple agonist. 27. Peptide Z1 has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X 3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His (H), X 2 represents Aib, X 3 represents His (H), X 4 represents Arg (R), Gly (G), Lys (K), or Ser (S), X 5 comprises or consists of Gly (G), Peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Gln (Q), Glu (E), His (H), or Lys (K), X 7 represents Ala (A) or Gln (Q), X 8 represents Gln (Q), Leu (L), or Thr (T), X 9 represents Ala (A), Gly (G), or Gln (Q), X 10 represents Glu (E) or Lys (K), X 11 represents Arg (R), Gln (Q), Glu (E), Gly (G), His (H), Lys (K), Thr (T), or Tyr (Y), X 12 represents Ala (A) or Lys (K), X 13 represents Asp (D) or Thr (T), X 14 represents Arg (R) or Lys (K), X 15 represents Ala (A) or Ser (S)) and is included in or consists of any one of Embodiments 1 to 7 and 9 to 13 of the GLP-1 / GIP / Amylin receptor triple agonist described above. 28. Peptide Z1 has an amino acid sequence according to formula IIa (SEQ ID NO: 3): X 1 X 2 X3 GTFTSDYSILLEEQAAREFIEWLLAGGPSX 4 X 5 (IIa) (wherein X 1 represents His, X 2 represents Aib, X 3 represents His(H), X 4 represents Lys(K), X 5 represents Gly(G)) and contains or consists of Peptide Z2 has an amino acid sequence according to formula IIIa (SEQ ID NO: 4): ASX 6 LSTAX 7 X 8 X 9 RLSAX 10 LHX 11 LX 12 X 13 LPX 14 TETGSGX 15 P (IIIa) (wherein X 6 represents Glu(E) or His(H), X 7 represents Ala(A) or Gln(Q), X 8 represents Leu(L) or Thr(T), X 9 represents Ala(A), Gly(G), or Gln(Q), X 10 represents Glu(E), X 11 represents Arg(R), Gln(Q), or Glu(E), X 12 represents Ala(A), X 13 represents Asp(D) or Thr(T), X 14 represents Arg(R), X 15The GLP-1 / GIP / amylin receptor triple agonist according to embodiment 27, comprising or consisting of (representing Ser(S)). 29. In formula IIIa (SEQ ID NO: 4), X 6 represents Glu(E) or His(H), X 7 represents Ala(A) or Gln(Q), X 8 represents Leu(L) or Thr(T), X 9 represents Ala(A) or Gly(G), X 10 represents Glu(E), X 11 represents Arg(R), Gln(Q), or Glu(E), X 12 represents Ala(A), X 13 represents Thr(T), X 14 represents Arg(R), X 15 represents Ser(S), the GLP-1 / GIP / amylin receptor triple agonist according to embodiment 27 or embodiment 28. 30. The GLP-1 / GIP / amylin receptor triple agonist according to any one of embodiments 27 to 29, wherein the amino acid sequence of peptide Z1-L1-Z2 comprises or consists of HXHGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPSGGGEASHLSTAQTARLSAELHQLATLPRTETGSGSP (SEQ ID NO: 111) (wherein X represents Aib). 31. The GLP-1 / GIP / amylin receptor triple agonist according to any one of embodiments 1 to 7 and 9 to 13, wherein peptide Z1-L1-Z2 comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 20 to 124 (wherein X represents Aib). 32. X 1is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 19, 20, 24, 25, 26, 27, or 28, which represents His (H). 33. X 1 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 18, 19, 20, 24, 25, or 26, which represents Tyr (Y). 34. X 3 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 19, 20, 24, 25, or 26, which represents Glu (E). 35. X 3 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 18, 19, 20, 24, 25, 26, 27, or 28, which represents His (H). 36. X 4 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 16, 17, 18, 19, 20, 24, 25, 26, or 27, which represents Arg (R). 37. X 4 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 16, 18, 19, 20, 24, 25, 26, or 27, which represents Gly (G). 38. X 4 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 27, or 28, which represents Lys (K). 39. X 4 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 16, 17, 18, 20, 20, 24, 25, 26, or 27, which represents Ser (S). 40. X 5 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 16, 18, 19, 20, 24, 25, 26, 27, or 28, which represents Gly (G). 41. X 5The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, or 27, wherein X represents Lys (K). 42. X 6 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, or 27, wherein X represents Gln (Q). 43. X 6 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 27, 28, or 29, wherein X represents Glu (E). 44. X 6 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 16, 19, 24, 25, 26, 27, 28, or 29, wherein X represents His (H). 45. X 6 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, or 27, wherein X represents Lys (K). 46. X 7 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 24, 25, 26, 27, 28, or 29, wherein X represents Ala (A). 47. X 7 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 17, 19, 24, 25, 26, 27, 28, or 29, wherein X represents Gln (Q). 48. X 8 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, or 27, wherein X represents Gln (Q). 49. X 8 The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 24, 25, 27, 28, or 29, wherein X represents Leu (L). 50. X 8is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 24, 25, 26, 27, 28, or 29, which represents Thr (T). 51. X 9 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 24, 25, 27, 28, or 29, which represents Ala (A). 52. X 9 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 24, 25, 26, 27, 28, or 29, which represents Gly (G). 53. X 9 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 24, 25, 26, 27, or 28, which represents Gln (Q). 54. X 10 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 24, 25, 26, 27, 28, or 29, which represents Glu (E). 55. X 10 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, or 27, which represents Lys (K). 56. X 11 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 24, 25, 26, 27, 28, or 29, which represents Arg (R). 57. X 11 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 24, 27, 28, or 29, which represents Gln (Q). 58. X 11 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 27, 28, or 29, which represents Glu (E). 59. X 11is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, or 27, which represents Gly (G). 60. X 11 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, or 27, which represents His (H). 61. X 11 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 26, or 27, which represents Lys (K). 62. X 11 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, or 27, which represents Thr (T). 63. X 11 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, or 27, which represents Tyr (Y). 64. X 12 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 25, 26, 27, 28, or 29, which represents Ala (A). 65. X 12 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 24, 26, or 27, which represents Lys (K). 66. X 13 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 27, or 28, which represents Asp (D). 67. X 13 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 16, 18, 24, 25, 26, 27, 28, or 29, which represents Thr (T). 68. X 14 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 24, 26, 27, 28, or 29, which represents Arg (R). 69. X 14 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 25, 26, or 27, representing Lys (K). 70. X 15 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, or 27, representing Ala (A). 71. X 15 is the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 7, 14, 15, 18, 19, 23, 24, 25, 26, 27, 28, or 29, representing Ser (S). 72. Peptide Z1 has an amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein X 51 represents Aib, X 52 represents Ile (I) or Lys (K), X 53 represents Arg (R), X 54 represents Glu (E), X 55 represents Leu (L) or I (Ile), X 56 represents Ala (A), X 57 represents Gly (G) or Glu (E)) and includes or consists of the GLP-1 / GIP / amylin receptor triple agonist according to Embodiment 8. 73. Peptide Z2 has an amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein X 58 represents Ser(S), X 59 represents His(H), X 60 represents Gln(Q), X 61 represents Thr(T), X 62 represents Gln(Q), X 63 represents Lys(K), X 64 represents Leu(L)) as described in Embodiment 8 or Embodiment 72, or consists of, a GLP-1 / GIP / amylin receptor triple agonist. 74. Peptide Z1 has the amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein X 51 represents Aib, X 52 represents Ile(I) or Lys(K), X 53 represents Arg(R), X 54 represents Glu(E), X 55 represents Leu(L) or I(Ile), X 56 represents Ala(A), X 57 represents Gly(G) or Glu(E)) and contains or consists of Peptide Z2 has the amino acid sequence according to formula XIIa (SEQ ID NO: 165): AX 58 X 59 LSTAX 60 X 61 X 62 RLSAELHX 63 LATX 64 PRTETGSGSP (XIIa) (wherein X 58 represents Ser(S), X 59 represents His(H), X 60 represents Gln(Q), X 61 represents Thr(T), X 62 represents Gln(Q), X 63 represents Lys(K), X 64 represents Leu(L)) and is included in or consists of any one of Embodiment 8, 72, or 73 of the GLP-1 / GIP / amylin receptor triple agonist. 75. Peptide Z1 has the amino acid sequence according to formula Xa (SEQ ID NO: 162): YX 51 EGTFTSDYSX 52 LLEEIAAX 53 EFIX 54 WLX 55 X 56 GGPSSX 57 (Xa) (wherein X 51 represents Aib, X 52 represents Ile(I) or Lys(K), X 53 represents Arg(R), X 54 represents Glu(E), X 55 represents Leu(L), X 56 represents Ala(A), X 57The GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiment 8 or 72 to 74, which comprises or consists of Gly (G). 76. Peptide Z1 has an amino acid sequence according to Formula XI (SEQ ID NO: 163): YX 51 EGTFTSDYSX 52 LLEEIAAREFIEWLLAGGPSSG (XI) (wherein, X 51 represents Aib, X 52 represents Ile (I) or Lys (K)) and which comprises or consists of the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiment 8 or 72 to 75. 77. Peptide Z2 has an amino acid sequence according to Formula XIII (SEQ ID NO: 166): ASX 59 LSTAQTQRLSAELHKLATLPRTETGSGSP (XIII) (wherein, X 59 represents Glu (E) or His (H)) and which comprises or consists of the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiment 8 or 72 to 77. 78. Peptide Z1-L1-Z2 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 170 to 242 (wherein X represents Aib) and which comprises or consists of the GLP-1 / GIP / amylin receptor triple agonist according to any one of Embodiments 1 to 7 and 9 to 13. 79. The GLP-1 / GIP / amylin receptor triple agonist according to any one of the preceding embodiments, wherein the backbone of peptide Z1-L1-Z2 contains 66 to 80 amino acid residues. 80. The GLP-1 / GIP / amylin receptor triple agonist according to any one of the preceding embodiments, wherein the backbone of peptide Z1-L1-Z2 contains 67, 68, 75, or 76 amino acid residues, preferably 76 amino acid residues. 81. The GLP-1 / GIP / amylin receptor triple agonist according to any one of the preceding embodiments, wherein the peptide is a peptide derivative containing an extension part. 82. The peptide is a peptide derivative containing an extension part, and the extension part is C 12 ~C 20 The GLP-1 / GIP / amylin receptor triple agonist according to any one of the preceding embodiments, which contains a protractor P that is a dicarboxylic acid. 83. The peptide is a peptide derivative containing an extension part, and the extension part is

