Triple agonists for GLP-1, GIP, and amyrin receptors, and their use

Abstract

The problem that the present invention aims to solve is to provide a more effective pharmaceutical agent that is potent in vitro and effective in reducing body weight, while simultaneously not causing a proportionally increased level of side effects, possessing improved pharmacokinetic properties, improved chemical stability, and being suitable for once-weekly administration in humans and / or oral administration. [Solution] The present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist having a balanced potency ratio across all three receptors and / or improved pharmacokinetic properties. The present invention also relates to pharmaceutical compositions comprising such a GLP-1 / GIP / amyrin receptor triple agonist, as well as their use as pharmaceuticals for the treatment of subjects having overweight, obesity, and associated comorbidities.

Description

[Technical Field]

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

[0002] Overweight and obesity are abnormal or excessive accumulations of body fat that pose a risk to an individual's overall health. The WHO considers Body Mass Index (BMI) to be the most convenient population-level measure of overweight and obesity. In adults, a BMI of 25 or higher is considered overweight, and a BMI of 30 or higher is considered obese. Obesity is further subdivided 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 for numerous serious medical conditions, including type 2 diabetes and its associated complications, as well as cardiovascular diseases such as heart disease and stroke, which are leading causes of death worldwide. Obesity is now recognized by the World Health Organization (WHO) as a problem that is spreading to the point of being prevalent among children. In 2016, 1.9 billion adults worldwide were reported to be obese, and in 2019, 38.3 million children under the age of five worldwide were reported to be obese. According to the WHO, 422 million people worldwide have diabetes, and 1.6 million deaths each year are directly attributable to diabetes. Therefore, there is a strong motivation, both for individuals and for society, to prevent and / or treat obesity.

[0004] When lifestyle modifications such as diet and exercise alone are insufficient to reduce the BMI of individuals living with obesity to an acceptable level, treatment with medications such as liraglutide, orlistat, and naltrexone-bupropion has been shown to induce some weight loss. Nevertheless, these weight losses are often not sustained and are too small for individuals with class II and class III obesity. In these cases, bariatric surgery has proven necessary. While bariatric surgery is currently the most effective treatment for achieving long-term weight loss, it is an invasive procedure that carries high risks and high costs for the patient. Therefore, effective and minimally invasive treatments 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 primarily by dipeptidyl peptidase-4 (DPP-4), resulting in a half-life of <2 minutes.

[0006] Several commercially available products containing long-acting GLP-1 receptor agonists as active ingredients 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 GLP-1 receptor agonists as active ingredients, liraglutide (Saxenda®) and semaglutide (Wegovy®), are approved for use in individuals living with overweight and at least one weight-related comorbidity, or in individuals living with obesity. The maximum efficacy achievable with GLP-1 receptor agonists is limited by tolerability. Side effects such as nausea and vomiting become increasingly pronounced with increasing doses.

[0008] Natural human GIP is a 42-amino acid polypeptide synthesized and secreted by specialized enteroendocrine K cells. These cells are mainly concentrated in the duodenum and proximal jejunum, but can also be found throughout the intestines. The main stimulant of GIP secretion is the intake of a carbohydrate and lipid-rich diet. After intake, circulating plasma GIP levels increase 10 to 20 times. Like GLP-1, GIP is an incretin hormone and appears to be a more potent incretin than GLP-1 in healthy individuals. However, in individuals living with type 2 diabetes, GIP loses 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 sustained-release) GIP analogs have been shown to reduce body weight and improve glycemic control. Regarding weight loss, this effect is relatively less pronounced in rodent models compared to long-acting GLP-1 analogs (Mroz et al, Mol Metab, 2019, 20:51-62). Furthermore, GIP analogs induce weight loss through additive / synergistic effects with long-acting GLP-1 analogs in dual administration (Finan et al, Sci Transl Med, 2013, 5(209):209ra151; Norregaard et al, Diabetes Obes Metab, 2018, 20(1):60-68), thus representing a favorable candidate for amplifying GLP-1-based pharmacological effects. As demonstrated in preclinical animal models, GIPR agonism can also be included as a monomolecule co-agonist partner to GLP-1 receptor agonism to amplify the weight loss and glycemic control improvements induced by GLP-1 (Finan et al, Sci Transl Med, 2013, 5(209):209ra151; Coskun et al, Mol Metab, 2018, 18:3-14). Two different peptides with high potency against both GLP-1R and GIPR (MAR709 and LY3298176, the latter known as tilzepatide) have been tested in multi-dose clinical trials. Clinical results demonstrated improvements in glycemic control and body weight that surpassed those achieved by equivalent administration of benchmark GLP-1 specific agonists (Frias et al, Cell Metab, 2017, 26(2):343-352; Frias et al, Lancet, 2018, 392(10160):2180-2193), demonstrating the translational aspects and therapeutic benefits of co-targeting of GLP-1 receptors and GIP receptors.

[0010] The compound tirzepatide was approved in 2022 for the treatment of diabetes, demonstrating the recent concept of co-targeting of GLP-1 and GIP receptors using GLP-1 / GIP co-agonists. Furthermore, tirzepatide is also useful in treating obesity, as a Phase III clinical trial showed that high doses of tirzepatide (15 mg) helped patients lose 20.9% (mean) of body weight after 72 weeks of treatment, including a 20-week dose escalation period (AM Jastreboff, LJ Aronne, NN Ahmad, et al., N Engl J Med 2022;387:205-216). Tirzepatide has also recently been approved for weight management in individuals with a BMI > 30 or BMI > 27 and at least one weight-related comorbidity (trade name: Zepbound®).

[0011] Aside from tilzepatide, which is described in WO2016 / 111971A1, GLP-1 / GIP synergists and their potential medical uses are described in several patent applications, including WO2006 / 086769, WO2010 / 011439, WO2013 / 164483, WO2014 / 192284, WO2015 / 067715, WO2015 / 022420, WO2015 / 086728, WO2015 / 086729, WO2016 / 111971, WO2020 / 023386, US2014 / 162945, US2014 / 357552, and WO2022 / 018186.

[0012] Amylin is a 37-amino acid polypeptide hormone produced in pancreatic beta (β) cells and secreted there simultaneously with insulin. Amylin has a half-life of 15-20 minutes. It acts primarily through amylin receptors 1-3 (AMYR1-3), exerting 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, inducing satiety, and suppressing appetite. Other effects of amylin on the cardiovascular system and bones have also been reported.

[0013] Clinical studies have shown that amyrin receptor agonists may be useful in treating overweight, obesity, type 1 diabetes, and / or type 2 diabetes. Currently, one product (Symlin®) containing an amyrin receptor agonist (pramlyntide acetate) as the active ingredient is marketed. Symlin®, a liquid pharmaceutical composition for subcutaneous administration, is approved for use in patients with type 1 or 2 diabetes who are using basal and mealtime insulin and, despite optimal insulin therapy, are unable to achieve desired glycemic control. Pramlyntide has also been investigated for use in people living with overweight and obesity. Pramlyntide has a short half-life (less than 1 hour) and requires administration three times daily. As a result, there is a large diurnal variation in pramlyntide plasma levels.

[0014] There is a similar desire to extend the action of amyrin, and co-targeting of amyrin receptors and GLP-1 receptors has been described. Amyrin receptor agonists and their potential medical uses have been described in several patent applications, such as WO2012 / 168432, WO2016 / 034604, WO2022 / 129254, WO2022 / 063925, or US2022 / 0288168.

[0015] A fixed-dose combination of the amyrin receptor agonist caglilintide and the GLP-1 receptor agonist semaglutide is currently under investigation for the treatment of overweight and obesity (Lancet 2021;397:1736-48). The drug product under investigation is a separate liquid pharmaceutical composition for subcutaneous use. Clinical trials have demonstrated that the caglilintide and semaglutide combination induced greater weight loss than the maximum approved dose of semaglutide monotherapy in people living with obesity. No worsening of the side effect profile was observed. Co-agonists of the GLP-1 receptor and amyrin receptor, as well as their potential medical uses, are described in several patent applications, such as WO2022 / 129526A1. Among these, peptide co-agonists of the human GLP-1R receptor and amyrin receptor are disclosed that are potent, balanced, i.e., have similar levels of activation of both receptor systems, and exhibit oral bioavailability. Another example is WO2007 / 022123, which describes a hybrid polypeptide containing exendin covalently bound to amyrin. However, no GLP-1 receptor and amyrin receptor co-agonists have received market approval to date.

[0016] Finally, WO2023 / 288313 and WO2024 / 015922 disclose multi-agonist peptides useful as agents for the treatment and prevention of metabolic diseases and disorders, particularly diabetes and obesity. WO2023 / 288313 discloses peptides comprising two or more component peptides, including amyrin, GIP, GLP-1, and / or calcitonin. Specifically disclosed peptides are triple-agonists of the GLP-1 receptor, GIP receptor, and amyrin receptor, exhibiting activity against all three receptors and reducing food intake and body weight in animals.

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

[0018] The present invention relates to a GLP - 1 / GIP / Amylin receptor triple agonist, a peptide according to formula I: Z1 - L1 - Z2 (I) (wherein Z1 is a peptide GLP - 1 / GIP receptor co - agonist, L1 is a peptide linker, and Z2 is a peptide amylin receptor agonist), and the peptide according to formula (I) contains one lysine (Lys, K) and relates to a GLP - 1 / GIP receptor co - agonist.

[0019] In one aspect, the present invention relates to a GLP - 1 / GIP / Amylin receptor triple agonist, a peptide according to formula I: Z1 - L1 - Z2 (I) where the peptide contains one lysine (Lys, K) residue, and wherein: Z1 is an amino acid sequence according to formula III (SEQ ID NO: 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (wherein, X2 represents Aib, X 12 represents Ile (I) or Lys (K), X20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72This relates to a GLP-1 / GIP / amyrin receptor triple agonist, which is a peptide containing a C-terminal amide comprising Leu(L) or Glu(E).

[0020] In some embodiments of peptide Z1, X2 is Aib, and X 12 is Ile(I) or Lys(K), and X 20 is Arg(R), and X 24 is Glu(E), and X 27 is Leu(L) or Ile(I), X 28 Ala(A) and X 30 is Gly(G) or Ala(A), X 31 It is Gly(G), Ala(A), or Pro(P), and X 33 is Ser(S), and X 34 It is Gly(G).

[0021] In some embodiments of peptide Z2, X 52 is Ser(S), and X 53 is Glu(E) or His(H), and X 58 is Ala(A) or Gln(Q), and X 59 is Leu(L) or Thr(T), X 60 is Gly(G) or Gln(Q), and X 68 is Gln(Q), Glu(E), or Lys(K), and X 72 It is Leu(L).

[0022] In some embodiments, the GLP-1 / GIP / amyrin receptor triple agonist is YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAQLGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 230), or YX2EGTFTSDYSILLEEIAAREFIEWLLAGGASSGAGEAPGEAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 243), or YX2EGTFTSDYSKLLEEIA AREFIEWLLAGGPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (Sequence ID 244), or YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (Sequence ID 246), or YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence ID 250), or YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGGSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence ID 251), or An amino acid sequence containing or consisting of YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence ID 252), where each X2 is Aib.

[0023] In some embodiments, the GLP-1 / GIP / amyrin receptor triple agonist is, for example, at position 12 of Z1 (X 12 ) or 18th place in Z2 (X 68 It includes an extension portion that increases the half-life of peptide Z1-L1-Z2, which is bound via lysine residues of ).

[0024] In a second aspect, the present invention further relates to a pharmaceutical composition comprising such a GLP-1 / GIP / amyrin receptor triple agonist and one or more pharmaceutically acceptable excipients, and in particular to the medical use of the triple agonist for use in the treatment of subjects whose initial BMI is 27 or greater, for example 30 or greater, in the presence of at least one weight-related comorbidity, which is optional.

[0025] In a third aspect, the present invention relates to a balanced GLP-1 / GIP / amyrin receptor triple agonist capable of selectively activating or "acting" all three of the GLP-1 receptor, GIP receptor, and amyrin receptor to similar levels.

[0026] Alternatively, in a fourth aspect, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist having improved pharmacokinetic properties.

[0027] Alternatively, in a fifth aspect, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist suitable for once-weekly administration.

[0028] Alternatively, in a sixth aspect, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist preferred for oral administration.

[0029] Alternatively, in a seventh aspect, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist that reduces food intake.

[0030] Alternatively, in an eighth aspect, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist having improved chemical stability. The present invention can also solve further problems that become apparent from the disclosure of exemplary embodiments and aspects. [Modes for carrying out the invention]

[0031] The present invention is a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Z1-L1-Z2(I) This invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising (wherein Z1 is a peptide GLP-1 / GIP receptor co-agonist, L1 is a peptide linker, and Z2 is a peptide amyrin receptor agonist), wherein the peptide following formula (I) contains one lysine molecule (Lys, K).

[0032] The compounds disclosed herein are referred to as "GLP-1 / GIP / amyrin receptor tri-agonists," "GLP-1 receptor-GIP receptor-amyrin receptor tri-agonists," or "GLP-1 / GIP / amyrin receptor triple agonists."

[0033] The GLP-1 / GIP / amyrin receptor triple agonist comprises peptide Z1, a GLP-1 / GIP receptor co-agonist, peptide linker L1, and peptide Z2, an amyrin receptor agonist. The GLP-1 / GIP / amyrin receptor triple agonist is a compound capable of binding to each of the three GLP-1, GIP, and amyrin receptors, activating each receptor GLP-1R, GIPR, and amyrin receptor, and thus eliciting a response at each receptor.

[0034] The compounds disclosed herein are agonists for the receptors GLP-1, GIP, and amyrin, respectively. Therefore, the compounds of the present invention are GLP-1 receptor agonists, GIP receptor agonists, and amyrin receptor agonists. It is possible to activate or “actuate” all three receptors—GLP-1, GIP, and amyrin—and it is a “GLP-1 / GIP / amyrin receptor triple agonist.” A GLP-1 / GIP / amyrin receptor triple agonist may provide similar levels of activation for all three receptors—GLP-1, GIP, and amyrin—and this is then referred to as a “balanced GLP-1 / GIP / amyrin receptor triple agonist,” or simply a “balanced triple agonist.”

[0035] A "receptor agonist" or "agonist" can be defined as a ligand, such as a compound, that binds to a biological receptor and activates it, thereby producing a biological response. A full agonist can be defined as one that elicits a response of the same magnitude as that of a natural ligand (see, for example, "Principles of Biochemistry," AL Lehninger, DL Nelson, MM Cox, Second Edition, Worth Publishers, 1993, page 763). Receptors can be activated by either endogenous agonists, such as endogenous hormones, or exogenous agonists, such as pharmaceuticals.

[0036] 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 to produce a biological response characteristic of its 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 to produce a biological response characteristic of its native ligand.

[0037] 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 natural glucagon-like peptide 1 (GLP-1). Semaglutide, disclosed in Example 4 of WO2006 / 097537, is an example of an exogenous GLP-1 receptor agonist.

[0038] 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 the innate glucose-dependent insulinotropic polypeptide (GIP).

[0039] A "GLP-1 / GIP receptor co-agonist" can be defined as a compound that can bind to both the GLP-1 receptor and the GIP receptor, and can activate both receptors. An example of a GLP-1 / GIP co-agonist is tilzepatide, described in WO2016 / 111971.

[0040] An “amyrin receptor agonist” can be defined as a compound capable of binding to and activating the amyrin receptor (AMYR) and the calcitonin receptor (CTR). The amyrin receptor consists of two components, namely the calcitonin receptor (CTR) and a heterodimer of one of three receptor activity-modifying proteins (RAMP1-3), resulting in three possible complexes, AMYR1-3. Unless otherwise specified herein, “amyrin receptor” refers to at least amyrin receptor 3 (AMYR3). Nevertheless, some co-activation to other receptors may be expected. A “complete” amyrin receptor agonist can be defined as an amyrin receptor agonist capable of eliciting an amyrin receptor response on a scale similar to that of natural amyrin. Amyrin receptor agonists are often also calcitonin receptor agonists. Examples of amyrin receptor agonists are human amyrin, pramlintide, and kaglilintide (disclosed in WO2012 / 168432). It should be noted that all headings and subheadings in this specification are for convenience only and should not be construed as limiting the invention.

[0041] The use of any examples or illustrative phrases provided herein (e.g., "such as") is intended solely to clarify the invention and, unless otherwise requested, does not limit the scope of the invention.

[0042] Certain terms are first defined so that the present invention may be more easily understood. In the following, 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.

[0043] Unless otherwise specified herein, terms presented in the singular form generally include plural situations. The terms “a” or “an” are intended to mean “one or more.”

[0044] The term “comprise” when preceding an enumeration of processes or elements, as well as its variations such as “comprises” and “comprising,” is intended to mean that the addition of further processes or elements is optional and not excluded. As disclosed herein, non-restrictive terms such as “comprises” and “comprising” may be replaced with restrictive terms such as “consists of” and “consisting of.”

[0045] The term "approximately" is used herein to mean roughly, roughly, or around that. When the term "approximately" is used in conjunction with a numerical range, the range is modified by extending the boundaries above and below the stated number. Generally, the term "approximately" can be modified by 10 percent above or below (higher or lower) the stated value.

[0046] Amino acids are molecules that contain an amine group and a carboxylic acid group, as well as one or more additional groups, often called side chains, which are of a choice. The term "amino acid" includes standard amino acids (genetically encoded) and non-proteinogenic amino acids. Non-exclusive examples of non-proteinogenic amino acids include Aib (α-aminoisobutyric acid or 2-aminoisobutyric acid) and the D isomers of standard amino acids. In peptides for which optical isomers are not listed, all amino acid residues should be understood herein to mean the L isomer unless otherwise specified.

[0047] In this specification, “amino acid substitution” or “substitution” refers to one or more amino acids that are replaced by an equal number of amino acids in the peptide backbone. Substitutions may, but are not limited to, conservative substitutions. For example, amino acids may be substituted with amino acids having similar biochemical properties; for example, a basic amino acid may be substituted with another basic amino acid (e.g., lysine to arginine); an acidic amino acid may be substituted with another acidic amino acid (e.g., glutamic acid to aspartic acid); a neutral amino acid may be substituted with another neutral amino acid (e.g., threonine to serine); a charged amino acid may be substituted with another charged amino acid (e.g., glutamic acid to lysine); a hydrophilic amino acid may be substituted with another hydrophilic amino acid (e.g., asparagine to glutamine); a hydrophobic amino acid may be substituted with another hydrophobic amino acid (e.g., alanine to valine); a polar amino acid may be substituted with another polar amino acid (e.g., serine to threonine); an aromatic amino acid may be substituted with another aromatic amino acid (e.g., phenylalanine to tryptophan); and an aliphatic amino acid may be substituted with another aliphatic amino acid (e.g., leucine to isoleucine).

[0048] As used herein, the term “excipient” broadly refers to any component other than the active pharmaceutical ingredient (API).

[0049] The terms “identity” or “sequence identity” known in the art refer to the relationship between sequences of two or more polypeptides, determined by comparing their sequences. In the art, “identity” also means the degree of sequence relevance between polypeptides, determined by the number of matches between strings of two or more amino acid residues. “Identity” measures the percentage of perfect matches between the smaller of two or more sequences that have gap alignments (if any) addressed 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 expansion, respectively; or, for example, by (I) comparing two optimally aligned sequences across a comparison window (e.g., the length of the longer sequence, the length of the shorter sequence, a specified window); (2) determining the number of positions containing identical monomers (e.g., the same amino acid occurring in both sequences) to obtain the number of matched positions; (3) dividing the number of matched 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 obtain the “sequence identity” rate. For example, if both peptides A and B are 20 amino acids long and have identical amino acids except for one position, then peptides A and B have 95% sequence identity.

[0050] As used herein, the terms “polypeptide” or “peptide” refer to a single chain of amino acids linked by one or more amide (or peptide) bonds, including oligopeptides. The terms “polypeptide” and “peptide” are to be used interchangeably herein.

[0051] As used herein, the terms “half-life” or “plasma half-life” refer to the time required for half the amount of a substance administered to an individual to be metabolized or eliminated from that individual’s serum or plasma by normal biological processes.

[0052] As used herein, the term “treatment” or any variation thereof refers to a medical therapy for any human subject in need of treatment. This term includes administering a therapeutically effective amount of the peptides disclosed herein sufficient to reduce or eliminate at least one symptom of the disorder in question. However, “treatment” does not necessarily have to be curative. The timing and purpose of such treatment may vary from individual to individual, depending on the subject’s current health status. Thus, such treatment may be prophylactic, palliative, symptomatic, and / or curative. With respect to the present invention, prophylactic, palliative, symptomatic, and / or curative treatments may represent distinct embodiments of the invention.

[0053] As used herein, the terms “prevent,” “prevent,” or “prevent,” or variations thereof, mean protecting a person from the onset of at least one symptom of a disease or reducing the severity of a symptom of a disability.

[0054] The term “compound” is used herein to refer to a molecular entity, and therefore a “compound” may have different structural elements in addition to the minimum elements defined for each compound or group of compounds. A compound can be a peptide or a derivative thereof, insofar as it contains the defined structural and / or functional elements. The term “compound” is also intended to encompass its pharmaceutically relevant forms, i.e., the compound as defined herein, or its pharmaceutically acceptable salts, amides, or esters.

[0055] The compounds disclosed herein may be potent GLP-1 receptor agonists.

[0056] The compounds disclosed herein may be potent GIP receptor agonists.

[0057] The compounds disclosed herein may be potent amyrin receptor agonists.

[0058] The in vitro potency of the 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 logarithmic concentration and the effect of the compound is established. Furthermore, the response should be variable from 0 to 100%. The potency of a compound is its EC (effective concentration) 50 It can be explained using values. EC 50 This represents the concentration of the compound at which 50% of its maximum effect is observed in the assay, as described, for example, in Example 4. EC 50 The lower the value, the more potent the compound.

[0059] The compounds disclosed herein may provide similar levels of activation to all three GLP-1 receptors, GIP receptors, and amyrin receptors, i.e., they may be “balanced,” and may be referred to as “balanced GLP-1 / GIP / amyrin receptor triple agonists,” or simply “balanced triple agonists.” Relatively “balanced” receptor activation is favored because the relative ratio of the GLP-1, GIP, and amyrin receptor agonist activities of the compounds is locked in the molecule, and it is impossible to titrate the three receptor agonists against each other. Ultimately, if the molecule is “balanced,” it can be administered so that all three hormonal systems are activated without the side effects outweighing the benefits.

[0060] Minimum effectiveness (i.e., the highest number of ECs) 50 The potency (A) of receptors with a value is defined as the highest potency (i.e., the lowest number of ECs). 50A triple agonist having a potency ratio (A / B) of less than 50, preferably less than 30, obtained by dividing the potency (B) of the receptor having a specific value (C) is defined as a "balanced triple agonist" or "balanced GLP-1 / GIP / amyrin receptor triple agonist" (based on assays in the absence of human serum albumin (HSA), as shown in Tables 19 and 20 of Example 4). For example, compound 183 has an EC of 14.7 pM against the GLP-1 receptor. 50 , 2.17 pM EC against the GIP receptor 50 , and 7.08 pM EC2 against the amyrin receptor 50 It has the following properties. Therefore, it has the lowest potency against hGLP-1, with (A) corresponding to 14.7 pM, and the highest potency against the GIP receptor, with (B) corresponding to 2.17 pM. Thus, the potency ratio (A / B) is equal to 7 (appropriately rounded) obtained by dividing 14.7 pM (A) by 2.17 pM (B), which means that compound 183 is a "balanced triple agonist".

[0061] A compound that is potent against one receptor but much weaker against another can be "unbalanced." Such an "unbalanced triple agonist" is defined as a compound having a potency ratio (A / B) of 50 or more, or a potency ratio (A / B) of 30 or more. For example, reference compound 1 has a potency ratio (A / B) of 256 (i.e., 1680 pM (=A) divided by 6.55 pM (=B), appropriately rounded). For example, this reference compound is potent against the amyrin receptor (i.e., EC 50 The value is <30 pM), and it is weak against the GIP receptor (i.e., EC 50 (Value 221 pM), even weaker against the GLP-1 receptor (i.e., EC 50 (Value 1680 pM), it is impossible to achieve optimal efficacy from all three hormonal systems.

[0062] GLP-1 / GIP receptor co-agonist - Z1 peptide The present invention relates to a peptide according to formula I, which includes peptide Z1, a GLP-1 / GIP receptor co-agonist.

[0063] In one embodiment, the GLP-1 / GIP receptor co-agonist Z1 is derived from formula II (SEQ ID NO: 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) This peptide has up to 5 amino acid substitutions relative to the formula (where the amino acid at position X2 is Aib).

[0064] In one embodiment, the GLP-1 / GIP receptor co-agonist has an amino acid sequence according to formula (III) (SEQ ID NO: 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), preferably Arg(R). X 24 This represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E). X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), preferably Ala(A). X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly(G), Gln(Q), Ala(A), or Pro(P), preferably Pro(P) or Ala(A). X 33 This represents Glu(E) or Ser(S), preferably Ser(S). X 34This is a peptide containing or consisting of Gly(G) or Glu(E), preferably representing Gly(G).

[0065] In some embodiments, peptide Z1 disclosed herein may have up to five amino acid substitutions relative to formula II (SEQ ID NO: 1), the substitutions may occur at any of positions 1 through 34, preferably at positions 12, 17, 20, 24, 27, 28, 30, 31, 33, and / or 34, and more preferably at positions 12, 17, 27, 30, 31, and / or 33. The present invention encompasses variants of GLP-1 / GIP / amyrin receptor triple agonists disclosed herein, wherein peptide Z1 may contain one, two, three, four, or five amino acid substitutions relative to formula II (SEQ ID NO: 1).

[0066] Preferred substitutions include conservative substitutions in which an amino acid having similar biochemical properties or a structural analogue of the amino acid residue is included in place of an amino acid residue appearing in the sequence.

[0067] In one embodiment, the Z1 peptide according to formula III has up to 5 substitutions relative to formula II (sequence number 1).

[0068] In one embodiment, the GLP-1 / GIP receptor co-agonist Z1 is given by formula (II) (SEQ ID NO: 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) A peptide having up to 5 substitutions relative to (wherein X2 is Aib), Z1 is an amino acid sequence that follows formula (III) (SEQ ID NO: 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (wherein X2 represents Aib, X 12 represents Ile (I) or Lys (K), X 20 represents Arg (R) or Gln (Q), preferably Arg (R), X 24 represents Ala (A), Glu (E), or Gln (Q), preferably Glu (E), X 27 represents Leu (L) or Ile (I), X 28 represents Ala (A) or Gln (Q), preferably Ala (A), X 30 represents Gly (G) or Ala (A), X 31 represents Gly (G), Gln (Q), Ala (A), or Pro (P), preferably Ala (A), Gly (G) or Pro (P), X 33 represents Glu (E) or Ser (S), preferably Ser (S), X 34 represents Gly (G) or Glu (E), preferably Gly (G)) comprises or consists of.

[0069] In one embodiment, the GLP-1 / GIP receptor co-agonist Z1 is a peptide having up to 4 substitutions with respect to formula (II) (SEQ ID NO: 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG (II) (wherein X2 is Aib) and is a peptide having up to 4 substitutions, Z1 has an amino acid sequence according to formula (VII) (SEQ ID NO: 162): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII) (wherein X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 34 This includes or consists of Gly (G) or Glu (E).

[0070] In one embodiment, the Z1 peptide has an amino acid sequence according to formula IV (SEQ ID NO: 169): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGX 30 X 31 SSG(IV) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 27 This represents Leu (L) or Ile (I), X 30 This represents Gly (G) or Ala (A), X 31 It contains or consists of Ala (A), Gly (G), or Pro (P).

[0071] In one embodiment, the Z1 peptide comprises or consists of a peptide having an amino acid sequence selected from the group consisting of sequences shown in [Table 1].

[0072] [Table 1]

[0073] In one embodiment, the Z1 peptide includes or consists of SEQ ID NO: 22. In one embodiment, the Z1 peptide includes or consists of SEQ ID NO: 29. In one embodiment, the Z1 peptide includes or consists of SEQ ID NO: 31. In one embodiment, the Z1 peptide includes or consists of SEQ ID NO: 34.

[0074] L1 Peptide Linker The GLP-1 / GIP / amyrin receptor triple agonist peptide skeletons according to Formula I disclosed herein include a peptide linker L1 which may contain 1 to 14 amino acid residues, particularly standard amino acid residues. The peptide linker may contain 1 to 10 amino acid residues, particularly standard amino acid residues, such as 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. Specifically, the peptide linker may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues, particularly standard amino acid residues.

[0075] Peptide linker L1 is given by formula VIIIa: X 141 X 142 X 143 X 144 X 145 X 146 X 147 X 148 X 149 X 150 X 151 X 152 X 153 X 154 (VIIIa) (In the formula, X 141~154 X is independently selected from any naturally occurring or standard amino acid residues. 142~154 One of these can be represented by (which does not exist).

[0076] The GLP-1 / GIP / amyrin receptor triple agonist peptide skeleton disclosed herein comprises a peptide linker L1, which comprises or consists of an amino acid sequence according to formula VIIIa. Therefore, the GLP-1 / GIP / amyrin receptor triple agonist may comprise or consist of a peptide according to the amino acid sequence of SEQ ID NO: 5.

[0077] X 141~154 One of these can be selected from any non-aromatic amino acid residue. 141~154 One of these may be a charged amino acid. 141~154 One of these may be a polar amino acid. 141~154 One of these may be a hydrophobic amino acid.

[0078] X 141~154 Any of these can 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 141~154 One of these 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).

[0079] In one embodiment, the peptide linker L1 may be represented by formula VIIIa or an amino acid sequence according to formula IV: X 141 X 142 X 143 X 144 X 145 X 146 X 147 X 148 X 149 X 150 X 151 X 152 X 153 X 154(VIIIa) (In the formula, X 141 These represent Ala (A), Glu (E), and Gly (G), X 142 This represents Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), or does not exist. X 143 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Pro(P), or does not exist. X 144 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Pro(P), or does not exist. X 145 This represents Glu(E), Gly(G), Pro(P), Ser(S), Thr(T), or does not exist. X 146 This represents Glu(E), Gly(G), Leu(L), Gln(Q), or does not exist. X 147 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Phe(F), or does not exist. X 148 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Thr(T), Pro(P), Val(V), or does not exist. X 149 This represents Glu(E), Asn(N), Pro(P), Thr(T), or does not exist. X 150 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), Val(V), or does not exist. X 151 This represents Ala(A), or does not exist. X 152 This represents Gln(Q), or does not exist. X 153 This represents Thr(T), or does not exist. X 154 This represents Leu(L), or contains or consists of Leu(L) (or does not exist).

[0080] In one embodiment, the peptide linker L1 contains or consists of 1 to 10 amino acid residues, and is based on formula VIII: X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII) (In the formula, X 41~50 X is independently selected from any naturally occurring or standard amino acid residues. 42~50 One of these can be represented by (which does not exist).

[0081] The GLP-1 / GIP / amyrin receptor triple agonist peptide skeleton disclosed herein comprises a peptide linker L1, which comprises or consists of an amino acid sequence according to formula VIII. Thus, the GLP-1 / GIP / amyrin receptor triple agonist may comprise or consist of a peptide according to the amino acid sequence of SEQ ID NO: 10.

[0082] X 41~50 One of these can be selected from any non-aromatic amino acid residue. 41~50 One of these may be a charged amino acid. 41~50 One of these may be a polar amino acid. 41~50 One of these may be a hydrophobic amino acid.

[0083] X 41~50 Any of these can be independently selected from the group consisting of alanine (Ala, A), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), leucine (Leu, L), proline (Pro, P), serine (Ser, S), and valine (Val, V). Preferably, X 41~50One of these may be selected from the group consisting of alanine (Ala, A), glutamic acid (Glu, E), glycine (Gly, G), and proline (Pro, P).

[0084] In one embodiment, the peptide linker L1 may be represented by formula VIII, or an amino acid sequence according to formula VIII: X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII) (In the formula, X 41 This represents Ala (A), Glu (E), or Gly (G), X 42 This represents Glu(E), Gly(G), or does not exist. X 43 This represents Glu(E), Gly(G), Gln(Q), or does not exist. X 44 This represents Ala(A), Glu(E), Gly(G), or does not exist. X 45 This represents Glu(E), Gly(G), Pro(P), or does not exist. X 46 This represents Glu(E), Gly(G), or does not exist. X 47 This represents Gln(Q), Glu(E), or does not exist. X 48 This represents Ala(A), Glu(E), or does not exist. X 49 This represents Glu(E), Pro(P), or does not exist. X 50 This includes or consists of Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), and Val(V), or they do not exist.

[0085] In one embodiment, the peptide linker L1 may be represented by formula VIII, or an amino acid sequence according to formula VIII: X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII) (In the formula, X 41 This represents Ala (A) or Glu (E), X 42 This represents Glu(E), Gly(G), or does not exist. X 43 This represents Glu(E), Gly(G), Gln(Q), or does not exist. X 44 This represents Ala(A), Glu(E), Gly(G), or does not exist. X 45 This represents Glu(E), Gly(G), Pro(P), or does not exist. X 46 This represents Glu(E), Gly(G), or does not exist. X 47 This represents Gln(Q), Glu(E), or does not exist. X 48 This represents Ala(A), Glu(E), or does not exist. X 49 This represents Glu(E), Pro(P), or does not exist. X 50 This includes or consists of Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(s), and Val(V) (or does not exist).

[0086] In one embodiment, peptide linker L1 may be any one of the peptide linkers represented by SEQ ID NOs: 125-159. Peptide linker L1 may be any one of the peptide linkers listed in Table 2.

[0087] [Table 2-1] [Table 2-2]

[0088] In one embodiment, peptide linker L1 is A, E, G, AE, GE, AG, AGGGG (SEQ ID NO: 142), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), 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: 147), AGQAPGQAPV (SEQ ID NO: 147), AGQAPGQAPV (SEQ ID NO: 147), AGQAPGQAPP (SEQ ID NO: 148P (SEQ ID NO: 147), AGQAPGQAPP (SEQ ID NO: 148), AGQAPGQAPP (SEQ ID NO: 147), AGQAPGQAPP (SEQ ID NO: 148), AGQAPGQAPP (SEQ ID NO: 147), The following can be selected from the group consisting of (sequence number 149), EGQAPGQAPG (sequence number 150), AGQEPGQAPG (sequence number 151), AGQAEGQAPG (sequence number 152), AGQAPEQAPG (sequence number 153), AGQAPGEAPG (sequence number 154), AGQAPGQEPG (sequence number 155), AGQAPGQAEG (sequence number 156), AGQEPGQEPG (sequence number 157), AGQAPGQAP (sequence number 158), and AGQAPGEAPL (sequence number 159).