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[0289] Materials and Methods List of Abbreviations The following abbreviations are used below, which are in alphabetical order. Ado: 8-amino-3,6-dioxaoctanoic acid Aib: 2-aminoisobutyric acid amu: Atomic mass unit BHK baby hamster kidney Boc: t-butoxycarbonyl CAD: Charged aerosol detector cAMP: Cyclic adenosine monophosphate CRE: cAMP response element DCM: Dichloromethane DIC: N,N'-Diisopropylcarbodiimide DIO: Diet-induced obesity DMB: 2,4-Dimethoxybenzyl DMEM: Dulbecco's Modified Eagle Medium DMF: N,N-Dimethylformamide DTT: 1,4-Dithiothreitol EC50: Median effective concentration EDTA: Ethylenediaminetetraacetic acid ES: Electrospray FBS: Fetal bovine serum Fmoc: 9-Fluorenylmethyloxycarbonyl FWHM: Full width at half maximum GIP: Glucose-dependent insulinotropic polypeptide GLP-1: Glucagon-like peptide 1 hAMYR3: Human amylin receptor 3 hGIPR: Human glucose-dependent insulinotropic polypeptide receptor hGLP-1R: Human glucagon-like peptide 1 receptor HEPES: N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) HFIP: 1,1,1,3,3,3-Hexafluoro-2-propanol or hexafluoroisopropanol HPLC: High performance liquid chromatography HSA: Human serum albumin i.v.: Intravenous LCMS or LC-MS: Liquid chromatography mass spectrometry LLoQ: Lower limit of quantification Luc: Luciferase MeCN: Acetonitrile MRI: Magnetic resonance imaging MS: Mass spectrometry Mtt: 4-Methyltrityl NCA: Non-compartmental pharmacokinetics nd: Not determined OtBu: tert-Butoxy Oxyma Pure (registered trademark): Ethyl cyano-hydroxyimino-acetate Pbf: 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl PBS: Phosphate Buffered Saline PK: Pharmacokinetics QD: Once daily (once a day) QTof: Quadrupole Time of Flight RAMP3: Receptor Activity-Modifying Protein 3 RT: Room temperature s.c.: Subcutaneous SD: Sprague Dawley SEM: Standard Error of the Mean SPPS: Solid Phase Peptide Synthesis tBu: tert-Butyl TFA: Trifluoroacetic acid TIPS Triisopropylsilane TQ: Triple Quadrupole Trt: Triphenylmethyl or trityl UPLC: Ultra Performance Liquid Chromatography UV: Ultraviolet

[0290] Constituent units of fatty acids and special amino acids Synthesis of monomethyl octadecanedioate (C 18 For the synthesis of monomethyl octadecanedioate, see WO 2010 / 102886 (pages 27-28). C 12 -C 20 The corresponding monomethyl esters of dicarboxylic acids, in particular, C 16 dicarboxylic acid and C 20 dicarboxylic acid can be prepared based thereon.

[0291] Fmoc-Leu-Ser(ψ Me , Me pro)-OH, Fmoc-Tyr(tBu)-Ser(ψ Me , Mepro)-OH and Fmoc-Gly-(DMB)Gly-OH are commercially available from TechnoComm Ltd.