[0089] In one embodiment, peptide linker L1 is E, AE, AG, AGGGG (SEQ ID NO: 142), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), 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: 146) 49) The group may be selected from the following: 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).

[0090] In a preferred embodiment, the peptide linker L1 may be AG or AGEAPGEAPG (SEQ ID NO: 144).

[0091] In one embodiment, linker L1 contains or consists of 1 to 10 amino acid residues. In a preferred embodiment, the linker contains or consists of 1, 2, 5, 9, or 10 amino acid residues, more preferably 2 or 10 amino acid residues.

[0092] Amyrin receptor agonist - Z2 peptide The present invention relates to a peptide according to formula I, which includes peptide Z2, an amyrin receptor agonist.

[0093] In one embodiment, the amyrin receptor agonist Z2 is a C-terminal amide, and is defined by formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP(V) has up to 10 amino acid substitutions.

[0094] In one embodiment, the amyrin receptor agonist has an amino acid sequence according to formula VI (SEQ ID NO: 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This is a peptide containing or consisting of Leu(L) or Glu(E).

[0095] In one embodiment, the amyrin receptor agonist Z2 is a C-terminal amide, and is defined by formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP(V) has up to 10 amino acid substitutions, Z2 follows the amino acid sequence of formula XVI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This includes or consists of Leu (L) or Glu (E).

[0096] Z2 is the C-terminal amide, and its amino acid sequence follows formula IX (SEQ ID NO: 61): ASX 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATLPRTETGSGSP(IX) (In the formula, X 53 This represents Glu (E) or His (H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Gly(G) or Gln(Q), X 68 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting thereof (wherein represents Gln(Q), Glu(E), or Lys(K)).

[0097] Peptide Z2 disclosed herein may have up to 10 amino acid substitutions relative to formula V (SEQ ID NO: 2), the substitutions may occur at any of positions 1 through 32, preferably at positions 2, 3, 7, 8, 9, 10, 15, 18, 20, 21, 22, 24, and / or 31, and more preferably at positions 3, 8, 9, 10, and / or 18. The present invention encompasses variants of GLP-1 / GIP / amyrin receptor triple agonists disclosed herein, wherein peptide Z2 may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions relative to formula V (SEQ ID NO: 2). Preferred substitutions include the conservative substitutions described above.

[0098] In one embodiment, the Z2 peptide is a C-terminal amide and comprises or consists of a peptide having an amino acid sequence selected from the group consisting of the following.

[0099] [Table 3]

[0100] In one embodiment, the Z2 peptide includes or consists of SEQ ID NO: 2. In one embodiment, the Z2 peptide includes or consists of SEQ ID NO: 40. In one embodiment, the Z2 peptide includes or consists of SEQ ID NO: 53. In one embodiment, the Z2 peptide includes or consists of SEQ ID NO: 59.

[0101] GLP-GLP-1 / GIP / Amyrin receptor triple agonist peptide In one embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist, which is a peptide also referred to as "GLP-1 / GIP / amyrin receptor triple agonist peptide." The GLP-1 / GIP / amyrin receptor triple agonist comprises or consists of peptides Z1-L1-Z2, which include peptide Z1, peptide linker L1, and peptide Z2.

[0102] Peptide Z1 is a GLP-1 / GIP receptor co-agonist capable of binding to and activating both GLP-1 and GIP receptors. The C-terminus of peptide Z1 is bound to peptide linker L1 via a peptide bond.

[0103] 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.

[0104] Peptide Z2 is an amyrin receptor agonist capable of binding to and activating at least the amyrin receptor. The N-terminus of Z2 is bonded 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 NH2.

[0105] The molecular form may be a single-chain peptide backbone containing one lysine (Lys,K) residue. The one lysine (Lys,K) residue may be located in the peptide Z1 portion of the peptide backbone, or the one lysine (Lys,K) residue may be located in the peptide Z2 portion of the peptide backbone.

[0106] In one embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68This represents Gln(Q), Glu(E), or Lys(K), X 72 This relates to a GLP-1 / GIP / amyrin receptor triple agonist, which is a peptide containing a C-terminal amide comprising Leu(L) or Glu(E).

[0107] In another embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 follows the amino acid sequence of formula XVII (sequence number 62): YX2EGTFTSDYSX 12 LLEEIAAbIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (XVII) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 However, it is a peptide that contains or consists of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This relates to a GLP-1 / GIP / amyrin receptor triple agonist, which is a peptide containing a C-terminal amide comprising Leu(L) or Glu(E).

[0108] In another embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide containing up to 5 amino acid substitutions. L1 is a peptide linker, and Z2 is a C-terminal amide, and formula V (SEQ ID NO: 2): This relates to a GLP-1 / GIP / amyrin receptor triple agonist, which is a peptide containing up to 10 amino acid substitutions relative to ASELSTAALGRLSAELHELATLPRTETGSGSP(V).

[0109] In another embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide containing up to 5 amino acid substitutions. Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), preferably Arg(R). X 24 This represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E). X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 is a C-terminal amide, and formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP(V) is a peptide containing up to 10 amino acid substitutions. Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 However, it represents Gln(Q), Glu(E), or Lys(K), X 72 This relates to a GLP-1 / GIP / amyrin receptor triple agonist, which is a peptide containing a C-terminal amide comprising Leu(L) or Glu(E).

[0110] In another embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide having up to 4 amino acid substitutions. Z1 follows the amino acid sequence of formula VII (sequence number 162): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 34 This includes or consists of Gly (G) or Glu (E), L1 is a peptide linker, and Z2 contains a C-terminal amide, and formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP(V) is a peptide having up to 10 amino acid substitutions. Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising or consisting of Leu(L) or Glu(E).

[0111] In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention has an amino acid sequence according to formula VX (SEQ ID NO: 167): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGGPSSX 34 (VX) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 27 This represents Leu (L) or Ile (I), X 34 Peptide Z1, which contains or consists of Gly(G) or Glu(E), and the amino acid sequence according to Sequence ID No. 40: Peptide Z2 may contain or consist of ASHLSTAQTQRLSAELHKLATLPRTETGSGSP.

[0112] In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention has an amino acid sequence according to formula IV (SEQ ID NO: 169): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGX 30 X 31 SSG(IV) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 27 This represents Leu (L) or Ile (I), X 30 This represents Gly (G) or Ala (A), X 31 Peptide Z1, which contains or consists of Ala(A), Gly(G), or Pro(P), and Amino acid sequence following formula IX (sequence number 61): ASX 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATLPRTETGSGSP(IX) (In the formula, X 53 This represents Glu (E) or His (H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Gly(G) or Gln(Q), X 68 This may include peptide Z2 containing or consisting of Gln(Q), Glu(E), or Lys(K).

[0113] In one embodiment, the backbone of peptide Z1-L1-Z2 contains or consists of 66 to 80 amino acid residues, for example, 66 to 76 amino acid residues.

[0114] In one embodiment, the backbone of peptide Z1-L1-Z2 contains or consists of 67, 68, 71, 75, or 76 amino acid residues.

[0115] In a preferred embodiment, the backbone of peptide Z1-L1-Z2 contains or consists of 68 or 76 amino acid residues.

[0116] In one embodiment, the backbone of peptide Z1-L1-Z2 includes or consists of an amino acid sequence according to SEQ ID NO: 10. In another embodiment, the backbone of peptide Z1-L1-Z2 includes or consists of an amino acid sequence according to SEQ ID NO: 5.

[0117] In one embodiment, the GLP-1 / GIP / amyrin 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 NOs. 170-252 shown in [Table 4].

[0118] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0119] In certain embodiments, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist peptide, wherein the peptide comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 246, SEQ ID NO: 250, SEQ ID NO: 251, and SEQ ID NO: 252.

[0120] In some embodiments of the present invention, 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 (i.e., sequence identity) with formula II (SEQ ID NO: 1), and 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 (i.e., sequence identity) with formula V (SEQ ID NO: 2).

[0121] In some embodiments of the present invention, the GLP-1 / GIP / amyrin receptor triple agonists disclosed herein are cysteine ​​(Cys,C) residue-free and / or disulfide crosslinks. The term “disulfide crosslink” in relation to human amyrin and its analogues refers to a functional group having the structure RSS-R', and may also be referred to as “SS bond”.

[0122] GLP-1 / GIP / amyrin receptor triple agonists may exhibit various properties that make them useful as pharmaceuticals, as described herein.

[0123] extension part In one embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist which may further include an extended portion. In such a case, the triple agonist is referred to as a “peptide derivative” or a “GLP-1 / GIP / amyrin receptor triple agonist derivative.” Thus, the addition of the term “derivative” means that an extended portion exists and one or more compounds containing the extended portion are referred to as “one derivative” or “multiple derivatives.”

[0124] The molecular form may be a single-chain peptide backbone containing one lysine (Lys,K) residue. The one lysine (Lys,K) residue may be located in the peptide Z1 portion of the peptide backbone, or the one lysine (Lys,K) residue may be located in the peptide Z2 portion of the peptide backbone. The one lysine residue is referred to herein as "L P It can be covalently bonded to an extended portion that may be called "-P", and "L P " is an optional linker, and "P" is a protractor. The peptide backbone of the GLP-1 / GIP / amyrin receptor triple agonist of the present invention typically contains about 66 to about 76 amino acid residues linked together by peptide bonds.

[0125] As used herein, the term “extended portion” means having half-life extension properties and including “protractor P” and an optional “linker L” P This refers to the part that includes "L P The general formula is "L" where is the optional linker and P is the protractor. P It can be represented by "-P".

[0126] As used herein, the term “protractor” refers to a molecule capable of increasing the plasma half-life of the peptide to which it is bound. Thus, the term “extension” refers to the extension of the half-life, and therefore, “protractor,” “extension portion,” or “half-life extension portion” serves the purpose of extending the plasma half-life of the peptide disclosed herein.

[0127] Furthermore, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention has a long plasma half-life relative to the dosing interval, thus reducing variability in steady-state exposure and thus enabling once-weekly administration. The compounds disclosed herein are orally bioavailable and therefore may be suitable for oral administration to subjects requiring it. Both the peptide backbone and the extended portion have been manipulated and purified to achieve compounds having all of the above properties.

[0128] Each extension LP -P covalently binds to the epsilon-amino group of a lysine residue within the peptide backbone of the GLP-1 / GIP / amyrin receptor triple agonist of the present invention. The binding site is generally referred to as R1.

[0129] In one embodiment, the extended portion L P -P can be attached to the epsilon position (i.e., the amino group) of a single lysine (Lys, K) residue. In one embodiment, the extended portion L P -P is, for example, the Z1 peptide (X) of formula III (sequence number 168), formula IV (sequence number 169), formula VII (sequence number 162), formula XV (sequence number 167), or formula XVII (sequence number 62). 12 It can bind to the epsilon position (i.e., the amino group) of a lysine (Lys, K) residue within the peptide Z1 portion of the peptide backbone (the "Z1" in Z1-L1-Z2), such as the lysine (Lys, K) residue at position 12 of ). In one embodiment, the extended portion L P -P can bind to the epsilon position (i.e., the amino group) of the lysine (Lys, K) residue in SEQ ID NOs. 22, 23, 27, and 30-34, preferably in SEQ ID NOs. 22 or 31.

[0130] In one embodiment, the extended portion L P -P is the 18th position (X) of formula VI (sequence number 165), formula IX (sequence number 61), formula X (sequence number 166), or formula XIV (sequence number 4). 68 It can bind to the epsilon position (i.e., the amino group) of the lysine (Lys, K) residue in the peptide Z2 portion (the "Z2" in Z1-L1-Z2) of the peptide backbone, such as the lysine (Lys, K) residue in ). In one embodiment, the extended portion L P -P can bind to the epsilon position (i.e., the amino group) of a lysine (Lys, K) residue in SEQ ID NO: 40, SEQ ID NOs: 45-51, or SEQ ID NO: 58, preferably in SEQ ID NO: 40.

[0131] In one embodiment, the extended portion L P-P can bind to the epsilon position (i.e., the amino group) of a lysine (Lys, K) residue in the GLP-1 / GIP / amyrin receptor triple agonist peptide of SEQ ID NO: 230, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 246, SEQ ID NO: 250, SEQ ID NO: 251, or SEQ ID NO: 252.

[0132] Optional linker L P If present, extension portion L P -P is Linker L P It covalently bonds to the peptide backbone via linker L. P If P is not present, P covalently bonds to the peptide backbone.

[0133] The GLP-1 / GIP / amyrin receptor triple agonist disclosed herein comprises or consists of a peptide containing one lysine (Lys, K) residue, to which a single extension is covalently / conjugated (at the epsilon amino group). The extension may consist of one protractor P. The extension may consist of one linker L P and may include one protractor P. The extension portion may include one linker L. P and may include 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.

[0134] With respect to chemical parts such as extensions disclosed herein, similarity and / or identity can be determined using any suitable computer program and / or algorithm known in the art.

[0135] The extended portion may non-covalently bind to albumin, thereby promoting the circulation of the peptide derivative of the present invention in the bloodstream and extending its plasma half-life. Therefore, those skilled in the art may also refer to the extended portion as the "albumin-binding portion."

[0136] Protractor (P) Protractor (P) may contain an acyl group. The acyl group may be branched or unbranched. The acyl group may be saturated or unsaturated. Protractor P may contain a fatty acid acyl group. The fatty acid acyl group may be branched or unbranched. The fatty acid acyl group may be saturated or unsaturated.

[0137] Protractor P may contain a distal carboxylic acid group.

[0138] Protractor P may contain fatty acid groups.

[0139] Protractor P may contain fatty acid groups and amide groups.

[0140] Protractor P may contain a distal carboxylic acid group and an amide group.

[0141] Protractor P may contain alkyl groups.

[0142] Protractor P may contain an aryl group.

[0143] Protractor P may contain a tetrazole group.

[0144] Protractor P may contain a sulfonic acid group.

[0145] Protractor P may contain a phenoxy group.

[0146] Protractor P may contain a benzoic acid group.

[0147] Protractor P may contain a phosphonic acid group.

[0148] The protractor is Chemical formula 1a: HOOC-(CH2) n The base may include the base defined by -CO-* (where n is an integer between 6 and 30), which is C (n+2) Diacid (for example, C 18 (Diacid) or [ka] The formula may include a group defined as follows: (wherein n is an integer between 6 and 30). An asterisk (*) indicates a radical bond point.

[0149] 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.

[0150] Protractor P may contain 6 to 30 consecutive -CH2- groups. 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, 26, 27, 28, 29, or 30 consecutive -CH2- groups.

[0151] Protractor P may contain 12 to 26 carbon atoms. Protractor P may contain 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 carbon atoms.

[0152] Protractor P may contain 10 to 26 consecutive -CH2- groups. Protractor P may contain a carbon chain containing 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 consecutive -CH2- groups.

[0153] Protractor P may contain 16 to 22 carbon atoms. The peptide derivative of the present invention may contain a single extended portion 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.

[0154] Protractor P may contain 14 to 20 consecutive -CH2- groups. Protractor P may contain a carbon chain containing 14, 15, 16, 17, 18, 19, or 20 consecutive -CH2- groups.

[0155] Protractor P may contain 16 to 22 consecutive carbon atoms and 14 to 20 consecutive -CH2- groups.

[0156] Protractor P may contain 16 consecutive carbon atoms and 14 consecutive -CH2- groups. Protractor P has the formula HOOC-(CH2) 14 C, which can be defined by -CO-* 16 It could be a diacid.

[0157] Protractor P may contain 18 consecutive carbon atoms and 16 consecutive -CH2- groups. Protractor P has the formula HOOC-(CH2) 16 C, which can be defined by -CO-* 18 It could be a diacid.

[0158] Protractor P may contain 20 consecutive carbon atoms and 18 consecutive -CH2- groups. Protractor P has the formula HOOC-(CH2) 18 C, which can be defined by -CO-* 20 It could be a diacid.

[0159] Protractor P may contain 22 consecutive carbon atoms and 20 consecutive -CH2- groups. Protractor P has the formula HOOC-(CH2) 20 C, which can be defined by -CO-* 22 It could be a diacid.

[0160] The term "fatty acid" refers to an aliphatic mono or dicarboxylic acid having 4 to 28 carbon atoms, which can be branched or unbranched, preferably unbranched, and can be saturated or unsaturated, preferably saturated.

[0161] As described above, the peptide derivatives disclosed herein consist of one lysine (Lys,K) residue and therefore one extension (L P The extended portion contains -P) and is attached to the peptide backbone described herein via the epsilon position (i.e., the amino group) of a lysine (Lys,K) residue (via an amide bond formed between the carboxylic acid group of the extended portion and the epsilon-amino group of the lysine residue). The extended portion may be attached to the epsilon position of one lysine (Lys,K) residue within the peptide backbone.