[0292] General methods of peptide synthesis The preparation of peptides (reference compounds and compounds of the present invention) was carried out using Fmoc chemistry with Symphony X from Protein Technologies, PurePep Chorus from Protein Technologies, MultiPep 2 from CEM, Vapourtec RS-500 from Vapourtec, or CS136XT from CSBioon in solid-phase peptide synthesis (SPPS). The Fmoc-protected amino acids used in this method are the following standardly recommended ones: for example, Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Boc-His(Trt)-OH, Fmoc-Aib-OH, Fmoc-Glu-OtBu, and Fmoc-Ado-OH, supplied by, for example, Gyros Protein Technologies, Bachem, Iris Biotech, or NovabioChem. For example, Fmoc-Leu-Ser(ψ Me,Me pro)-OH, Fmoc-Tyr(tBu)-Ser(ψ Me,Me pro)-OH, and Fmoc-Gly-(DMB)Gly-OH were introduced where applicable.

[0293] Fmoc-PAL AM resin or Rink-Amide AM resin was used, which were commercially available from NovabioChem. Subsequent amino acids were introduced in a stepwise procedure by a Symphony X peptide synthesizer according to the SPPS principle.

[0294] Fmoc deprotection was achieved with 20% piperidine in DMF containing 0.1M Oxyma Pure for 2 × 10 minutes. Introduction of substituents at the alpha position of the N-terminal amino acid (i.e., the extension containing the "protractor" P and optional "linker" L P ") was achieved using standard Fmoc-protected amino acids. Peptide coupling was carried out using DIC and collidine. The amino acid / Oxyma Pure solution (0.3M / 0.3M in DMF at a 5 - 10-fold molar excess) was first added to the resin. Then, the same molar equivalent of DIC was added (1.5M in DMF), followed by collidine (1.5M in DMF). Most commonly, this was mixed for 2 hours. In some cases, the coupling time was lengthened, additional DIC was added, or the coupling step was repeated. Subsequently, a capping step was performed using 1M acetic anhydride in DMF and collidine. Introduction of an extension to the epsilon nitrogen of lysine (Lys, K) within the sequence was achieved using Fmoc-Lys(Mtt)-OH. After synthesis of the peptide backbone sequence, the Mtt group was removed by treatment with HFIP / DCM / TIPS (75:23:2) for 5 minutes, followed by washing with DCM. The resin was then resuspended in HFIP / DCM / TIPS (75:23:2) for 2 × 25 minutes, and then washed with DCM and DMF. The extension was introduced in the above stepwise procedure using suitably protected building blocks of linker L P such as standard Fmoc-protected amino acids like Fmoc-8-amino-3,6-dioxaoctanoic acid or Fmoc-Glu-OtBu. Introduction of the protractor, fatty acid, was achieved using suitable building blocks such as, but not limited to, octadecanedioic acid mono-tert-butyl-ester.

[0295] General cleavage methods The peptide was cleaved from the resin using TFA / TIPS / H 2 O / DTT (90:4:3:3) for 2 - 3 hours. Subsequently, the peptide was precipitated into cold diethyl ether and centrifuged. The ether was decanted, and the peptide precipitate was washed with ether two more times.

[0296] General methods for purification and quantification of derivatives The crude peptide was dissolved in acetic acid / MeCN / Milli-Q water (45:10:45 or 40:20:40) and orthogonally purified by reverse-phase preparative HPLC (Waters Delta Prep 4000) on a column containing C18 silica gel. The first elution was performed using a gradient of MeCN increasing from 20% to 50% in Milli-Q water containing 1% ammonium bicarbonate. The relevant fractions were analyzed by UPLC. The fractions containing the target peptide were pooled and diluted with Milli-Q water (1:1) before the second reverse-phase preparative HPLC. The second elution was performed using a gradient of MeCN increasing from 20% to 50% in Milli-Q water containing 0.1% TFA. The relevant fractions were analyzed by UPLC. The fractions containing the pure target peptide were pooled. The resulting solution was analyzed (UPLC, LCMS), and the peptide derivative was quantified using a CAD-specific HPLC detector (Thermo-Fischer Vanquish HPLC-CAD). The product was dispensed into glass vials. The vials were capped with Millipore glass fiber prefilters. By lyophilization, the trifluoroacetate salt of the derivative was obtained as a white solid.

[0297] Synthesized compounds The compounds were prepared using the above methods.

[0298] Example 1: Reference compound Reference compound 1 (GLP-1 / GIP / amylin receptor triple agonist disclosed in WO 2023 / 288313, Example 1, peptide / compound number 16)

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[0299] Example 2: GLP-1 / GIP / Amylin Receptor Triple-Acting Agent According to the Present Invention Compound 10

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Table 7-1

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Table 7-16

[0300] Example 3: LCMS Characterization of the Synthetic Compounds LCMS Characterization Method The LCMS analysis was performed on a setup consisting of a Waters Acquity UPLC H Class system and a Waters Xevo G2-XS QTof. Eluent: A: Milli-Q water, B: MeCN, C: 2% formic acid + 0.1% TFA in Milli-Q water.

[0301] The analysis was performed at RT (column temperature 60 °C) by injecting an appropriate volume of the sample onto the column. The sample was eluted with a linear gradient of 5 - 95% B in A and a constant 5% C.

[0302] The UPLC conditions, detector settings, and mass spectrometer settings were as follows. Column: Waters Acquity BEH Shield, C-18, 1.7 μm, 2.1 mm × 50 mm. Gradient: Linear 5% - 95% B and a constant 5% C at 0.4 ml / min for 4.0 minutes. Total run time: 7.0 minutes. Detection: MS sensitivity mode, ionization method: ES. Scan: 50 - 5000 amu.

[0303] The monoisotopic masses of the synthetic compounds were recorded and their measured and calculated values are shown in Table 6.

Table 8-1

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Table 8-5

Table 8-6

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Table 8-10

[0304] Example 4: In Vitro Potency Assay of Human GLP-1 Receptor, Human GIP Receptor, and Human Amylin Receptor (High-Throughput Assay) GLP-1 Receptor Assay To determine the ability of a compound to activate or agonize the GLP-1 receptor, an in vitro potency assay on baby hamster kidney (BHK) cells expressing the human GLP-1 receptor (hGLP-1R) was performed as follows. To evaluate how the activation of the receptor might be affected by the presence of human serum albumin (HSA), in vitro assays were performed in the absence of HSA and in the presence of 1% (w / v) HSA. Unless otherwise indicated, references throughout this specification to the "GLP-1 receptor assay described in Example 4" refer to assay procedure Method A (hGLP-1R assay) described herein in the absence of HSA.

[0305] Assay Principle Activating the human GLP-1 receptor results in an increase in the intracellular concentration of cyclic AMP (cAMP) and transcriptional activation resulting from a promoter containing multiple copies of the cAMP response element (CRE). Therefore, it is possible to measure GLP-1 receptor activity using a CRE luciferase reporter gene introduced into baby hamster kidney (BHK) cells that co-express the human GLP-1 receptor.

[0306] Cells and assay reagents Cell stocks were prepared by culturing cell lines that stably express the human GLP-1 receptor and the CRE-responsive luciferase (CRE-Luc) reporter gene (BHK 467-12A KZ-10, prepared according to methods known to those skilled in the art) in growth medium consisting of DMEM (Gibco, 61965-026) supplemented with 10% FBS (Gibco, 16140-071 or 10100-147), 1% penicillin-streptomycin (Gibco, 15140-122), 1 mM Na-pyruvate (Gibco, 11360-039), 1 mg / mL G418 (Gibco, 10131-027), and 240 nM methotrexate (Pfizer, 15936). Cells at approximately 80-90% confluence were washed once with PBS (Gibco 14190-094) and detached from the cell flask using Versene (Gibco, 15040-033). After centrifugation, the cell pellet was resuspended in Recovery™ Cell Culture Freezing Medium (Gibco, 12648-010) or in medium consisting of DMEM (Gibco, 61965-026) supplemented with 20% FBS (Gibco, 16140-071 or 10100-147), 1% penicillin-streptomycin (Gibco, 15140-122), 1 mM Na-pyruvate (Gibco, 11360-039), 1 mg / mL G418 (Gibco, 10131-027), 240 nM methotrexate (Pfizer, 15936), and 10% DMSO (Sigma, D2650) at approximately 1.5×10 6Diluted to (1.5E+6) cells / mL. The cells were aliquoted and stored at -180 °C until use.

[0307] The assay buffer consisted of DMEM supplemented with either HSA or no HSA (Sigma, A9511), without phenol red (Gibco, 11880 - 028), 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).

[0308] Procedure - Method A (hGLP - 1R assay) To perform the assay, serial dilutions (10 - fold dilutions, 8 concentrations per compound) of the reference compound and GLP - 1 / GIP / Amylin receptor triple agonist were performed in assay buffer without HSA in a 96 - well plate. The frozen stock of hGLP - 1R BHK CRE - Luc cells was thawed in a 37 °C water bath, washed once in PBS (Gibco 14190 - 094), and diluted to 1.5×10 6 (1.5E+6) cells / mL in assay buffer with or without 2% (w / v) HSA (Sigma, A9511). For each dilution, a 50 μL aliquot of the reference compound or GLP - 1 / GIP / Amylin receptor triple agonist was added to 50 μL of the cell suspension with or without 2% (w / v) HSA (5.0×10 3 (5.0E+3) cells / well) in two 96 - well assay plates (ThermoFisher, 237105). The assay plates were incubated at 37 °C in 5% CO 2 for 3 hours, left at room temperature for 5 minutes, and then 100 μL steadylite plus™ (PerkinElmer / Revvity, 6066759) was added to each well. The plates were sealed and incubated at room temperature for 30 minutes with gentle shaking while protected from light. Luminescence was detected using a luminescence plate reader, e.g., Synergy 2 (BioTek). EC 50Values [pM] were calculated by non-linear curve fitting applying a four-parameter logistic model (Hill slope = 1) using GraphPad Prism (GraphPad Software, Boston, MA, USA) or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA).

[0309] Procedure - Method B (hGLP-1R assay) To perform the assay, serial dilutions of the reference compound and GLP-1 / GIP / Amylin receptor triple agonist (7-fold dilutions, 7 concentrations per compound, and 1 well containing only assay buffer) were performed in assay buffer in a 96-well plate. The serial dilutions were transferred to a 384-well assay plate (PerkinElmer / Revvity, 6007688) and mixed with an equal volume (10 μL) of assay buffer either without or containing 3% (w / v) HSA (Sigma, A-9511). The frozen stock of hGLP-1R BHK Cre-Luc cells was thawed in a 37 °C water bath, washed once in PBS (Gibco 14190-094), and diluted in assay buffer (without HSA) to 1.5×10 5 (1.5E+5) cells / mL and added (10 μL) to each well of the 384-well assay plate. After brief centrifugation, the assay plate was incubated at 37 °C in 5% CO2 for 3 h, equilibrated at room temperature for 10 min, and then 30 μL of steadylite plus™ (PerkinElmer / Revvity, 6066759) was added per well. The plate was sealed and incubated at room temperature for 30 min with gentle shaking while protected from light. Luminescence was detected using a luminescence plate reader, e.g., Synergy 2 (BioTek). EC 50Values [pM] were calculated by non-linear curve fitting applying a four-parameter logistic model (Hill slope = 1) using GraphPad Prism (GraphPad Software, Boston, MA, USA) or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA).

[0310] GIP Receptor Assay To determine the ability of a compound to activate or agonize the GIP receptor, an in vitro potency assay on baby hamster kidney (BHK) cells expressing the human GIP receptor (hGIPR) was performed as follows. To evaluate how receptor activation might be affected by the presence of human serum albumin (HSA), in vitro assays were performed in the absence of HSA and in the presence of 1% (w / v) HSA. Unless otherwise stated, references throughout this specification to the "GIP receptor assay described in Example 4" refer to assay procedure method A (hGIPR assay) described herein in the absence of HSA.

[0311] Assay Principle Activation of the human GIP receptor results in an increase in the intracellular concentration of cyclic AMP (cAMP) and transcriptional activation resulting from the promoter containing multiple copies of the cAMP response element (CRE). Therefore, it is possible to measure GIP receptor activity using the CRE luciferase reporter gene introduced into baby hamster kidney (BHK) cells co-expressing the human GIP receptor.

[0312] Cells and Assay Reagents The cell stock was prepared by culturing a cell line that stably expresses the human GIP receptor and contains the CRE-responsive luciferase (CRE-Luc) reporter gene (hGIPR BHK Cre-Luc2p clone #5, prepared according to methods known to those skilled in the art) in a growth medium consisting of DMEM (Gibco, 61965-026) supplemented with 10% fetal bovine serum (Gibco, 16140-071 or 10100-147), 0.5 mg / ml G418 (Gibco, 10131-027), 1% penicillin-streptomycin (Gibco, 15140-122), and 0.3 mg / ml hygromycin B (Invitrogen, 10687010) at 5% CO 2 and 37 °C. Cells at approximately 80-90% confluence were washed once with PBS (Gibco 14190-094) and detached from the cell flask using Versene (Gibco, 15040-066). After centrifugation, the cells were counted, resuspended, and diluted to approximately 1.5-3.0×10 6 (1.5E+6 - 3.0E+6) cells / mL in Recovery Cell Culture Freezing Medium (Gibco, 12648-010), and stored at -180 °C in suitable aliquots until use.

[0313] The assay buffer consisted of DMEM supplemented with either HSA or no HSA (Sigma, A9511), without phenol red (Gibco, 11880-028), 1× 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).