[0162] In one embodiment, the extended portion may bind to the epsilon position of the lysine (Lys, K) residue in peptide Z1 ("Z1" in Z1-L1-Z2) of the peptide backbone. In particular, the extended portion may bind to the X of formula III (SEQ ID NO: 168) or formula VII (SEQ ID NO: 162) of peptide Z1. 12 It can bind to the epsilon position of lysine (Lys, K) at position 12. In particular, the extended portion can bind to the epsilon position of lysine (Lys, K) at position 12 of peptide Z1.

[0163] In one embodiment, the extended portion may 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).

[0164] In one embodiment, the extended portion may bind to the epsilon position of the lysine (Lys, K) residue in peptide Z2 ("Z2" in Z1-L1-Z2) of the peptide backbone. In particular, the extended portion may bind to the X of formula VI (SEQ ID NO: 165) of peptide Z2. 68The extended portion can bind to the epsilon position of lysine (Lys,K) at position 18. In particular, the extended portion can bind to the epsilon position of the lysine (Lys,K) residue at position 18 of peptide Z2. In a preferred embodiment, the extended portion can bind to the epsilon position of the lysine (Lys,K) residue at position 18 of peptide Z2.

[0165] In some embodiments, the GLP-1 / GIP / amyrin receptor triple agonist comprising the peptide derivative disclosed herein may comprise a protractor P selected from any one of those listed in [Table 5]. R1 is (a) the backbone of the peptide derivative, more specifically the epsilon amino group of lysine, or (b) the linker L of the same option. P This represents the binding site to [the specified molecule]. Based on the disclosure herein, those skilled in the art may, at their discretion, determine other chemical moieties for use as protractors in the specific peptide derivatives disclosed herein after some limited routine experiments.

[0166] [Table 5]

[0167] In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist is C 12 ~C 20 It contains peptide derivatives including protractor P, which is a diacid.

[0168] In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist is C 16 diacid, C 18 Diacids, and C 20 The peptide derivative comprises a protractor P selected from the group consisting of diacids.

[0169] In a preferred embodiment, the GLP-1 / GIP / amyrin receptor triple agonist is C 18 Dioxide (chemical formula 5), ​​C 20 Dioxide (chemical formula 6), or C 19It contains a peptide derivative that includes protractor P, which is a phosphonic acid (chemical formula 32).

[0170] Linker L P In one embodiment, the protractor is directly bound / conjugated onto the backbone of the peptide derivative, i.e., linker L P Do not use (i.e., by covalent bonds, e.g., amide bonds).

[0171] In other embodiments, the protractor is linked to linker L P The peptide derivative is covalently conjugated using the extension (L) as described above. P -P) is an optional linker L P Includes Linker L P It may contain several “linker elements.” Linker elements may be selected so that they improve the overall properties of the molecule, for example, by improving oral bioavailability, half-life conversion, or extension effects, and thus improving the overall exposure profile when the compound is administered orally.

[0172] Linker L P This may include Ado, Aeep or Aeeep, Ahx, Ala, ε-Lys, Glu, γGlu, Gly, Ser, sulfonamide, Thr, and / or Trx.

[0173] Linker L P This is represented by the following chemical formula (where an asterisk (*) indicates a radical bond point): Formula 9a: *NH-(CH2)2-(O-(CH2)2) k -O-(CH2) n -CO-* [ka] It may include at least a portion that can be expressed by (wherein k is an integer in the range of 1 to 5, and n is an integer in the range of 1 to 5).

[0174] When k=1 and n=1, the linker element may be designated as Ado, or 8-amino-3,6-dioxaoctanoyl, which has the following chemical formula: Formula 10a: *NH-(CH2)2-O-(CH2)2-O-CH2-CO-* or [ka] It can be represented by:

[0175] When k=1 and n=2, the linker element may be designated as Aeep, which has the following chemical formula: Formula 12a: *NH-(CH2)2-O-(CH2)2-O-(CH2)2-CO-* or [ka] It can be represented by:

[0176] When k=2 and n=2, the linker element may be designated Aeeep, which has the following chemical formula: Chemical formula 13a:*-NH-(CH2) 2- O-(CH2)2O-(CH2)2-O-(CH2)2-CO-* or [ka] It can be represented by:

[0177] Linker L P It 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-CH2-CH2-CH2-CO-* or [ka] It holds.

[0178] Linker L P It may contain Trx. Trx is also known as tranexamic acid, trans-4-(aminomethyl)cyclohexanecarboxylic acid, and has the following chemical formula: Chemical formula 15a:*-NH-CH2-(C6H 10 )-CO-* or [ka] It holds.

[0179] Linker L P It may contain Ahx. Ahx is also called aminocaproic acid or 6-aminohexanoic acid, and has the following chemical formula: Chemical formula 16a: *-NH-(CH2)5-CO-* or [ka] It holds.

[0180] Linker L P It may contain epsilon-lysine (ε-Lys).

[0181] Linker L P It may contain lysine (Lys).

[0182] Linker L P It may contain alanine (Ala).

[0183] Linker L P It may contain glycine (Gly).

[0184] Linker L P It may contain serine (Ser).

[0185] Linker L P It may contain glutamic acid (Glu). Linker L P teeth, [ka] Linker L may contain Glu diradicals such as (wherein the formula, the Glu diradical may be included p times, and p is an integer in the range of 1 to 3). P As, or Linker L P Any one of the amino acids disclosed above, used as part of the above, may be used as an L-isomer or a D-isomer.

[0186] Chemical formula 17 may also be referred to as gamma-Glu, or simply γGlu, due to the fact that it is the gamma-carboxyl group of the amino acid glutamic acid used herein to connect to the epsilon-amino group of lysine. As described above, the other linker element may be, for example, another Glu residue or an Ado molecule. The amino group of Glu then forms an amide bond with the carboxyl group of the extended portion, or, if present, with the carboxyl group of, for example, an Ado molecule, or, if present, with the gamma-carboxyl group of another Glu.

[0187] The peptide derivatives disclosed herein are linkers selected from any one of those described in [Table 6] below. P It may include. R1 represents a residue in the peptide backbone to which the extension is attached, and P represents a protractor.

[0188] In some embodiments, the peptide derivative includes an extended portion, and the protractor chemical formula 4, or chemical formula 5, or chemical formula 6, or chemical formula 32 is L as shown in [Table 6] below. P 1, L P 2, L P 3, L P 4, L P 5, or L P It is attached to the peptide backbone using linker number 6.

[0189] In some embodiments, the peptide derivative includes an extended portion, and the protractor chemical formula 5 is L as shown in [Table 6] below. P 1, L P 2, LP 3, L P 4, L P 5, or L P Linker 6 is used to bond to the peptide backbone, and therefore the extended portion is linked to linker L of chemical formulas 18, 19, 20, 21, 33, or 34. P It contains as such, and contains chemical formula 5 as protractor P.

[0190] In some embodiments, the peptide derivative includes an extended portion, and the protractor chemical formula 6 is L as shown in [Table 6] below. P 1, L P 2, L P 3, L P 4, L P 5, or L P Linker 6 is used to bond to the peptide backbone, and therefore the extended portion is linked to linker L of chemical formulas 18, 19, 20, 21, 33, or 34. P It contains as such, and contains chemical formula 6 as protractor P.

[0191] In some embodiments, the peptide derivative includes an extended portion, and the protractor chemical formula 32 is L as shown in [Table 6] below. P 1, L P 2, L P 3, L P 4, L P 5, or L P Linker 6 is used to bond to the peptide backbone, and therefore the extended portion is linked to linker L of chemical formulas 18, 19, 20, 21, 33, or 34. P It contains as such, and contains chemical formula 32 as protractor P.

[0192] In a preferred embodiment, the peptide derivative includes an extended portion, the extended portion of which is linked to chemical formula 20 or chemical formula 21 by linker L P It contains as such, and contains chemical formula 5 or chemical formula 6 as protractor P.

[0193] In preferred embodiments, the peptide derivative includes an extended portion, and the protractor chemical formula 5 is L as shown in [Table 6] below. P It is bonded to the peptide backbone using linker 3, and therefore the extended portion is linked to linker L of chemical formula 20. P It contains as such, and contains chemical formula 5 as protractor P.

[0194] In preferred embodiments, the peptide derivative includes an extended portion, and the protractor chemical formula 6 is L as shown in [Table 6] below. P It is bonded to the peptide backbone using linker 3, and therefore the extended portion is linked to linker L of chemical formula 20. P It contains as such, and contains chemical formula 6 as protractor P.

[0195] Based on the disclosure herein, a person skilled in the art may, at their discretion, determine the optimal L for use with the specific peptide derivatives disclosed herein after some limited routine experiments. P It should be possible to determine the linker.

[0196] [Table 6-1] [Table 6-2]

[0197] In some embodiments, the peptide derivative includes an extension selected from the group shown in [Table 7]. R1 represents a residue in the peptide backbone to which the extension is attached.

[0198] [Table 7-1] [Table 7-2]

[0199] In one embodiment, the extension is selected from a list consisting of chemical formulas 27, 35, 36, and 36. In a preferred embodiment, the extension is chemical formula 27.

[0200] In one embodiment, free lysine is one C 16 Gamma-gamma diacitate-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]) can function as a conjugation site for binding, and therefore the peptide derivative of the present invention includes an extended portion, the extended portion of which is C 16 This is the fatty acid portion of diacid (S)gamma-Glu 2xAdo.

[0201] In one embodiment, free lysine is one C 18 Gamma-gamma diacitate-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 therefore the peptide derivative of the present invention includes an extended portion, the extended portion of which is C 18 This is the fatty acid portion of diacid (S)gamma-Glu 2xAdo.

[0202] In one embodiment, free lysine is one C 20 Gamma-gamma diacitate-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 therefore the peptide derivative of the present invention includes an extended portion, the extended portion of which is C 20 This is the fatty acid portion of diacid (S)gamma-Glu 2xAdo.

[0203] In one embodiment, free lysine is one C 18 It can function as a conjugation site for binding the gamma-glucan diacitate fatty acid moiety (IUPAC name [(4S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butanoyl]), and therefore the peptide derivative of the present invention includes an extended portion, which is C 18 This is the diacid (S)gamma-Glu fatty acid portion.

[0204] In one embodiment, free lysine is one C 20 It can function as a conjugation site for binding the gamma-glucan diacitate fatty acid moiety (IUPAC name [(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butanoyl]), and therefore the peptide derivative of the present invention includes an extended portion, which is C 20 This is the diacid (S)gamma-Glu fatty acid portion.

[0205] In a preferred embodiment, free lysine is one C 18 Gamma-gamma diacitate-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 therefore the peptide derivative of the present invention includes an extended portion, the extended portion of which is C 18 This is the fatty acid portion of diacid (S)gamma-Glu 2xAdo.

[0206] In a preferred embodiment, free lysine is one C 20Gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]) can function as a conjugation site for binding, and therefore the peptide derivative of the present invention includes an extended portion, the extended portion of which is C 20 This is the fatty acid portion of diacid (S)gamma-Glu 2xAdo.

[0207] In the most preferred embodiment, free lysine is one C 18 Gamma-gamma diacitate-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]) can function as a conjugation site for binding, and therefore the peptide derivative of the present invention includes an extended portion, the extended portion of which is C 18 This is the fatty acid portion of diacid (S)gamma-Glu 2xAdo.

[0208] GLP-1 / GIP / amyrin receptor triple agonist derivative As described above, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention may include a peptide linker and may further include an extension portion. Therefore, in another embodiment, the present invention is a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This is a peptide containing a C-terminal amide that includes or consists of Leu(L) or Glu(E), This invention relates to a GLP-1 / GIP / amyrin receptor triple agonist in which the peptide is a peptide derivative containing an extended portion selected from [Table 7].

[0209] In another embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 follows the amino acid sequence of formula XVII (sequence number 62): YX2EGTFTSDYSX 12 LLEEIAAbIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (XVII) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This is a peptide containing a C-terminal amide that includes or consists of Leu(L) or Glu(E), This invention relates to a GLP-1 / GIP / amyrin receptor triple agonist in which the peptide is a peptide derivative containing an extended portion selected from [Table 7].

[0210] In another embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide containing up to 5 amino acid substitutions. Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), preferably Arg(R). X 24 This represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E). X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 contains a C-terminal amide and follows the amino acid sequence of formula VI (SEQ ID NO: 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68LATX 72 PRTETGSGSP (VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This is a peptide containing or consisting of Leu(L) or Glu(E), This invention relates to a GLP-1 / GIP / amyrin receptor triple agonist in which the peptide is a peptide derivative containing an extended portion selected from [Table 7].

[0211] In another embodiment, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention is a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X20 This represents Arg(R) or Gln(Q), preferably Arg(R). X 24 This represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E). X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), preferably Ala(A). X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly(G), Gln(Q), Ala(A), or Pro(P), preferably Pro(P) or Ala(A). X 33 This represents Glu(E) or Ser(S), preferably Ser(S). X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), preferably representing Gly(G). L1 is E, AE, AG, AGGGG (sequence number 142), AGQAPGQAPG (sequence number 136), AGQAPGQAPL (sequence number 137), AGEAPGQAPG (sequence number 143), AGEAPGEAPG (sequence number 144), AGQAPGQAPA (sequence number 145), AGQAPGQAPE (sequence number 146), AGQAPGQAPP (sequence number 147), AGQAPGQAPS (sequence number 148), AGQAPGQAPV (sequence number 149), EGQAPGQAPG (sequence number 150), AGQEP A peptide linker selected from the group consisting of GQAPG (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), preferably AG or AGEAPGEAPG (SEQ ID NO: 144), and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This is a peptide containing a C-terminal amide that includes or consists of Leu(L) or Glu(E), This invention relates to a GLP-1 / GIP / amyrin receptor triple agonist in which the peptide is selected from [Table 7], preferably a peptide derivative containing an extended portion having chemical formula 27.

[0212] In another embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 follows the amino acid sequence of formula XVII (sequence number 62): YX2EGTFTSDYSX 12 LLEEIAAbIX 24 WLX 27 X 28 GX 30 X 31 SX 33X 34 (XVII) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 24 This represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E). X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), preferably Ala(A). X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu(E) or Ser(S), preferably Ser(S). X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), preferably representing Gly(G), and L1 is E, AE, AG, AGGGG (sequence number 142), AGQAPGQAPG (sequence number 136), AGQAPGQAPL (sequence number 137), AGEAPGQAPG (sequence number 143), AGEAPGEAPG (sequence number 144), AGQAPGQAPA (sequence number 145), AGQAPGQAPE (sequence number 146), AGQAPGQAPP (sequence number 147), AGQAPGQAPS (sequence number 148), AGQAPGQAPV (sequence number 14 9) A peptide linker selected from the group consisting of 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), preferably AG or AGEAPGEAPG (SEQ ID NO: 144), and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly(G) or Ser(S), preferably Ser(S). X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala(A), Gly(G), or Gln(Q), preferably Gly(G) or Gln(Q), X 68This represents Gln(Q), Glu(E), or Lys(K), X 72 This is a peptide containing a C-terminal amide comprising Leu(L) or Glu(E), preferably Leu(L), This invention relates to a GLP-1 / GIP / amyrin receptor triple agonist in which the peptide is selected from [Table 7], preferably a peptide derivative containing an extended portion having chemical formula 27.

[0213] In another embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide containing up to 5 amino acid substitutions. Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), preferably Arg(R). X 24 This represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E). X 27 This represents Leu (L) or Ile (I), X28 This represents Ala(A) or Gln(Q), preferably Ala(A). X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly(G), Gln(Q), Ala(A), or Pro(P), preferably Pro(P) or Ala(A). X 33 This represents Glu(E) or Ser(S), preferably Ser(S). X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), preferably representing Gly(G), and L1 is E, AE, AG, AGGGG (sequence number 142), AGQAPGQAPG (sequence number 136), AGQAPGQAPL (sequence number 137), AGEAPGQAPG (sequence number 143), AGEAPGEAPG (sequence number 144), AGQAPGQAPA (sequence number 145), AGQAPGQAPE (sequence number 146), AGQAPGQAPP (sequence number 147), AGQAPGQAPS (sequence number 148), AGQAPGQAPV (sequence number 149), EGQAPGQAPG (sequence number 150), AGQEP A peptide linker selected from the group consisting of GQAPG (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), preferably AG or AGEAPGEAPG (SEQ ID NO: 144), and Z2 contains a C-terminal amide and follows the amino acid sequence of formula VI (SEQ ID NO: 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly(G) or Ser(S), preferably Ser(S). X 53 This represents Gln(Q), Glu(E), or His(H), preferably Glu(E) or His(H). X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala(A), Gly(G), or Gln(Q), preferably Gly(G) or Gln(Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This is a peptide containing or consisting of Leu(L) or Glu(E), preferably Leu(L), and This invention relates to a GLP-1 / GIP / amyrin receptor triple agonist in which the peptide is selected from [Table 7], preferably a peptide derivative containing an extended portion having chemical formula 27.

[0214] In yet another aspect, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist comprising a peptide according to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide having up to 4 amino acid substitutions. and Z1 follows the amino acid sequence of formula VII (sequence number 162): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X28 GGPSSX 34 (VII) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 34 This includes or consists of Gly (G) or Glu (E), L1 is a peptide linker 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 of formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP(V) is a peptide having up to 10 amino acid substitutions. and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 (representing Leu(L) or Glu(E)) contains or consists of, This invention relates to a GLP-1 / GIP / amyrin receptor triple agonist in which the peptide is a peptide derivative containing an extended portion.