[0314] Procedure - Method A (hGIPR assay) One day before the assay, the hGIPR BHK Cre-Luc cells were thawed and seeded at 5.0×10 3(5.0E+3) cells / well were plated in a 96-well culture plate (PerkinElmer / Revvity, 6005680). The plate was then incubated at 37 °C for 21 - 23 hours using 5% CO 2 On the day of the assay, the GLP-1 / GIP / Amylin receptor triple agonist or reference compound was diluted in assay buffer using 7 points, 10-fold titration and a blank (absence of compound). Each compound was diluted and tested in duplicate in each experiment. In the plate containing cells, the growth medium was removed and the cells were washed twice with 100 μL of PBS (Gibco 14190-094). 50 μL of the test compound dilution was added to the plate containing cells preceded by 50 μL of assay buffer with or without 2% (w / v) HSA (Sigma, A9511). The cell plate was incubated in a 5% CO 2 incubator at 37 °C for 3 hours. The plate was then transferred to room temperature and 100 μL of steadylite plus™ (PerkinElmer / Revvity, 6066759) was added. The plate was sealed and gently shaken at room temperature for 30 minutes protected from light. Finally, luminescence (as an indicator of receptor activation) was measured with a Mithras reader (Berthold Technologies, DE). EC 50 values [pM] were calculated by non-linear curve fitting applying a 4-parameter logistic model (Hill slope = "shared value for all datasets") using GraphPad Prism (GraphPad Software, Boston, MA, USA).

[0315] Procedure - Method B (hGIPR assay) To perform the assay, serial dilutions of the reference compound and the GLP-1 / GIP / amylin receptor triple agonist (7-fold dilutions, 7 concentrations per compound, and 1 well containing only assay buffer) were prepared in assay buffer in a 96-well plate. The serial dilutions were transferred to a 384-well assay plate (PerkinElmer / Revvity, 6007688) and mixed with an equal volume (10 μL) of assay buffer with or without 3% HSA (Sigma, A-9511). The frozen stock of hGIPR BHK Cre-Luc cells was thawed in a 37 °C water bath, washed once in PBS (Gibco 14190-094), and diluted to 5 (1.5E+5) cells / mL in assay buffer (without HSA) and added (10 μL) to each well of the 384-well assay plate. After a brief centrifugation, the assay plate was incubated at 37 °C in 5% CO2 for 3 h, equilibrated at room temperature for 10 min, and then 30 μL of steadylite plus™ (PerkinElmer / Revvity, 6066759) was added per well. The plate was sealed and incubated at room temperature for 30 min with gentle shaking while protected from light. Luminescence was detected with a luminescence plate reader, e.g., Synergy 2 (BioTek). EC 50 values [pM] were calculated by non-linear curve fitting applying a 4-parameter logistic model (Hill slope = 1) using GraphPad Prism (GraphPad Software, Boston, MA, USA) or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA).

[0316] Amylin Receptor Assay To determine the ability of a compound to activate or agonize the amylin receptor, an in vitro potency assay against baby hamster kidney (BHK) cells expressing the human amylin receptor (hAMYR3) was performed as follows. To evaluate how receptor activation might be affected by the presence of human serum albumin (HSA), in vitro assays were performed in the absence of HSA and in the presence of 1% (w / v) HSA. Unless otherwise indicated, references throughout this specification to the “amylin receptor assay described in Example 4” refer to assay procedure method A (hAMYR3 assay) described herein in the absence of HSA.

[0317] Assay Principle Activation of the human amylin 3 receptor results in an increase in the intracellular concentration of cAMP and transcriptional activation resulting from a promoter containing multiple copies of the cAMP response element (CRE). Therefore, it is possible to measure hAMYR3 receptor activity using a CRE luciferase reporter gene introduced into baby hamster kidney (BHK) cells that co-express hAMYR3.

[0318] Cells and Assay Reagents The BHK cell line was transfected according to methods known to those skilled in the art (Hollex-1 cell line, obtained from Zymogentics described in U.S. Patent No. 5,622,839) to stably express the human calcitonin receptor (a) and the CRE-responsive luciferase (CRE-Luc) reporter gene. The cell line was further transfected with human receptor activity-modifying protein 3 (RAMP3) using standard methods. This converts the human calcitonin receptor into the human amylin-3(a) receptor (hAMYR3).

[0319] The cell stock was prepared by culturing the hAMYR3 BHK Cre-Luc cell line in a growth medium consisting of DMEM (Gibco, 31966-021) supplemented with 10% FBS (Gibco, 16140-071 or 10100-147), 1% penicillin-streptomycin (Gibco, 15140-122), 0.5 mg / mL gentamicin (Gibco, 10131-027), 0.4 mg / mL hygromycin (Invitrogen, 10687010), and 250 nM methotrexate (Sigma, A6770). Cells at approximately 80-90% confluence were washed once with PBS (Gibco 14190-094) and detached from the cell flask using Versene (Gibco, 15040-033) or TrypLE™ (Gibco, 12605-010). After centrifugation, the cell pellet was resuspended and diluted to approximately 2.5-4.0×10 6 (2.5E+6 - 4.0E+6) cells / mL in Recovery™ Cell Culture Freezing Medium (Gibco, 12648-010). The cells were aliquoted and stored at -180 °C until use.

[0320] The assay buffer consisted of phenol red-free DMEM (Gibco, 11880-028) supplemented with 0.1% (v / v) Pluronic F-68 (Gibco, 24040-032) with or without HSA (Sigma, A9511), 1X GlutaMAX (Gibco, 35050-038), 10 mM HEPES (Gibco, 15630-056), and 1% (w / v) ovalbumin (Sigma, A5503).

[0321] Procedure - Method A (hAMYR3 assay) To perform the assay, BHK hAMYR3 / CRE-Luc cells were thawed, washed once with PBS (Gibco 14190-094), and 4.0×10 3(4.0E+3) cells / well were seeded at a cell density. The plates were incubated overnight at 37 °C in 5% CO 2 medium. On the day of the assay, the cells were washed once in assay PBS (Gibco 14190-094). Serial dilutions of the reference compound and the GLP-1 / GIP / amylin receptor triple agonist (7-fold dilutions, 7 concentrations per compound, one well containing assay buffer only) were performed in assay buffer with or without 1% (w / v) HSA (Sigma, A9511) in a 96-well plate, and 30 μL of each concentration was added to a 384-well assay plate containing the cells. The assay plates were incubated at 37 °C in 5% CO 2 medium for 3 hours, after which 30 μL of steadylite plus™ (PerkinElmer / Revvity, 6066759) was added to each well. The assay plates were sealed and incubated at room temperature for 5 minutes with gentle shaking, followed by incubation for 30 minutes without shaking while protected from light. Luminescence was detected using a luminescence plate reader, such as Synergy 2 (BioTek). EC 50 values [pM] were calculated by non-linear curve fitting applying a four-parameter logistic model (Hill slope = 1.5, bottom response shared within each plate) using GraphPad Prism (GraphPad Software, Boston, MA, USA), or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA).

[0322] Procedure - Method B (hAMYR3) To perform the assay, hAMYR3 BHK Cre-Luc cells were thawed, washed once with PBS (Gibco 14190-094), and 4.0×10 3(4.0E+3) cells / well were seeded at a cell density. The plates were incubated overnight at 37 °C in 5% CO2. On the day of the assay, serial dilutions of the reference compound and the GLP-1 / GIP / amylin receptor triple agonist (7-fold dilutions, 7 concentrations per compound, and 1 well containing only assay buffer) were prepared in assay buffer in a 96-well plate. The serial dilutions were then mixed in a new 96-well plate with an equal volume (1:1:1 ratio) of assay buffer and either assay buffer with or without 3% HSA (Sigma, A-9511). 20 microliters of the solution mixture was transferred to the cells that had been pre-washed once with PBS (Gibco 14190-094). After a brief centrifugation, the assay plate was incubated at 37 °C in 5% CO 2 2 for 3 hours, equilibrated at room temperature for 10 minutes, and then 30 μL of steadylite plus™ (PerkinElmer / Revvity, 6066759) was added per well. The plate was sealed and incubated at room temperature for 30 minutes with gentle shaking while protected from light. Luminescence was detected using a luminescence plate reader, e.g., Synergy 2 (BioTek). EC 50 values [pM] were calculated by non-linear curve fitting applying a 4-parameter logistic model (Hill slope = 1.5, bottom response shared within each plate) using GraphPad Prism (GraphPad Software, Boston, MA, USA), or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA). [Table 9] [Table 10]

[0323] The results in Tables 7a and 7b indicate that reference compounds 4-7 are agonists or co-agonists for one or two of the GLP-1 receptor, GIP receptor, and amylin receptor (hAMYR3).

[0324] According to Table 7a, the activity data of reference compound 2 shows that linking the C-terminus of a potent GLP-1 / GIP co-agonist (tirzepatide) to the N-terminus of a potent amylin receptor agonist (cagrilintide) via a peptide linker does not result in a compound that is equally potent against these three receptors and necessarily functions as a GLP-1 / GIP / amylin receptor triple agonist (i.e., a compound according to the present invention). A comparison of reference compound 2 with reference compounds 5 (tirzepatide) and 6 (cagrilintide) illustrates this point. Reference compound 2 shows a significant loss of potency against the GLP-1 receptor and a further slight loss of potency against the amylin receptor when compared to the original compounds, reference compounds 5 (tirzepatide) and 6 (cagrilintide).

[0325] Reference compounds 1-3 show functional activation of all three receptors but are unbalanced triple agonists with an efficacy ratio (A / B) of 116-287 due to poor potency against all GLP-1 receptors.

Table 11-1

Table 11-2

Table 11-3

Table 12-1

Table 12-2

[0326] The results in Table 8a / b show that the compounds of the present invention exhibit potent functional activation of all three receptors, namely, the human GLP-1 receptor, the human GIP receptor, and the human amylin receptor (hAMYR3).

[0327] Most of the GLP-1 / GIP / amylin receptor triple agonists of the present invention have EC values comparable to those of the GIP, GLP-1, and amylin receptor agonists, as well as the GLP-1 / GIP co-agonist, disclosed herein as reference compounds 4-7, and activate different receptors. Furthermore, the GLP-1 / GIP / amylin receptor triple agonists of the present invention exhibit potent and balanced functional activation of all three receptors, as shown in Table 8a / b, and are balanced GLP-1 / GIP / amylin receptor triple agonists, in contrast to reference compounds 1, 2, and 3. 50 [Table 13] [Table 14] [Table 15-1] [Table 15-2] [Table 16-1] [Table 16-2]

[0328] Example 5: Experimental Protocol for an Efficacy Test on Appetite Using a Free-Feeding Rat Model Sprague Dawley (SD) rats from Taconic, Denmark were used in an acute food intake experiment following the principles of experimental animal management.

[0329] ​Rats had a normal body weight of 250 - 350 g at the start of the experiment. To acclimatize to the experimental setup, rats arrived at least 10 - 14 days before the start of the experiment. During this period, the animals were handled at least twice (fixed by restraint on the neck skin). Immediately upon arrival, the rats were changed to a reverse light cycle (dark from 11 am to 11 pm) and transferred to an automated food intake measurement system (HM2 system, MBRose; Faaborg, Denmark). The rats were allowed free access to solid feed (Altromin catalog number 1324, Brogaarden, Lynge, Denmark) and water and housed at room temperature (about 22 °C). To enable recording of individual food intake, rats were implanted with an ID chip. Three rats were housed in each cage. During the acclimation period for the rats to get used to the new light cycle and diet (LF 10% (D12450B), manufactured by Research Diets Inc.), the animals had free access to food and water. Since rats are normally active and consume most of their daily calories during the dark period, the rats were dosed in the morning just before lights out. Such a setup results in the lowest data variability and the highest test sensitivity. The triple-acting agent at each dose was tested in groups of 5 - 8 rats. A vehicle group of 6 - 8 rats was included in each set of the tests. Each cage contained animals from three different treatment groups (to rule out the possibility of a cage effect (e.g., cage malfunction) on food intake, the primary readout). The rats were dosed once subcutaneously (s.c.) with the peptide of interest at a body weight of 10 or 30 nmol / kg in vehicle (0.5 ml / kg) using a NovoPen® (Novo Nordisk, Bagsvaerd, Denmark).

[0330] The compounds of the present invention were formulated in the following vehicle: 8 mM phosphate, 250 mM glycerol, 0.007% polysorbate 20, pH 7.4 (20 or 60 nmol / ml).

[0331] After dosing, the rats were returned to their home cages where they had free access to solid feed and water. Food consumption was recorded individually and continuously by the HM2 system from 0 to 72 hours after administration of the test compound. The data acquired by the HM-2 system were stored in the HMBase SQL database (Firebird® relational database management system) and processed by HM2Lab software (MBRose; Faborg, Denmark) installed on an embedded computer. The feeding system is a high-sensitivity system with a load resolution of 0.001 g. In addition to recording food intake, this system records the number of feeding events defined as a 0.001 g decrease in food within 5 seconds (detailed information on the system can be found in Rathod, Y.D., and Di Fulvio, M. (2021). The feeding microstructure of male and female mice. PLoS One 16, e0246569). At the end of the experimental session, the animals were euthanized.

[0332] Table 11 shows the acute food intake in normal weight (lean) rats based on the above protocol for the efficacy test on appetite. These results enable the evaluation of the in vivo effect on food intake and provide an indicator of the duration of action of the compound. The data are presented as the mean inhibition rate relative to the mean food intake in the vehicle group on each test day (Day 1 [0 - 24 hours], Day 2 [24 - 48 hours], and Day 3 [48 - 72 hours]), and food intake was carried out in rats up to 72 hours. The food intake on each test day (e.g., Day 1) means the cumulative food intake during that day, i.e., over the course of that day (i.e., a 24-hour period).

Table 17-1

Table 17-2

[0333] As can be inferred from the data presented in Table 11, after dosing rats with a GLP-1 / GIP / amylin receptor triple agonist, many of them were observed to cause significant inhibition of food intake compared to vehicle treatment. Generally, the compounds in Table 11 showed a similar or improved reduction in food intake at doses much lower than the disclosed reference compound 1 dose level of 50 nmol / kg, compared to reference compound 1 disclosed in WO 2023 / 288313.

[0334] Example 6: Pharmacokinetic study in minipigs The purpose of this study was to determine the in vivo half-life (t 1 / 2 ) of the GLP-1 / GIP / amylin receptor triple agonists of the present invention after intravenous (i.v.) administration to minipigs, i.e., the residence time in the body and thus their duration of action. This was done in a pharmacokinetic (PK) study to determine the terminal-phase half-life (t 1 / 2 ) of the compound or derivative in question. The terminal-phase half-life means the time it takes to reduce a specific plasma concentration in the terminal elimination phase by half.