[0215] The GLP-1 / GIP / amyrin receptor triple agonist of the present invention may be a peptide derivative comprising any one of the peptides Z1 disclosed above, any one of the peptides Z2 disclosed above, any one of the peptide linkers L1 disclosed above, and any one of the extensions disclosed above. Based on the disclosures herein, those skilled in the art will be able to determine the optimal combination to form a specific peptide derivative that is a potent GLP-1 / GIP / amyrin receptor triple agonist having the specific properties described below.

[0216] The GLP-1 / GIP / amyrin receptor triple agonist of the present invention may be selected from compound numbers 104 to 197 described in Example 2 of this specification. Preferred GLP-1 / GIP / amyrin receptor triple agonists of the present invention are as follows: Compound 104: [ka] Compound 105: [ka] Compound 107: [ka] Compound 111: [ka] Compound 112: [ka] Compound 113: [ka] Compound 183: [ka]

[0217] Pharmaceutically acceptable salts The compounds of the present invention may be in the form of pharmaceutically acceptable salts or amides.

[0218] Salts are formed, for example, by chemical reactions between a base and an acid, such as 2NH3 + H2SO4 → (NH4)2SO4.

[0219] The salt may be a basic salt, an acidic salt, or neither (i.e., a neutral salt). Basic salts produce hydroxide ions in water, and acidic salts produce hydronium ions.

[0220] 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 portion and / or extension portion of the compounds of the present invention.

[0221] Non-limiting examples of anionic groups in the compounds of the present invention include free carboxylic acid groups, if present, in the extended portion and in the peptide backbone. The peptide backbone may contain free carboxylic acid groups in internal amino acid residues such as Asp(D) and Glu(E).

[0222] Non-limiting examples of cationic groups within the peptide backbone include, if present, the free amino group at the N-terminus, as well as any free amino groups of internal base amino acid residues such as His(H), Arg(R), and Lys(K).

[0223] The amides of the compounds of the present invention may be formed, for example, during peptide synthesis (based on the resin used), or by the reaction of a free carboxylic acid group with an amine or substituted amine, or by the reaction of a free or substituted amino group with a carboxylic acid. Amide formation may be from any free carboxylic acid group in the extension, a free amino group at the N-terminus of a peptide, and / or any free or substituted amino group in the peptide backbone.

[0224] In one embodiment, the derivative of the present invention is in the form of a pharmaceutically acceptable salt, preferably in the form of a trifluoroacetate salt.

[0225] Functional characteristics In a first functional aspect, the GLP-1 / GIP / amyrin receptor triple agonists of the present invention have good efficacy in each of the GLP-1 / GIP / amyrin receptors. Preferably, they are potent GLP-1 / GIP / amyrin receptor agonists, as reflected in their ability to activate each of the GLP-1 / GIP / amyrin receptors, or, alternatively, in a second functional aspect, the GLP-1 / GIP / amyrin receptor triple agonists of the present invention are balanced triple agonists. Or, alternatively, in a third functional aspect, the GLP-1 / GIP / amyrin receptor triple agonists of the present invention reduce in vivo food intake. Or, alternatively, in a fourth functional aspect, the GLP-1 / GIP / amyrin receptor triple agonists of the present invention have improved pharmacokinetic properties. Alternatively, in a fifth functional aspect, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention is chemically stable.

[0226] Bioactivity - In vitro efficacy According to the first functional aspect, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention is biologically active or potent with each of the GLP-1 / GIP / amyrin receptor triple agonist peptides capable of in vitro activating the GLP-1 / GIP / amyrin receptor, i.e., human GIP, GLP-1, and amyrin receptor.

[0227] When tested as described in the "GLP-1 Receptor Assay" (in the absence of HSA), the GLP-1 / GIP / amyrin receptor triple agonists disclosed herein have an EC of less than 125 pM, preferably less than 100 pM, e.g., less than 75 pM, more preferably less than 50 pM, e.g., less than 40 pM, most preferably less than 30 pM, e.g., less than 20 pM, e.g., less than 10 pM, e.g., less than 5 pM. 50 It may have a value.

[0228] When tested as described in the “GIP Receptor Assay” (in the absence of HSA), the GLP-1 / GIP / amyrin receptor triple agonist peptides disclosed herein have an EC of less than 125 pM, preferably less than 100 pM, e.g., less than 75 pM, more preferably less than 50 pM, e.g., less than 40 pM, most preferably less than 30 pM, e.g., less than 20 pM, e.g., less than 10 pM, e.g., less than 5 pM. 50 It may have a value.

[0229] When tested as described in the “Amyrin Receptor Assay” (in the absence of HSA), the GLP-1 / GIP / amyrin receptor triple agonist peptides disclosed herein have an EC of less than 125 pM, preferably less than 100 pM, e.g., less than 75 pM, more preferably less than 50 pM, e.g., less than 40 pM, most preferably less than 30 pM, e.g., less than 20 pM, e.g., less than 10 pM, e.g., less than 5 pM. 50 It may have a value. The GLP-1 / GIP / amyrin receptor triple agonists disclosed herein act on or activate amyrin receptors.

[0230] The GLP-1 / GIP / amyrin receptor triple agonists disclosed herein may be tested for GLP-1, GIP, and / or amyrin activity, as described in Example 4.

[0231] The stronger the compound, the greater its EC 50 The value decreases. GLP-1 / GIP / amyrin receptor triple agonists reduce EC to approximately 100 pM or less in the human GLP-1 receptor function assay (see Example 4). 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 90 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 80 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 75 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 70 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 60 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 50 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 40 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 30 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 25 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 20 pM or less in human GLP-1 receptor function assays. 50It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 15 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 10 pM or less in human GLP-1 receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 5 pM or less in human GLP-1 receptor function assays. 50 The GLP-1 / GIP / amyrin receptor triple agonists disclosed herein may have efficacy similar to that of semaglutide or tilzepatide.

[0232] GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 125 pM or less in a human GIP receptor function assay (see Example 4). 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists reduce EC to approximately 100 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 90 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 80 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 75 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 70 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 60 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 50 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 40 pM or less in human GIP receptor function assays. 50It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 30 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 25 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 20 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 15 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 10 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 9 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 8 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 7 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 6 pM or less in human GIP receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 5 pM or less in human GIP receptor function assays. 50 The GLP-1 / GIP / amyrin receptor triple agonists disclosed herein may have efficacy similar to that of tilzepatide.

[0233] The GLP-1 / GIP / amyrin receptor triple agonist exhibited an EC of approximately 125 pM or less in a human amyrin receptor function assay (see Example 4). 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists reduce EC to approximately 100 pM or less in human amyrin receptor function assays. 50It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 90 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 80 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 75 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 70 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists have an EC of approximately 60 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 50 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 40 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 30 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 25 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 20 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 15 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 10 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 9 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 8 pM or less in human amyrin receptor function assays.50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 7 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 6 pM or less in human amyrin receptor function assays. 50 It may have the following characteristics. GLP-1 / GIP / amyrin receptor triple agonists exhibit an EC of approximately 5 pM or less in human amyrin receptor function assays. 50 The GLP-1 / GIP / amyrin receptor triple agonists disclosed herein may have efficacy similar to that of caglilintide.

[0234] Bioactive - Balanced GLP-1 / GIP / amyrin receptor triple agonist In a second functional aspect, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention, when measured without HSA in the assay described in Example 4, activates human GIP, GLP-1, and amyrin receptors in vitro and has a potency ratio (A / B) of less than 50, preferably less than 30.

[0235] In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist, when measured without HSA in the assay described in Example 4, activates human GIP, GLP-1, and amyrin receptors in vitro and has a potency ratio A / B of less than 50. In another embodiment, the GLP-1 / GIP / amyrin receptor triple agonist, when measured without HSA in the assay described in Example 4, activates human GIP, GLP-1, and amyrin receptors in vitro and has a potency ratio A / B of less than 30.

[0236] The balanced GLP-1 / GIP / amyrin receptor triple agonist of the present invention, when measured without HSA in the assay described in Example 4, activates human GIP, GLP-1, and amyrin receptors in vitro and has a potency ratio (A / B) of less than 50, preferably less than 30, i.e., the potency of the least potent receptor (A) divided by the potency of the most potent receptor (B). The triple agonists disclosed herein may have potency ratios (A / B) of less than 50, preferably less than 30 or less than 20, for example less than 19, less than 18, less than 17, less than 16, more preferably less than 15, for example less than 14, less than 13, less than 12, most preferably less than 11, for example less than 10, less than 9, less than 8, and less than 7.

[0237] Bioactivity - In vivo pharmacology In a third functional aspect, the GLP-1 / GIP / amyrin receptor triple agonists disclosed herein may reduce food intake in subjects, such as normal-weight rats or SD rats. Administration of the GLP-1 / GIP / amyrin receptor triple agonists disclosed herein may result in a rapid reduction in food intake. The in vivo effect of the GLP-1 / GIP / amyrin receptor triple agonists on food intake in rats may be evaluated as described in Example 5. A 100% (hypothetical) reduction in food intake relative to or compared to the vehicle means that the rats will not eat.

[0238] In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist disclosed herein can reduce food intake on day 1 (0-24 hours) by at least 10%, preferably at least 30% or 50%, for example, at least 70%, compared to the vehicle, after a single subcutaneous administration of 10 nmol / kg. The GLP-1 / GIP / amyrin receptor triple agonist disclosed herein can reduce food intake on day 1 (0-24 hours) by 1% to 100%, for example, 15% to 95%, preferably 40% to 85%, and more preferably 50% to 80%, compared to the vehicle, after a single subcutaneous administration of 10 nmol / kg.

[0239] In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist disclosed herein can reduce food intake on day 2 (24-48 hours) by at least 15% compared to the vehicle, preferably at least 30% or 50% compared to the vehicle, for example, at least 70% compared to the vehicle, after a single subcutaneous administration of 10 nmol / kg. The GLP-1 / GIP / amyrin receptor triple agonist disclosed herein can reduce food intake on day 2 (24-48 hours) by 1% to 100%, for example, 15% to 95%, preferably 40% to 95% compared to the vehicle, and more preferably 70% to 95% compared to the vehicle, after a single subcutaneous administration of 10 nmol / kg.

[0240] In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist disclosed herein can reduce food intake on day 1 (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 / amyrin receptor triple agonist disclosed herein can reduce food intake on day 2 (24-48 hours) by at least 15%, preferably at least 35%, compared to the vehicle, after a single subcutaneous administration of 30 nmol / kg.

[0241] Pharmacokinetic profile In a fourth functional aspect, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention has improved pharmacokinetic properties, such as an increased terminal phase half-life.

[0242] Half-life is an important parameter because a long half-life indicates that low-frequency administration of the compound may be possible. Based on the disclosure herein, those skilled in the art may, at their discretion, determine the extension portion for use with the specific peptide derivatives disclosed herein after several limited routine experiments. The GLP-1 / GIP / amyrin receptor triple agonists or peptide derivatives of the present invention have a long half-life relative to the dosing interval and therefore reduce the variability of steady-state exposure.

[0243] The in vivo pharmacological effects, including the half-life of the GLP-1 / GIP / amyrin receptor triple agonists described herein, may be evaluated as described in Example 6. In some embodiments, the half-life is the in vivo half-life (t1 / 2) in miniature pigs or rats after intravenous administration, as described, for example, in Example 6. The half-life of the GLP-1 / GIP / amyrin receptor triple agonist in miniature pigs may be about 90 hours or longer. The half-life of the GLP-1 / GIP / amyrin receptor triple agonist in miniature pigs may be at least 80 hours, preferably at least 90 hours. The half-life of the GLP-1 / GIP / amyrin receptor triple agonist in miniature pigs may be 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 150, 160, or more than 170 hours. The half-life of the GLP-1 / GIP / amyrin receptor triple agonist in miniature pigs may be 80 to 200 hours, for example, 90 to 190 hours, or for example, 95 to 185 hours. The half-life of the GLP-1 / GIP / amyrin receptor triple agonist in rats may be about 5 hours or longer. The half-life of the GLP-1 / GIP / amyrin receptor triple agonist in rats may be at least 8 hours, preferably at least 10 hours. The half-life of the GLP-1 / GIP / amyrin receptor triple agonist in rats may be 5, 6, 7, 8, 9, 10, 12, 14, 16, 20, or more than 25 hours. The half-life of the GLP-1 / GIP / amyrin receptor triple agonist in rats may be 5 to 50 hours, for example, 10 to 35 hours, or for example, 12 to 30 hours.

[0244] In one embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist suitable for once-weekly administration. The GLP-1 / GIP / amyrin 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.

[0245] In one embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist suitable for oral administration. The GLP-1 / GIP / amyrin receptor triple agonist described herein is orally bioavailable, i.e., can be present in the bloodstream after each oral administration. Therefore, the compound is suitable for oral administration to subjects who require it.

[0246] chemical properties In a fifth aspect, the present invention relates to a GLP-1 / GIP / amyrin 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 (HMWPs), deamides, isomers, and hydrolysis products, which have potentially reduced biological potency and / or increased immunogenicity compared to the intact polypeptide. Chemical stability can be determined by measuring the loss of purity, for example by SEC-HPLC and / or LCMS, for example, as described in Example 7 herein, or by measuring the amount of chemical degradation products at various time points after exposure to different environmental conditions. The GLP-1 / GIP / amyrin receptor triple agonist of the present invention has a loss of purity per week of less than 10.0 percent, preferably less than 5.0 percent, for example 4.0 or 3.0 percent, more preferably less than 2.0 percent, and most preferably less than 1.5 percent, as determined in Example 7 herein, when incubated at 37°C.

[0247] Both the peptide backbone and the extended portion are manipulated and purified to achieve peptide derivatives possessing all of the above characteristics.

[0248] Method of generation The triple agonists disclosed herein may be produced 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”, Oxford University Press, 2000, edited by WCChan and PDWhite. In some embodiments, methods for preparing triple agonists are described herein. In some embodiments, the methods for preparing triple agonists described herein include a solid-phase peptide synthesis step.

[0249] Alternatively, the compound, peptide sequence, or portion of the peptide sequence may be generated by recombinant methods, for example, by culturing a host cell capable of expressing the peptide, which contains a DNA sequence encoding a triple-acting peptide sequence, in a suitable nutrient medium under conditions that allow peptide expression. Non-limiting examples of host cells suitable for the expression of these peptides include Escherichia coli, Saccharomyces cerevisiae, and mammalian BHK or CHO cell lines.

[0250] Triple agonists containing non-natural amino acids and / or covalently bonded substituents (extensions) can be produced as described under “General Methods for Peptide Synthesis” in the Laboratory Department. Alternatively, see, for example, Hodgson et al: “The synthesis of peptides and proteins containing non-natural amino acids”, Chemical Society Reviews, vol.33, no.7(2004), pp. 422-430.

[0251] The triple agonists described herein, including the extended portion, may be produced, for example, as described under “General Methods for Peptide Synthesis” in the Laboratory Section. In some embodiments, the extended portion is constructed as part of solid-phase peptide synthesis or is produced separately and then linked via a single lysine residue after solid-phase peptide synthesis.

[0252] Specific examples of methods for preparing some of the triple agonists described herein are provided below.

[0253] A further aspect of the present invention relates to a method for preparing the receptor triple agonist described herein.

[0254] In one embodiment, a method for preparing the compounds described herein includes a solid-phase peptide synthesis step. The extension portion may be constructed sequentially as part of the solid-phase peptide synthesis or may be generated separately and linked via lysine residues after peptide synthesis.

[0255] Pharmaceutical composition In a further embodiment, the present invention relates to a pharmaceutical composition comprising the GLP-1 / GIP / amyrin receptor triple agonist. A pharmaceutical composition comprising the GLP-1 / GIP / amyrin receptor triple agonist disclosed herein and one or more pharmaceutically acceptable excipients is disclosed herein. A pharmaceutical composition comprising the GLP-1 / GIP / amyrin receptor triple agonist disclosed herein and one or more pharmaceutically acceptable excipients can be prepared using methods known to those skilled in the art.

[0256] The term "pharmaceutically acceptable excipient" refers to any component in a pharmaceutical composition that is not a pharmaceutically active ingredient or a GLP-1 / GIP / amyrin receptor triple agonist disclosed herein. The term "pharmaceutically acceptable excipient" also means an excipient that is generally safe, non-toxic, and acceptable for human medicinal use, and is useful in preparing a pharmaceutical composition. Such excipients may be, for example, solids, liquids, or semi-solids.

[0257] Excipients may be functional or inert and may serve a variety of purposes, for example, as buffers, isotonic agents, carriers, vehicles, fillers, binders, lubricants, disintegrants, flow regulators, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, or combinations thereof, and / or to improve the administration and / or absorption of pharmacopoeia active ingredients. The amount of each excipient used may vary within the conventional range of the art.

[0258] The technologies and excipients that may be used are, for example, in the 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), and Remington: The Science and Practice of Pharmacy (e.g., 23 editions). rd This is described in edition, Remington and Allen, Eds., Pharmaceutical Press (2021, and subsequent editions).