[0335] Study Female Göttingen minipigs were obtained from Ellegaard Göttingen Minipigs (Dalmose, Denmark) and those approximately 8 - 12 months old and approximately 20 - 30 kg in body weight were used in the study. The minipigs (pigs with permanent catheters) were individually housed in a hut with straw bedding and were fed Altromin 9023 minipig feed (Altromin Spezialfutter GmbH & Co. KG) once a day with restricted feeding.

[0336] After 3 weeks of acclimation, two permanent central venous catheters were implanted into the caudal vena cava of each animal. The animals were allowed to recover for at least 10 days after surgery and were then used in a repeated pharmacokinetic study with a suitable washout period during continuous dosing.

[0337] The compound of the present invention was formulated in the following vehicle: 8 mM phosphate, 250 mM glycerol, 0.007% polysorbate 20, pH 7.4 (40 nmol / ml).

[0338] Intravenous injection of the derivative (volume corresponding to a dose of 0.05 ml / kg and 2 nmol / kg / derivative) was given through one catheter, and blood samples were collected at predetermined time points up to 14 days after dosing (preferably from another catheter).

[0339] Blood samples (e.g., 1.3 ml) were collected into tubes coated with EDTA (1.6 mg of K 3 EDTA / K to obtain 1 ml of EDTA / blood 3 EDTA) in 1.3 ml tubes and then centrifuged at 4°C and 2000×g for 10 minutes.

[0340] Sampling and analysis Plasma was pipetted into Micronic tubes stored on dry ice within 30 minutes after centrifugation and then kept at -20°C until analyzed for the plasma concentration of the compound using LCMS.

[0341] The plasma concentration of the peptides of the present invention was assayed by plasma protein precipitation and analyzed by liquid chromatography-mass spectrometry (LC-MS). Standards were prepared by spiking blank plasma from minipigs with compounds in the typical range of 0.05 - 200 nM. The LLoQ was typically in the range of 0.2 - 2 nM. Standards, plasma blanks, or test samples were prepared for LC-MS by protein precipitation by adding 4 volumes of ethanol containing 20 nM internal standard (structurally similar analog with a different mass) to 1 volume of sample, followed by centrifugation at 6200 rpm for 10 minutes at 4°C. The supernatant was diluted with 1 volume of Milli-Q water containing 1% formic acid and then injected into the LC-MS system. Individual plasma concentration-time profiles were analyzed by non-compartmental pharmacokinetic method (NCA) in Phoenix v.6.4 (Pharsight Inc., Mountain View, CA, USA) and the resulting terminal-phase half-life (harmonic mean) was determined. LC-MS analysis was performed using a TurboFlow HPLC system from Thermo Fisher Scientific (Bremen, Germany) coupled to either a Q Exactive Orbitrap or Altis Triple Quadrupole (TQ) mass spectrometer. The LC mobile phase consisted of A: MQ water with 5% organic solvent (50% methanol / 50% acetonitrile) and 1% formic acid, and B: MQ water with 95% organic solvent (50% methanol / 50% acetonitrile) and 1% formic acid. A TurboFlow Cyclone 0.5×100 mm column from Thermo Fischer Scientific (Bremen, Germany) was used for extraction and then analytical elution was performed on an XBridge Peptide BEH C18 300Å, 3.5μm, 2.1×50 mm column, both of which were operated at 60°C. Typically, 40 - 45%B and 75 - 80%B were used for packing and elution of the TurboFlow column, respectively, followed by a typical linear gradient elution of about 45%B - 85%B over 2.33 minutes on the analytical column.The Orbitrap mass spectrometer was operated in positive ionization mode at a spray voltage of 4.0 kV using the Parallel Reaction Monitoring scan mode that uses a 5 m / z separation window at the most abundant charge state of the compound with a resolution of 35K on the Orbitrap MS. The TQ mass spectrometer was operated in positive ionization mode at a spray voltage of 4.0 kV using the Single Reaction Monitoring scan mode that uses Q1 and Q3 resolutions of 1.2 (FWHM).

[0342] For all compounds, the individual optimal fragmentation collision energies were found and used. The data were processed using the Quan browser in Thermo Fisher Scientific (Bremen, Germany) Xcalibur software by fitting the data to a linear calibration curve (weighting of 1 / x 2 ) used to calculate the concentration in plasma samples. Quality control samples were included. The deviation between the nominal and calculated concentrations in the standards and quality control samples was less than 15%.

[0343] Results:

Table 18

[0344] Example 7: Evaluation of Chemical Stability in Formulations Assays were performed to investigate the extent of in vitro chemical degradation over time when incubated at 37 °C for 2 weeks.

[0345] The peptide solution was prepared by dissolving the lyophilized powder in 8 mM phosphate buffer pH 7.4 to a target of 1 mg / mL. The pH of the peptide solution was adjusted to 7.4 with 0.02 M HCl or 0.02 M NaOH. The samples were filled into Agilent HPLC vials equipped with fixed inserts. The vials were capped to prevent evaporation. The HPLC vials were incubated at 37 °C, and the samples were collected at different time points over a two-week period, rapidly frozen at -80 °C, and stored at -20 °C until analysis.

[0346] Sample analysis was performed using UPLC combined with UV detection at 215 nm and MS (UPLC-UV-MS). 1 μL of the sample was injected into a Waters Acquity UPLC equipped with a flow-through needle injection system and onto a Waters Acquity CSH C18 column (1×150 mm) with a particle size of 1.7 μm, maintained at 55 °C. A flow rate of 100 μL / min was delivered by a binary solvent management pump with 0.1% formic acid in water as solvent A and 0.1% formic acid in acetonitrile as solvent B. Gradient elution was performed using 20% B from 0 - 2 min, followed by 20 - 50% B from 2 - 20 min over a total run time of 30 min. The peptide identity was confirmed by MS, and the peak purity, area %, from the UV signal at 215 nm was plotted against time, and the purity loss per week was calculated using the slope from linear regression (Table 13).

Table 19-1

Table 19-2

[0347] All GLP-1 / GIP / Amylin receptor triple agonists tested in this assay showed acceptable chemical stability with an acceptable degradation rate (less than 6% purity loss per week) in aqueous buffer (37 °C). Most of the GLP-1 / GIP / Amylin receptor triple agonists tested showed good chemical stability with a purity loss of less than 3.0% per week, or even better chemical stability (purity loss of less than 1.5% per week). Therefore, the GLP-1 / GIP / Amylin receptor triple agonists of the present invention are considered to be chemically stable in solution.

[0348] Example 8: Subchronic Treatment in Diet-Induced Obese (DIO) Rats The purpose of this example was to evaluate the in vivo effects of selected triple agonists on pharmacodynamic parameters such as body weight and food intake in diet-induced obese (DIO) mice. Animals were treated once daily by subcutaneous injection with a liquid formulation of the triple agonist being tested to evaluate the effects on body weight and food intake (daily and cumulative).

[0349] Diet-induced obese male Sprague Dawley rats were purchased from Charles River (Ecully, France). Rats were initially housed in pairs at room temperature on a 12-hour light:12-hour dark cycle with lights on at 0600 h and had free access to a 45% high-fat diet (D12451, Research Diets, Inc., NJ). Two weeks before the start of the study, rats were switched to a reverse light-dark cycle (12:12 h) with lights on from 21.00 to 09.00 h. Five days before the start of treatment, animals were weighed and MRI scanned (EchoMRI™, TX, USA) to obtain body composition data. Rats were divided into seven groups (n = 8) matched for body weight and fat mass (P>0.91 between groups for both body weight and fat mass tested by one-way analysis of variance followed by Tukey's multiple comparison test), and rats from the same group were not housed in pairs. Details of the groups are shown in Table 14 below. An age-matched normal-weight control group fed a standard chow diet (Altromin 1324, Altromin International) throughout life was included as a reference. At the start of the study, the mean body weight of the DIO rats was 958 ± 16.4 g (mean ± SEM). The mean body weight of the normal-weight controls was 796 ± 21.4 g (mean ± SEM). Body weight and daily food intake were collected by manual weighing (during the 4 days before the start of treatment, 0 to 1 h before lights out (pre-treatment / baseline phase)). Subsequently, rats were sham-handled to acclimatize them to the dosing procedure during treatment (restrained at the neck skin). The diet was changed daily between the baseline and treatment phases. The treatment phase was continued for 4 weeks (28 days) by daily subcutaneous injection (QD, subcutaneous) at a volume of 0.5 ml / kg.

[0350] The compounds of the present invention were formulated in the following vehicle: 8 mM phosphate, 250 mM glycerol, 0.007% polysorbate 20, pH 7.4 (at 0.6 nmol / ml, 2 nmol / ml, 6 nmol / ml, 12 nmol / ml, and 20 nmol / ml depending on the dose). Rats were dosed with NovoPen® (Novo Nordisk, Bagsvaerd, Denmark) immediately before weighing, 0 to 1 hour before the start of the dark phase. Two test compounds were titrated gradually towards a maintenance dose of either 3 nmol / kg or 10 nmol / kg as shown in Table 14.

Table 20

[0351] The results of this study are shown in Figures 1, 2, and 3, and Table 15. Table 15 shows the effects on cumulative food intake, absolute body weight, and relative body weight of DIO rats treated daily for up to 28 days with vehicle and compounds 52 or 77 of the present invention (3 nmol / kg and 10 nmol / kg respectively) according to the dose titration schedule shown in Table 14.

Table 21

[0352] The second column of Table 15 shows the cumulative food intake from days 0 to 28 of treatment (in kcal units). DIO rats received subcutaneous doses once daily according to the titration schedule described in Table 14. Data are shown as mean ± SEM, n = 6 - 8. These results are also shown in Figure 3. It can be seen that treatment with the GLP-1 / GIP / amylin receptor triple agonist compounds 52 and 77 induced a reduction in food intake.

[0353] The third column of Table 15 shows the absolute body weights (g) of rats dosed with vehicle, Compound 52, or Compound 77 (at 3 nmol / kg and 10 nmol / kg, respectively) on Day 0 and Day 28 of the treatment period. DIO rats received subcutaneous doses once daily according to the titration schedule described in Table 14. Data are shown as mean ± SEM, n = 6 - 8. The last column of Table 15 shows the percent (body weight %) of body weight on Day 0 in DIO rats during a 28-day treatment period using Compound 52 and 77 (at 3 nmol / kg and 10 nmol / kg, respectively). For example, a relative body weight of 80% on Day 28 means that the rat only has 80% of its body weight on Day 0, or in other words, the rat has lost 20% of its initial body weight (Day 0). DIO rats received subcutaneous doses once daily according to the titration schedule described in Table 14. Data are shown as mean ± SEM, n = 6 - 8. These results are also shown in Figure 1. It can be seen that treatment with the GLP-1 / GIP / Amylin receptor triple agonist compounds 52 and 77 induced weight reduction both absolutely and relatively.

[0354] From Table 15, it can be seen that treatment with the GLP-1 / GIP / Amylin receptor triple agonist compounds 52 and 77 induced a reduction in food intake that led to weight loss at all concentrations. Treatment with the GLP-1 / GIP / Amylin receptor triple agonist compounds 52 and 77 at the same concentrations (3 nmol / kg or 10 nmol / kg) induced an equivalent reduction in food intake that led to equivalent weight loss. The effects of food intake reduction and weight loss were concentration-dependent, with food intake reduction and weight loss being smaller at 3 nmol / kg and higher at 10 nmol / kg.

[0355] The present invention is not limited to the specific methodologies, protocols, and reagents described herein, which may vary without departing from the scope of the present disclosure. It should be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0356] The elements of the present invention have been described above. These elements have been enumerated using specific embodiments. However, it goes without saying that these embodiments may be combined in any manner and in any number to create additional embodiments that fall within the scope of the present disclosure. The various described examples and preferred embodiments should not be construed as limiting the present invention to only the explicitly described embodiments. This description is understood to support and encompass embodiments that combine the explicitly described embodiments with any number of disclosed elements and / or preferred elements. Further, unless otherwise indicated by the context, any permutation and combination of all the elements described in this application should be considered to be disclosed by the description of this application.

[0357] Documents cited throughout the text of this specification (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.) are hereby incorporated by reference in their entirety, regardless of whether above or below. Nothing in this specification should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.

[0358] Certain features of the present invention are illustrated and described herein, but many modifications, substitutions, changes, and equivalents will occur to those skilled in the art. Accordingly, it should be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the present invention.

Claims

1. A GLP-1 / GIP / amylin receptor triple agonist, Compound 52 【Chemistry 1】 or Compound 55 【Chemistry 2】 or Compound 58 【Chemistry 3】 or Compound 68 【Chemistry 4】 or Compound 77 【Chemistry 5】 or Compound 101 【Chemistry 6】 A GLP-1 / GIP / amylin receptor triple agonist.

2. Compound 52 【Chemistry 7】 2. The GLP-1 / GIP / amylin receptor triple agonist of claim 1,

3. Compound 68 【Chemistry 8】 2. The GLP-1 / GIP / amylin receptor triple agonist of claim 1,

4. Compound 77 【Chemistry 9】 2. The GLP-1 / GIP / amylin receptor triple agonist of claim 1,

5. A pharmaceutical composition comprising a GLP-1 / GIP / amylin receptor triple agonist according to any one of claims 1 to 4, and one or more pharma- ceutically acceptable excipients.

6. A pharmaceutical composition according to claim 5 for use as a medicament.

7. 6. The pharmaceutical composition of claim 5, for use in treating a subject with an initial body mass index (BMI) of 25 or greater, 27 or greater, or 28 or greater, or 30 or greater, optionally in the presence of at least one weight-related comorbidity.

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