[0259] The pharmaceutical compositions containing GLP-1 / GIP / amyrin receptor triple agonists disclosed herein may be for oral administration.

[0260] The pharmaceutical compositions containing the GLP-1 / GIP / amyrin receptor triple agonist disclosed herein may be, for example, solid pharmaceutical compositions (e.g., tablets or capsules) containing the active pharmaceutical ingredient as lyophilized or spray-dried compositions, and may be used as is, dissolved before use, or combined with excipients in the formulation.

[0261] A pharmaceutical composition may be a solid pharmaceutical composition comprising, as described in the art, a compound disclosed herein, a salt of N-[8-(2-hydroxybenzoyl)amino]caprylate, preferably sodium N-(8-(2-hydroxybenzoyl)amino)caprylate, and one or more further excipients. For example, a solid pharmaceutical composition may be as described in WO2012 / 080471, WO2013 / 139694, WO2013 / 189988, WO2019 / 149880, WO2019 / 215063, WO2021 / 219710, or WO2023 / 012263A1.

[0262] Alternatively, the pharmaceutical compositions comprising the GLP-1 / GIP / amyrin receptor triple agonist disclosed herein may be liquid compositions, such as aqueous compositions. Such liquid compositions may be suitable for oral administration or parenteral administration, for example, intravenous, intramuscular, or subcutaneous administration.

[0263] Liquid compositions suitable for injection can be prepared using conventional techniques in the pharmaceutical industry, which involve dissolving and mixing components as needed 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 compositions may be sterilized, for example, by sterile filtration. Techniques and excipients that may be used to prepare liquid formulations are, for example, found in the 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), and Remington: The Science and Practice of Pharmacy (e.g., 23 editions). rd This is described in edition, Remington and Allen, Eds., Pharmaceutical Press (2021, and subsequent editions). Preferably, in embodiments in which the pharmaceutical composition is in a liquid formulation, the liquid formulation provides improved stability.

[0264] A pharmaceutical composition is typically administered to a subject already suffering from a disease, such as those listed below, in an amount sufficient to cure, alleviate, or partially prevent the disease and its complications. An amount sufficient to achieve this is defined as the "therapeutic effective dose." As will be understood by those skilled in the art, the effective dose for this purpose depends on the severity of the disease, as well as the subject's weight and overall condition.

[0265] In some embodiments, the dose of the compound delivered by subcutaneous administration may be about 0.1 mg to 500 mg of the compound per day, depending on the severity of the condition, 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.

[0266] The preferred dose may also be adjusted for a particular compound based on its properties, including its in vivo half-life or mean residence time and its biological activity. For example, the compound to be delivered may be administered once daily in one embodiment, or once weekly in another embodiment. Thus, the pharmaceutical composition may be used to be administered approximately once daily, for example, once every 12 to 36 hours, for example, once every 18 to 30 hours, for example, once every 24 hours, or approximately once weekly, for example, once every 6 to 8 days.

[0267] In one embodiment, the present invention relates to an injection device containing the pharmaceutical composition.

[0268] Pharmaceutical indications In a further embodiment, the present invention relates to a GLP-1 / GIP / amyrin receptor triple agonist disclosed herein for use as a pharmaceutical agent.

[0269] The GLP-1 / GIP / amyrin receptor triple agonists disclosed herein are It may be used for the following medical treatments or indications: (i) Prevention and / or treatment of all forms of diabetes, including hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (young-onset adult-onset diabetes), 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-dependent type 2 diabetes; and / or delaying the progression from insulin-free type 2 diabetes to insulin-dependent type 2 diabetes. (iii) For example, prevention and / or treatment of eating disorders such as obesity by reducing food intake, weight loss, or suppression of appetite that induces satiety; treatment or prevention of bulimia, food cravings, bulimia nervosa and / or obesity induced by the administration of antipsychotic drugs or steroids; reduction of gastric motility and / or delay of gastric emptying. (iv) Maintaining weight after successful weight loss (either drug-induced or diet and exercise-induced), i.e., preventing weight gain after successful weight loss. (v) Prevention and / or treatment of cardiovascular disease, such as delaying or reducing the occurrence 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) Prevention and / or treatment of 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 fatty liver disease, MASH), (vii) Prevention and / or treatment of cognitive impairments such as those caused by Alzheimer's disease, (viii) Prevention and / or treatment of chronic kidney disease, (ix) Prevention and / or treatment of obstructive sleep apnea.

[0270] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In further specific embodiments, 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.

[0271] As used herein, the term “treatment” refers to any medical therapy for any human or other vertebrate subject in need of treatment. Such subject is expected to have undergone a physical examination by a physician or veterinarian who has made a provisional or definitive diagnosis indicating that the use of such particular treatment would be beneficial to the health of the human or other vertebrate. The timing and purpose of such treatment may vary from individual to individual, depending on the subject’s current health status. Therefore, such treatment may be prophylactic, palliative, symptomatic, and / or curative.

[0272] In some embodiments, the indications are (i) and (iii). In some embodiments, the indications are (ii) and (iii).

[0273] The World Health Organization (WHO) defines overweight and obesity as abnormal or excessive accumulation of body fat that poses a risk to an individual's overall health. Generally, all subjects suffering from obesity are also considered to be overweight. Subjects suffering from obesity can be adults or children, and “children” include infants, toddlers, and adolescents. The term pre-obese is also used in this field as an alternative to overweight. The WHO considers Body Mass Index (BMI) to be the most convenient population-level measure of overweight and obesity. 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) / square meters (m²) 2 This is height in units of ).

[0274] For adults, the WHO defines overweight and obesity as follows: Overweight means having a BMI of 25 or higher, and obesity means having a BMI of 30 or higher.

[0275] For children, the WHO takes age into consideration when defining overweight and obesity. For children under 5 years of age, overweight means having a BMI for height that is 2 standard deviations above the median WHO growth standard for children, and obesity means having a BMI for height that is 3 standard deviations above the median WHO growth standard for children. Overweight and obesity are defined for children aged 5–19 years as follows: Overweight means having a BMI for age that is 1 standard deviation above the median WHO growth standard, and obesity means having a BMI for age that is 2 standard deviations above the median WHO growth standard.

[0276] Nevertheless, as illustrated in [Table 8] below for adults, diagnostic criteria for underweight, normal range, pre-obese / overweight, and obese can vary across countries / populations.

[0277] [Table 8-1] [Table 8-2]

[0278] Guidelines for Asian populations were published by Misra A et al. J Assoc Physicians India. 2009;57:163-70. Guidelines for Chinese populations were published 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. Guidelines for Japanese populations were published in 2016 by the Japanese Society for the Study of Obesity (JASSO) in Guidelines for the management of obesity disease. Guidelines for Taiwanese populations were published in 2023 by the Health Promotion Administration (HPA) and the Ministry of Health and Welfare of the Taiwanese government in the second edition of their “Evidence-Based Guideline on Adult Obesity Prevention and Management”.

[0279] In some embodiments, the subject suffering from obesity is a human being, such as an adult or a child (including infants, toddlers, and adolescents). Therefore, a human subject suffering from obesity may have a BMI of 25 or greater, or 27 or greater, or 28 or greater, or 30 or greater, and this subject may also be referred to as obese. Obesity can be Class I, Class II, Class III, or Class IV obesity (as defined in Table 8). In some embodiments, a 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 a human subject may have a BMI of ≥40.

[0280] In some embodiments, the present invention relates to methods for treating or preventing overweight in the presence of at least one weight-related comorbidity, at an optional choice. In one embodiment, the GLP-1 / GIP / amyrin receptor triple agonist disclosed herein is for use in the treatment of subjects having an initial body mass index (BMI) of 25 or greater, 27 or greater, 28 or greater, or 30 or greater, in the presence of at least one weight-related comorbidity, at an optional choice.

[0281] In some embodiments, the present invention relates to the use of formulations for the treatment or prevention of overweight in the presence of at least one weight-related comorbidity, which is optionally selected. In some embodiments, the overweight subject is a human being, such as an adult or a child (including infants, toddlers, and adolescents). In some embodiments, the overweight adult human subject may have a BMI of 23 or greater, or 24 or greater, or 25 or greater, or 27 or greater. In some embodiments, the overweight human subject has a BMI in the range of 24 to <27, 24 to <27, 24 to <28, 25 to <30, or 27 to <30. In some embodiments, the weight-related comorbidity is selected from the group consisting of hypertension, glycemic disorders (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 subjects.

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

[0284] The compounds disclosed herein may, optionally, be administered as an adjunct to a low-calorie diet and increased physical activity for chronic weight management in adult subjects who are obese, i.e., have an initial body mass index (BMI) of 25 or greater, or 27 or greater, or 28 or greater, or 30 or greater, in the presence of at least one weight-related comorbidity (e.g., hypertension, dysglycemic disorder (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, or obstructive sleep apnea), or in adult subjects who are overweight, i.e., have an initial body mass index (BMI) of 23 or greater, or 24 or greater, or 25 or greater, or 27 or greater.

[0285] Specific Embodiments 1. A GLP-1 / GIP / amyrin receptor triple agonist, comprising a peptide conforming to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide containing up to 5 amino acid substitutions. L1 is a peptide linker, and Z2 is a C-terminal amide, and formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP(V) is a peptide containing up to 10 amino acid substitutions, and is a GLP-1 / GIP / amyrin receptor triple agonist.

[0286] 2. GLP-1 / GIP / amyrin receptor triple agonists, comprising peptides conforming to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), preferably Arg(R). X 24 This represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E). X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This is a peptide containing or consisting of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 GLP-1 / GIP / amyrin receptor triple agonists are peptides containing or comprising a C-terminal amide (representing Leu(L) or Glu(E)).

[0287] 3. Peptides following formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide having up to 5 amino acid substitutions, and Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This includes or consists of Gly (G) or Glu (E), L1 is a peptide linker, and Z2 is a peptide containing a C-terminal amide, and Z2 has an amino acid sequence that follows formula VI (SEQ ID NO: 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting thereof (where represents Leu(L) or Glu(E)).

[0288] 4. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein Z1 is a peptide having up to four amino acid substitutions relative to formula II (sequence number 1).

[0289] 5. GLP-1 / GIP / amyrin receptor triple agonists, which are peptides conforming to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide having up to 4 amino acid substitutions. and Z1 follows the amino acid sequence of formula VII (sequence number 162): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 34This includes or consists of Gly (G) or Glu (E), L1 is a peptide linker, and Z2 contains a C-terminal amide, and formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP(V) is a peptide having up to 10 amino acid substitutions. and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 A GLP-1 / GIP / amyrin receptor triple agonist comprising or consisting of Leu(L) or Glu(E).

[0290] 6. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein 6.1 lysine (Lys, K) residues are present in peptide Z1 or peptide Z2.

[0291] 7. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein 7.1 lysine (Lys, K) residues are present in peptide Z1.

[0292] 8. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 6, wherein 8.1 lysine (Lys, K) residues are present in peptide Z2.

[0293] 9. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein formula I comprises one or less lysine (Lys, K) residues.

[0294] 10. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the GLP-1 / GIP / amyrin receptor triple agonist does not contain a cysteine ​​(Cys, C) residue.

[0295] 11. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the GLP-1 / GIP / amyrin receptor triple agonist does not contain disulfide crosslinking.

[0296] 12.X 12 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Lys(K).

[0297] 13.X 12 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of embodiments 1 to 11, wherein Ile(I).

[0298] 14.X 20 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Arg(R).

[0299] 15.X 20 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 13 is Gln(Q).

[0300] 16.X 24 is Glu(E), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of the preceding embodiments.

[0301] 17.X 24 is Ala(A), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of Embodiments 1 to 15.

[0302] 18.X 24 is Gln(Q), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of Embodiments 1 to 15.

[0303] 19.X 27 is Leu(L), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of the preceding embodiments.

[0304] 20.X 27 is Ile(I), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of Embodiments 1 to 18.

[0305] 21.X 28 is Ala(A), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of the preceding embodiments.

[0306] 22.X 28 is Gln(Q), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of Embodiments 1 to 20.

[0307] 23.X 30 is Gly(G), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of the preceding embodiments. [[ID=z]]

[0308] 24.X 30 is Ala(A), a GLP-1 / GIP / Amylin receptor triple agonist as described in any one of Embodiments 1 to 22.

[0309] 25.X 31 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of the prior embodiments, which is Pro(P).

[0310] 26.X 31 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of Embodiments 1 to 24, which is Ala(A).

[0311] 27.X 31 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of Embodiments 1 to 24, which is Gly(G).

[0312] 28.X 31 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of Embodiments 1 to 24, which is Gln(Q).

[0313] 29.X 33 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of the prior embodiments, which is Ser(S).

[0314] 30.X 33 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of Embodiments 1 to 28, which is Glu(E).

[0315] 31.X 34 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of the prior embodiments, which is Gly(G).

[0316] 32.X 34 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of Embodiments 1 to 30, which is Glu(E).

[0317] 33.X 30 X 31 is the GLP-1 / GIP / Amylin receptor triple agonist described in any one of the prior embodiments, which is Gly-Pro(GP).

[0318] 34.X 30 X 31 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 32 is Gly-Ala (GA).

[0319] 35.X 30 X 31 However, Ala-Pro(AP) is a GLP-1 / GIP / amyrin receptor triple agonist as described in any one of Embodiments 1 to 32.

[0320] 36.X 30 X 31 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 32 is Gly-Gly (GG).

[0321] 37.X 31 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 32, wherein the GLP-1 / GIP / amyrin receptor triple agonist represents Gly(G), Gln(Q), or Ala(A).

[0322] 38.Z1 is an amino acid sequence that follows formula IV (sequence number 169): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGX 30 X 31 SSG (IV) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 27 This represents Leu (L) or Ile (I), X 30 This represents Gly (G) or Ala (A), X 31 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting thereof (wherein represents Ala(A), Gly(G), or Pro(P)).

[0323] 39.Z1 is an amino acid sequence that follows formula XI (sequence number 163): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLLAGGPSSG (XI) (In the formula, X2 represents Aib, X 12 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting thereof (where is Ile(I) or Lys(K)).

[0324] 40. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein Z1 comprises or consists of an amino acid sequence selected from the following list. [Table 9] (In the equation, X2 is Aib.)

[0325] 41. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein Z1 comprises or consists of an amino acid sequence selected from the following list. [Table 10] (In the equation, X2 is Aib.)

[0326] 42. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein Z1 comprises or consists of the amino acid sequence of Sequence ID No. 22.

[0327] 43. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 41, wherein Z1 comprises or consists of the amino acid sequence of Sequence ID No. 29.

[0328] 44. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 41, wherein Z1 comprises or consists of the amino acid sequence of Sequence ID No. 31.

[0329] 45. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 41, wherein Z1 comprises or consists of the amino acid sequence of Sequence ID No. 34.

[0330] 46. ​​A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide linker L1 comprises 1 to 14, 1 to 10, 2 to 9, or 5 amino acid residues.

[0331] 47. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, 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), and Asn(N).

[0332] 48. The amino acid sequence of peptide linker L1 follows formula VIIIa: X 141 X 142 X 143 X 144 X 145 X 146 X 147 X 148 X 149 X 150 X 151 X 152 X 153 X 154 (VIIIa) (In the formula, X 141 These represent Ala (A), Glu (E), and Gly (G), X 142 This represents Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), or does not exist. X 143This represents Ala(A), Gln(Q), Glu(E), Gly(G), Pro(P), or does not exist. X 144 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Pro(P), or does not exist. X 145 This represents Glu(E), Gly(G), Pro(P), Ser(S), Thr(T), or does not exist. X 146 This represents Glu(E), Gly(G), Leu(L), Gln(Q), or does not exist. X 147 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Phe(F), or does not exist. X 148 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Thr(T), Pro(P), Val(V), or does not exist. X 149 This represents Glu(E), Asn(N), Pro(P), Thr(T), or does not exist. X 150 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), Val(V), or does not exist. X 151 This represents Ala(A), or does not exist. X 152 This represents Gln(Q), or does not exist. X 153 This represents Thr(T), or does not exist. X 154 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting of Leu(L) (or not present).

[0333] 49. The GLP-1 / GIP / amylin receptor triple agonist according to any one of the preceding embodiments, wherein the peptide linker L1 comprises 1 to 10 amino acid residues selected from the group consisting of Ala (A), Glu (E), Gln (Q), Gly (G), Leu (L), Pro (P), Ser (S), and Val (V).

[0334] 50. The peptide linker L1 has an amino acid sequence according to formula VIII: X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII) (wherein, X 41 represents Ala (A), Gly (G) or Glu (E), X 42 represents Glu (E), Gly (G), or does not exist, X 43 represents Glu (E), Gly (G), Gln (Q), or does not exist, X 44 represents Ala (A), Glu (E), Gly (G), or does not exist, X 45 represents Glu (E), Gly (G), Pro (P), or does not exist, X 46 represents Glu (E), Gly (G), or does not exist, X 47 represents Gln (Q), Glu (E), or does not exist, X 48 represents Ala (A), Glu (E), or does not exist, X 49 represents Glu (E), Pro (P), or does not exist, X 50A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting of (wherein represents Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(s), Val(V), or not present).

[0335] 51. The amino acid sequence of peptide linker L1 follows formula VIII: X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII) (In the formula, X 41 This represents Ala (A) or Glu (E), X 42 This represents Glu(E), Gly(G), or does not exist. X 43 This represents Glu(E), Gly(G), Gln(Q), or does not exist. X 44 This represents Ala(A), Glu(E), Gly(G), or does not exist. X 45 This represents Glu(E), Gly(G), Pro(P), or does not exist. X 46 This represents Glu(E), Gly(G), or does not exist. X 47 This represents Gln(Q), Glu(E), or does not exist. X 48 This represents Ala(A), Glu(E), or does not exist. X 49 This represents Glu(E), Pro(P), or does not exist. X 50A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting of (wherein represents Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(s), Val(V), or not present).

[0336] 52. Peptide linker L1 is A, E, G, AE, AG, 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), AGGGG (SEQ ID NO: 142), AGE42), AGEAPGQAPG (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), AGGGG (SEQ ID NO: 142), AGEAPGQAP Column number 143), AGEAPGEAPG (sequence number 144), AGQAPGQAPA (sequence number 145), AGQAPGQAPE (sequence number 146), AGQAPGQAPP (sequence number 147), AGQAPGQAPS (sequence number 148), AGQAPGQAPV (sequence number 149), EGQAPGQAPG (sequence number 150), AGQEPGQAPG (sequence number 151), AGQAEGQAPG (sequence number 152), AGQ A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments, selected from the group consisting of APEQAPG (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).

[0337] 53. Peptide linker L1 is A, E, G, AE, AG, GE, AGGGG (SEQ ID NO: 142), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), 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 ( A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, selected from the group consisting of 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).

[0338] 54. Peptide linker L1 is E, AE, AG, AGGGG (SEQ ID NO: 142), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), AGEAPGQAPG (SEQ ID NO: 143), AGEAPGEAPG A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments, selected from the group consisting of (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).

[0339] 55. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide linker L1 is selected from the group consisting of AG and AGEAPGEAPG (SEQ ID NO: 144).

[0340] 56.X 52 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Ser(S).

[0341] 57.X 52 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 55 is Gly(G).

[0342] 58.X 53 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Glu(E).

[0343] 59.X 53 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 57 is His(H).

[0344] 60.X 53 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 57 is Gln(Q).

[0345] 61.X 58 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Ala(A).

[0346] 62.X 58 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 60 is Gln(Q).

[0347] 63.X 59 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Leu(L).

[0348] 64.X 59 However, the GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 62 is Thr(T).

[0349] 65.X 60 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Gly(G).

[0350] 66.X 60 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 64 is Gln(Q).

[0351] 67.X 60 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of embodiments 1 to 64, wherein Ala(A).

[0352] 68.X 68 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Gln(Q).

[0353] 69.X 68 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of embodiments 1 to 67 is Glu(E).

[0354] 70.X 68 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 67 is Lys(K).

[0355] 71.X 72 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments is Leu(L).

[0356] 72.X 72 However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 70 is Glu(E).

[0357] 73.Z2 is the amino acid sequence that follows formula IX (sequence number 61): ASX 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATLPRTETGSGSP(IX) (In the formula, X 53 This represents Glu (E) or His (H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Gly(G) or Gln(Q), X 68 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting thereof (wherein represents Gln(Q), Glu(E), or Lys(K)).

[0358] 74.Z2 is the amino acid sequence that follows formula X (sequence number 166): ASX 53 LSTAQTQRLSAELHKLATLPRTETGSGSP (X) (In the formula, X 53 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting thereof (where is Glu(E) or His(H)).

[0359] 75. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein Z2 comprises or consists of an amino acid sequence selected from the group consisting of the following. [Table 11]

[0360] 76. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein Z2 comprises or consists of an amino acid sequence selected from the group consisting of the following. [Table 12]

[0361] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein 77.Z2 comprises or consists of the amino acid sequence of Sequence ID No. 59.

[0362] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 76, wherein 78.Z2 comprises or consists of the amino acid sequence of Sequence ID No. 40.

[0363] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 76, wherein 79.Z2 comprises or consists of the amino acid sequence of Sequence ID No. 53.

[0364] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 76, wherein 80.Z2 comprises or consists of the amino acid sequence of Sequence ID No. 2.

[0365] 81. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting of the amino acid sequence of peptide Z1-L1-Z2 as follows: Z1 is selected from the following group: [Table 13] L1, E, AE, AG, AGGGG (SEQ ID NO: 142), AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), 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), EGQA Selected from the group consisting of PGQAPG (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), Z2 is selected from the following group: [Table 14-1] [Table 14-2]

[0366] 82. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting of the amino acid sequence of peptide Z1-L1-Z2 as follows: Z1 is selected from the following group: [Table 15] L1 is selected from the group consisting of AG and AGEAPGEAPG (SEQ ID NO: 144), Z2 is selected from the following group: [Table 16]

[0367] 83. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein peptide Z1-L1-Z2 comprises or consists of an amino acid sequence selected from the group comprising SEQ ID NOs. 170-252.

[0368] 84. Peptides Z1-L1-Z2 are YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAQLGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 230), or YX2EGTFTSDYSILLEEIAAREFIEWLLAGGASSGAGEAPGEAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 243), or YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 244), or YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 246), or YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (SEQ ID NO: 250), or YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGGSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence ID 251), or A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising or consisting of an amino acid sequence selected from the group consisting of YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (SEQ ID NO: 252) (wherein each X2 is Aib).

[0369] 85. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide Z1-L1-Z2 skeleton comprises or consists of 66 to 80 amino acid residues, for example, 66 to 76 amino acid residues or 67 to 75 amino acid residues.

[0370] 86. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide Z1-L1-Z2 skeleton comprises or consists of 67, 68, 71, 75, or 76 amino acid residues.

[0371] 87. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide Z1-L1-Z2 skeleton contains or consists of 68 amino acid residues.

[0372] 88. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide Z1-L1-Z2 skeleton contains or consists of 76 amino acid residues.

[0373] 89. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein peptides Z1-L1-Z2 are peptide derivatives including the extended portion.

[0374] 90. Peptide Z1-L1-Z2 is a peptide derivative containing an extended portion, and the extended portion is C 12 ~C 20 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising protractor P, which is a diacid.

[0375] 91. Peptide Z1-L1-Z2 is a peptide derivative containing an extended portion, and the extended portion is [ka] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, comprising protractor P selected from the group consisting of the following.

[0376] 92. Peptide Z1-L1-Z2 is a peptide derivative containing an extended portion, and the extended portion is C 18 diacid, C 20 Diacids, and C 19 It comprises a protractor P selected from the group consisting of phosphonic acids, preferably protractor P is C 20 A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments, which is a diacid (chemical formula 6).

[0377] 93. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein peptide Z1-L1-Z2 is a peptide derivative containing an extended portion, the extended portion being bound to the epsilon position of a single lysine (Lys, K) residue.

[0378] 94. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein peptides Z1-L1-Z2 are peptide derivatives including an extended portion, the extended portion being bound to the epsilon amino group of a lysine (Lys,K) residue in peptide Z1, or to the epsilon amino group of a lysine (Lys,K) residue in peptide Z2.

[0379] 95. Peptide Z1-L1-Z2 is a peptide derivative containing an extended portion, and the extended portion is at position 12 (X) of peptide Z1. 12 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein one lysine (Lys, K) is bound to the epsilon amino group in )

[0380] 96. Peptide Z1-L1-Z2 is a peptide derivative containing an extended portion, and the extended portion is at position 18 (X) of peptide Z2. 68A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein one lysine (Lys, K) is bound to the epsilon amino group in )

[0381] 97. Peptides Z1-L1-Z2 are peptide derivatives containing an extended portion, and the extended portion is a linker L selected from the group consisting of the following. P A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, further comprising: [ka]

[0382] 98. Peptides Z1-L1-Z2 are peptide derivatives containing an extended portion, wherein the extended portion is a linker L selected from the group consisting of chemical formulas 20, 33, and 34. P It further includes, preferably, linker L P However, the GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments has chemical formula 20.

[0383] 99. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide Z1-L1-Z2 is a peptide derivative containing an extended portion, and the extended portion is selected from the group consisting of the following: [ka] [ka] [ka] (In the formula, R1 is the bond site of the epsilon-amino group of lysine (Lys, K).)

[0384] 100. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide Z1-L1-Z2 is a peptide derivative including an extended portion, and the extended portion is selected from the group consisting of chemical formulas 27, 35, 36, and 37.

[0385] 101. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein peptide Z1-L1-Z2 is a peptide derivative including an extended portion, and the extended portion has chemical formula 27.

[0386] 102. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein peptide Z1-L1-Z2 is a peptide derivative selected from the group consisting of compound numbers 104-197 of Example 2 herein.

[0387] 103. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein peptide Z1-L1-Z2 is a peptide derivative selected from the group consisting of compound numbers 104-193 and 196-197 of Example 2 herein.

[0388] 104. Compound 104 of Example 2 in this specification, a GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the prior embodiments. [ka]

[0389] 105. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 103, wherein compound 105 of Example 2 in this specification. [ka]

[0390] 106. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 103, wherein compound 107 of Example 2 in this specification. [ka]

[0391] 107. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 103, wherein compound 111 of Example 2 in this specification. [ka]

[0392] 108. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 103, wherein compound 112 of Example 2 in this specification. [ka]

[0393] 109. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 103, wherein compound 113 of Example 2 in this specification. [ka]

[0394] 110. Compound 183 of Example 2 in this specification: [ka] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of embodiments 1 to 103.

[0395] 111. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the peptide has a C-terminal amide modification.

[0396] 112. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which can activate the human GIP receptor.

[0397] 113. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which can activate the human GIP receptor in an assay using whole cells expressing the human GIP receptor.

[0398] 114. When measured without HSA in the assay described in Example 4, human GIP receptors were measured in vitro, preferably with an EC of less than 125 pM. 50 And, more preferably, an EC of less than 100 pM 50 Therefore, most preferably, the EC is less than 50 pM. 50 A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments, which is activated by [the specified agent].

[0399] 115. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which can activate the human GLP-1 receptor.

[0400] 116. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which can activate the human GLP-1 receptor in an assay using whole cells expressing the human GLP-1 receptor.

[0401] 117. When measured without HSA in the assay described in Example 4, human GLP-1 receptors were measured in vitro, preferably with an EC of less than 125 pM. 50 And, more preferably, an EC of less than 100 pM 50 Therefore, most preferably, the EC is less than 50 pM. 50 A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments, which is activated by [the specified method].

[0402] 118. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which can activate the human amyrin receptor.

[0403] 119. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which can activate the human amyrin receptor in an assay using whole cells expressing the human amyrin receptor.

[0404] 120. When measured without HSA in the assay described in Example 4, human amyrin receptors were measured in vitro, preferably with an EC of less than 125 pM. 50 And, more preferably, an EC of less than 100 pM 50 Therefore, most preferably, the EC is less than 50 pM. 50 A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments, which is activated by [the specified method].

[0405] 121. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which can activate the human GIP receptor, the human GLP-1 receptor, and the human amyrin receptor.

[0406] 122. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which can activate human GIP receptor, human GLP-1 receptor, and human amyrin receptor in an assay using whole cells expressing human GIP receptor, human GLP-1 receptor, and human amyrin receptor.

[0407] 123. As described in Example 4, when measured without HSA, human GIP receptor, human GLP-1 receptor, and human amyrin receptor were measured in vitro, preferably with an EC of less than 125 pM. 50 And, more preferably, an EC of less than 100 pM 50 Therefore, most preferably, the EC is less than 50 pM. 50 A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments, which is activated by [the specified method].

[0408] 124. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, which activates the human GIP receptor, human GLP-1 receptor, and human amyrin receptor in vitro when measured without HSA, and has an efficacy ratio of less than 50, e.g., less than 30.

[0409] 125. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the potency ratio is less than 20.

[0410] 126. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, wherein the potency ratio is less than 15, most preferably less than 10.

[0411] 127. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, having improved pharmacokinetic properties.

[0412] 128. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, having an increased half-life.

[0413] 129. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, having an increased half-life of 80 to 200 hours, preferably 90 to 190 hours, and more preferably 95 to 185 hours, as determined in the miniature pig described in Example 6.

[0414] 130. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, having an increased half-life of 40 to 145 hours, preferably 90 to 140 hours, and more preferably 85 to 125 hours, as determined in the miniature pig described in Example 6.

[0415] 131. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, having an extended half-life of 5 to 50 hours, preferably 10 to 35 hours, and more preferably 12 to 30 hours, as determined in the rats described in Example 6.

[0416] 132. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, having improved chemical stability.

[0417] 133. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, having improved chemical stability and having a purity loss of 5.0 percent or less per week, preferably less than 3.0 percent per week, and more preferably less than 2.0 percent per week, as determined by Example 7 described herein, etc.

[0418] 134. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior embodiments, having an in vivo effect of reducing food intake in normal-weight rats, as determined by an experimental protocol for efficacy testing on appetite, such as Example 5 described herein.

[0419] 135. A pharmaceutically acceptable salt of a GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the prior embodiments.

[0420] 136. A pharmaceutical composition comprising a GLP-1 / GIP / amyrin receptor triple agonist described in any one of the prior embodiments, and one or more pharmaceutically acceptable excipients.

[0421] 137. The pharmaceutical composition according to Embodiment 136 for oral or subcutaneous administration.

[0422] 138. A pharmaceutical composition according to either embodiment 136 or 137, which is a solid pharmaceutical composition.

[0423] 139. A solid pharmaceutical composition according to Embodiment 138, which is a tablet.

[0424] 140. A solid pharmaceutical composition according to either one of Embodiment 138 or Embodiment 139, comprising a salt of N-[8-(2-hydroxybenzoyl)amino]caprylate, preferably sodium N-(8-(2-hydroxybenzoyl)amino)caprylate and magnesium stearate.

[0425] A solid pharmaceutical composition according to any one of Embodiments 138 to 140, comprising 141.75 to 600 mg of sodium N-(8-(2-hydroxybenzoyl)amino)caprylate and 7 to 8.5 mg of magnesium stearate.

[0426] 142. A pharmaceutical composition according to any one of embodiments 136 to 141, for administration approximately once a day, for example, once every 12 to 36 hours, for example, once every 18 to 30 hours, for example, once every 24 hours, or for administration approximately once a week, for example, once every 6 to 8 days.

[0427] 143. An injection device comprising a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135, or a pharmaceutical composition according to any one of Embodiments 136 to 142.

[0428] 144. A GLP-1 / GIP / amyrin receptor triple agonist peptide according to any one of Embodiments 1 to 88, for use as an intermediate in the production of a GLP-1 / GIP / amyrin receptor triple agonist peptide derivative according to any one of Embodiments 89 to 135.

[0429] 145. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135, or a pharmaceutical composition according to any one of Embodiments 136 to 142, for use as a pharmaceutical.

[0430] 146. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135, or a pharmaceutical composition according to any one of Embodiments 136 to 142, for use in the treatment of type 2 diabetes, obesity, metabolic dysfunction-associated steatohepatitis (MASH), and / or cardiovascular disease.

[0431] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135, or a pharmaceutical composition according to any one of Embodiments 136 to 142, for use in the treatment of subjects having an initial body mass index (BMI) of 147.25 or higher, 27 or higher, 28 or higher, or 30 or higher.

[0432] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135, or a pharmaceutical composition according to any one of Embodiments 136 to 142, for use in the treatment of subjects having an initial body mass index (BMI) of 148.25 or higher, 27 or higher, or 28 or higher, 30 or higher, in the presence of at least one weight-related comorbidity.

[0433] 149. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135, or a pharmaceutical composition according to any one of Embodiments 136 to 142, for use as an adjunct to a low-calorie diet and increased physical activity for chronic weight management in adult subjects suffering from obesity, i.e., an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher, or in adult subjects suffering from overweight, i.e., an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher.

[0434] 150. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135, or a pharmaceutical composition according to any one of Embodiments 136 to 124, for use as an adjunct to a low-calorie diet and increased physical activity for chronic weight management in adult subjects who are obese, i.e., have an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 30 or higher, in the presence of at least one weight-related comorbidity, or in adult subjects who are overweight, i.e., have an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher.

[0435] 151. Use according to Embodiment 148 or Embodiment 150, wherein at least one weight-related comorbidity is selected from the group consisting of hypertension, glycemic disorders (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, and obstructive sleep apnea.

[0436] 152. Use of a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135 or a pharmaceutical composition according to any one of Embodiments 136 to 142 in the manufacture of a pharmaceutical for the treatment of type 2 diabetes, obesity, metabolic dysfunction-associated steatohepatitis (MASH), and / or cardiovascular disease.

[0437] 153. Use of a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135 or a pharmaceutical composition according to any one of Embodiments 136 to 142 in the manufacture of a pharmaceutical for the treatment of subjects having an initial body mass index (BMI) of 25 or greater, 27 or greater, or 28 or greater, or 30 or greater, in the presence of at least one weight-related comorbidity of any choice.

[0438] 154. Use of a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135 or a pharmaceutical composition according to any one of Embodiments 136 to 142 in the manufacture of a pharmaceutical for the treatment of an adult subject suffering from obesity, i.e., having an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher, or an adult subject suffering from overweight, i.e., having an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher, in the presence of at least one weight-related comorbidity of any choice.

[0439] 155. Use of a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135 or a pharmaceutical composition according to any one of Embodiments 136 to 142 in the manufacture of a pharmaceutical for chronic weight management in adult subjects suffering from obesity, i.e., an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher, or in adult subjects suffering from overweight, i.e., an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher, in the manufacture of a pharmaceutical for chronic weight management in adult subjects suffering from obesity, i.e., an initial body mass index (BMI) of 25 or higher, or 24 or higher, or 25 or higher, or 27 or higher, in the presence of at least one weight-related comorbidity of any choice.

[0440] 156. The use of the pharmacopoeia according to Embodiment 154 or Embodiment 155, in which the pharmacopoeia is an adjunct to a low-calorie diet and increased physical activity for chronic weight management in adult subjects suffering from obesity or overweight.

[0441] 157. A method for treating type 2 diabetes, obesity, metabolic dysfunction-associated steatohepatitis (MASH), and / or cardiovascular disease, comprising administering a pharmaceutically appropriate amount of a GLP-1 / GIP / amyrin receptor triple agonist described in any one of embodiments 1 to 135 to a person in need thereof.

[0442] 158. A method for treating a human subject whose initial body mass index (BMI) is 25 or greater, 27 or greater, 28 or greater, or 30 or greater, comprising administering to the human subject a pharmaceutically appropriate amount of a GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 135.

[0443] 159. A method for reducing excess body weight in a human subject, comprising administering to the human subject a pharmaceutically appropriate amount of a GLP-1 / GIP / amyrin receptor triple agonist described in any one of Embodiments 1 to 135, in combination with a low-calorie diet and increased physical activity.

[0444] 160. The method according to Embodiment 158 ​​or Embodiment 159, wherein the human subject is an adult subject suffering from overweight and has an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher.

[0445] 161. The method according to Embodiment 158 ​​or Embodiment 159, wherein the human subject is an adult subject suffering from obesity and has an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher.

[0446] 162. The method according to any one of embodiments 158 to 161, wherein the human subject has at least one weight-related comorbidity selected from the group consisting of hypertension, glycemic disorder (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, and obstructive sleep apnea.

[0447] 163. A method for preparing a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Embodiments 1 to 135.

[0448] 164. The method according to Embodiment 163, comprising a step of solid-phase peptide synthesis.

[0449] Specific alternative embodiments 1. A GLP-1 / GIP / amyrin receptor triple agonist, comprising a peptide conforming to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide containing up to four amino acid substitutions. L1 is a peptide linker, and Z2 is a C-terminal amide, and formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (V) is a peptide containing up to 10 amino acid substitutions, and is a GLP-1 / GIP / amyrin receptor triple agonist.

[0450] 2. The GLP-1 / GIP / amyrin receptor triple agonist according to Alternative Embodiment 1, wherein 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 with formula II (SEQ ID NO: 1), and 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 with formula V (SEQ ID NO: 2).

[0451] 3. A GLP-1 / GIP / amyrin receptor triple agonist according to alternative embodiments 1-2, wherein one lysine (Lys, K) residue is present in peptide Z1 or peptide Z2.

[0452] 4. GLP-1 / GIP / amyrin receptor triple agonists according to alternative embodiments 1-3, wherein the GLP-1 / GIP / amyrin receptor triple agonist does not contain a cysteine ​​(Cys,C) residue.

[0453] 5. GLP-1 / GIP / amyrin receptor triple agonists according to alternative embodiments 1 to 4, wherein the GLP-1 / GIP / amyrin receptor triple agonist does not contain disulfide crosslinking.

[0454] 6. Z1 is given by Equation II (Sequence No. 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide having up to 4 amino acid substitutions. and Z1 follows the amino acid sequence of formula VII (sequence number 162): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 34 This includes or consists of Gly (G) or Glu (E), L1 is a peptide linker, and Z2 contains a C-terminal amide and is of formula V (SEQ ID NO: 2): ASELSTAALGRLSAELHELATLPRTETGSGSP(V) It is a peptide having up to 10 amino acid substitutions, and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 A GLP-1 / GIP / amyrin receptor triple agonist according to Alternative Embodiments 1-5, comprising or consisting thereof (where represents Leu(L) or Glu(E)).

[0455] 7. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 6, wherein the peptide linker L1 comprises 1 to 14, 1 to 10, 4 to 10, or 9 to 10 amino acid residues.

[0456] 8. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 7, 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), and Asn(N).

[0457] 9. The amino acid sequence of peptide linker L1 follows formula VIIIa: X 141 X 142 X143 X 144 X 145 X 146 X 147 X 148 X 149 X 150 X 151 X 152 X 153 X 154 (VIIIa) (In the formula, X 141 These represent Ala (A), Glu (E), and Gly (G), X 142 This represents Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), or does not exist. X 143 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Pro(P), or does not exist. X 144 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Pro(P), or does not exist. X 145 This represents Glu(E), Gly(G), Pro(P), Ser(S), Thr(T), or does not exist. X 146 This represents Glu(E), Gly(G), Leu(L), Gln(Q), or does not exist. X 147 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Phe(F), or does not exist. X 148 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Thr(T), Pro(P), Val(V), or does not exist. X 149 This represents Glu(E), Asn(N), Pro(P), Thr(T), or does not exist. X 150 This represents Ala(A), Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), Val(V), or does not exist. X 151 This represents Ala(A), or does not exist. X 152 This represents Gln(Q), or does not exist. X 153 This represents Thr(T), or does not exist. X 154 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 1 to 8, comprising or consisting of Leu(L) (or not present).

[0458] 10. Peptide linker L1 is 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), ALQAPGQAP G (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), AGGGG (SEQ ID NO: 142), AGEAPGQAPG (SEQ ID NO: 143), AGEAPG EAPG (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), AG A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 9, comprising or consisting of an amino acid sequence selected from the group consisting of QAPGEAPG (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).

[0459] 11. A GLP-1 / GIP / amyrin receptor triple agonist according to alternative embodiment 10, wherein the peptide linker L1 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).

[0460] 12. The amino acid sequence of peptide Z2 follows formula XIV (sequence number 4): ASX 53 LSTAX 58 X 59 X 60 RLSAX 65 LHX 68 LX 70 X 71 LPX 74 TETGSGX 81 P(XIV) (In the formula, X 53 This represents Lys(K), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Gln(Q), Leu(L), or Thr(T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 65 This represents Glu(E), X 68 This represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), X 70 This represents Ala(A), X 71 This represents Asp(D) or Thr(T), X 74 This represents Arg(R), X 81 This represents Ala (A) or Ser (S). or X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Gln(Q), Leu(L), or Thr(T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X65 This represents Lys(K), X 68 This represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), X 70 This represents Ala(A), X 71 This represents Asp(D) or Thr(T), X 74 This represents Arg(R), X 81 This represents Ala (A) or Ser (S). or X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Gln(Q), Leu(L), or Thr(T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 65 This represents Glu(E), X 68 This represents Lys(K), X 70 This represents Ala(A), X 71 This represents Asp(D) or Thr(T), X 74 This represents Arg(R), X 81 This represents Ala (A) or Ser (S). or X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Gln(Q), Leu(L), or Thr(T), X 60This represents Ala (A), Gly (G), or Gln (Q), X 65 This represents Glu(E), X 68 This represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), X 70 This represents Lys(K), X 71 This represents Asp(D) or Thr(T), X 74 This represents Arg(R), X 81 This represents Ala (A) or Ser (S). or X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Gln(Q), Leu(L), or Thr(T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 65 This represents Glu(E), X 68 This represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), X 70 This represents Ala(A), X 71 This represents Asp(D) or Thr(T), X 74 This represents Lys(K), X 81 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 1-5 and 7-11, comprising or consisting thereof (where represents Ala(A) or Ser(S)).

[0461] 13. The amino acid sequence of peptide Z1 follows formula VX (sequence number 167): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGGPSSX 34 (VX) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 27 This represents Leu (L) or Ile (I), X 34 A GLP-1 / GIP / amyrin receptor triple agonist according to Alternative Embodiment 6, comprising or consisting thereof (where is Gly(G) or Glu(E)).

[0462] 14. Peptide Z2 has the following amino acid sequence: A GLP-1 / GIP / amyrin receptor triple agonist according to Alternative Embodiment 6 or Alternative Embodiment 13, comprising or consisting of ASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 40).

[0463] 15. The amino acid sequence of peptide Z1 follows formula XV (sequence ID 167): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGGPSSX 34 (XV) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 27 This represents Leu (L) or Ile (I), X 34 This includes or consists of Gly(G) or Glu(E), and Peptide Z2 has the following amino acid sequence: A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 6, 13, or 14, comprising or consisting of ASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 40).

[0464] 16. The amino acid sequence of peptide Z1 follows formula XI (sequence number 163): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLLAGGPSSG(XI) (In the formula, X2 represents Aib, X 12 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 6 or 13-15, comprising or consisting thereof (where is Ile(I) or Lys(K)).

[0465] 17. The amino acid sequence of peptide Z2 follows formula X (sequence number 166): ASX 59 LSTAQTQRLSAELHKLATLPRTETGSGSP(X) (In the formula, X 59 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 6 or 13-16, comprising or consisting thereof (where is Glu(E) or His(H)).

[0466] 18. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1-5 and 7-11, wherein peptide Z1-L1-Z2 comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs. 170-242 (wherein X2 represents Aib).

[0467] 19. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide Z1-L1-Z2 skeleton comprises 66 to 80 amino acid residues.

[0468] 20. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide Z1-L1-Z2 skeleton comprises 67, 68, 75, or 76 amino acid residues, preferably 76 amino acid residues.

[0469] 21. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide is a peptide derivative comprising an extended portion.

[0470] 22. The peptide is a peptide derivative including an extended portion, and the extended portion is C 12 ~C 20 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, comprising protractor P, which is a diacid.

[0471] 23. The peptide is a peptide derivative including an extended portion, and the extended portion is [ka]

[0472] 24. The peptide is a peptide derivative including an extended portion, and the extended portion is C 16 diacid, C 18 diacid, C 20 Diacids, and C 19 It comprises a protractor P selected from the group consisting of phosphonic acids, preferably protractor P is C 18 Diacid or C 20 A GLP-1 / GIP / amyrin receptor triple agonist, which is a diacid, as described in any one of the prior alternative embodiments.

[0473] 25. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide is a peptide derivative comprising an extension, the extension being bound to the epsilon position of a single lysine (Lys, K) residue.

[0474] 26. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide is a peptide derivative comprising an extension, the extension being bound to the epsilon position of a lysine (Lys,K) residue in peptide Z1 or to the epsilon position of a lysine (Lys,K) residue in peptide Z2.

[0475] 27. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide is a peptide derivative comprising an extension, the extension being bound to the epsilon position of a lysine (Lys, K) residue at position 12, 33, or 34 of peptide Z1, preferably at position 12 or 33 of peptide Z1.

[0476] 28. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide is a peptide derivative comprising an extension, the extension being bound to the epsilon position of a lysine (Lys, K) residue at position 3, 15, 18, 20, or 24 of peptide Z2.

[0477] 29. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide is a peptide derivative comprising an extension, the extension being bound to the epsilon position of a lysine (Lys, K) residue at position 15 or 18 of peptide Z2.

[0478] 30. The peptide is a peptide derivative containing an extended portion, and the extended portion is a linker L selected from the group consisting of the following. P GLP-1 / GIP / amyrin receptor triple agonists as described in any one of the prior alternative embodiments, further including: [ka]

[0479] 31. The peptide is a peptide derivative containing an extended portion, wherein the extended portion is linked to chemical formula 20 or chemical formula 21 by linker L P A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, comprising chemical formula 5 or chemical formula 6 as protractor P.

[0480] 32. The peptide is a peptide derivative containing an extended portion. The extended portion is (i) a linker L selected from the group shown in [Table 6]. P (ii) a protractor P selected from the group presented in [Table 5], wherein the extended portion is selected from the group presented in [Table 7], and is a GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments.

[0481] 33. The peptide is a peptide derivative including an extended portion, and the extended portion is C 18 Diacid (S) gamma-Glu 2xAdo fatty acid moiety (chemical formula 28) or C 20 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, comprising the diacitic (S)gamma-Glu 2xAdo fatty acid moiety (chemical formula 27).

[0482] 34. The amino acid sequence of peptide Z1 follows formula VII (sequence number 162): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 34 This includes or consists of Gly (G) or Glu (E), Peptide linker L1 contains or consists of an amino acid sequence selected from the group consisting of E, AG, AGQAPGQAPG (SEQ ID NO: 136), AGQAPGQAPL (SEQ ID NO: 137), AGGGG (SEQ ID NO: 142), AGEAPGQAPG (SEQ ID NO: 143), and AGQAPGEAPG (SEQ ID NO: 154). Peptide Z2 has the amino acid sequence following formula VI (SEQ ID NO: 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 (representing Leu(L) or Glu(E)) contains or consists of, A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 1 to 33, wherein the peptide is a peptide derivative containing an extended portion.

[0483] 35. The peptide is a peptide derivative including an extended portion, and the extended portion is C 12 ~C 20 A GLP-1 / GIP / amyrin receptor triple agonist according to alternative embodiment 34, comprising protractor P, which is a diacid.

[0484] 36. The peptide is a peptide derivative containing an extended portion, and the extended portion is a linker L selected from the group shown in [Table 6]. P A GLP-1 / GIP / amyrin receptor triple agonist according to alternative embodiment 35, further comprising the above.

[0485] 37. The amino acid sequence of peptide Z1 follows formula XI (sequence number 163): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLLAGGPSSG(XI) (In the formula, X2 represents Aib, X 12 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 34 to 36, comprising or consisting thereof (where is Ile(I) or Lys(K)).

[0486] 38. The amino acid sequence of peptide Z2 follows formula X (sequence number 166): ASX 59 LSTAQTQRLSAELHKLATLPRTETGSGSP(X) (In the formula, X 59 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 34 to 37, comprising or consisting thereof (where is Glu(E) or His(H)).

[0487] 39. GLP-1 / GIP / amyrin receptor triple agonists, which are peptides conforming to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide having up to 4 amino acid substitutions. and Z1 follows the amino acid sequence of formula VII (sequence number 162): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII) (In the formula, X2 represents Aib, X 22 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 34 This includes or consists of Gly (G) or Glu (E), L1 is a peptide linker containing or consisting of 1-14, 1-10, 4-10, or 9-10 amino acid residues, and Z2 contains a C-terminal amide, Equation V (Sequence ID 2): ASELSTAALGRLSAELHELATLPRTETGSGSP (V) is a peptide having up to 10 amino acid substitutions. and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 This includes or consists of Leu (L) or Glu (E), The peptide is a peptide derivative including an extended portion, and the extended portion is C 16 ~C 20 The protractor P is a diacid, and the linker L is selected from the group shown in [Table 6]. P A GLP-1 / GIP / amyrin receptor triple agonist, which also includes the following.

[0488] 40. A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the preceding alternative embodiments, wherein the compound is selected from compound numbers 120-197 and 211-221 of Example 2 as described herein.

[0489] 41. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, wherein the peptide has a C-terminal amide modification.

[0490] 42. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, which can activate the human GIP receptor.

[0491] 43. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, which can activate the human GIP receptor in an assay using whole cells expressing the human GIP receptor.

[0492] 44. When measured without HSA in the assay described in Example 4, human GIP receptors were measured in vitro, preferably with an EC of less than 125 pM. 50 And, more preferably, an EC of less than 100 pM 50 Therefore, most preferably, the EC is less than 50 pM. 50 A GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding alternative embodiments, which is activated by [unspecified action].

[0493] 45. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, which can activate the human GLP-1 receptor.

[0494] 46. ​​A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, which can activate the human GLP-1 receptor in an assay using whole cells expressing the human GLP-1 receptor.

[0495] 47. When measured without HSA in the assay described in Example 4, human GLP-1 receptors were measured in vitro, preferably with an EC of less than 125 pM. 50 And, more preferably, an EC of less than 100 pM 50 Therefore, most preferably, the EC is less than 50 pM. 50 A GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding alternative embodiments, which is activated by [unspecified action].

[0496] 48. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, which can activate the human amyrin receptor.

[0497] 49. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, which can activate the human amyrin receptor in an assay using whole cells expressing the human amyrin receptor.

[0498] 50. When measured without HSA in the assay described in Example 4, the human amyrin receptor was measured in vitro, preferably with an EC of less than 125 pM. 50 And, more preferably, an EC of less than 100 pM 50 Therefore, most preferably, the EC is less than 50 pM. 50 A GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding alternative embodiments, which is activated by [unspecified action].

[0499] 51. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, which can activate the human GIP receptor, the human GLP-1 receptor, and the human amyrin receptor.

[0500] 52. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the prior alternative embodiments, which can activate human GIP receptor, human GLP-1 receptor, and human amyrin receptor in an assay using whole cells expressing human GIP receptor, human GLP-1 receptor, and human amyrin receptor.

[0501] 53. When measured without HSA in the assay described in Example 4, human GIP receptor, human GLP-1 receptor, and human amyrin receptor were measured in vitro, preferably with an EC of less than 125 pM. 50 And, more preferably, an EC of less than 100 pM 50 Therefore, most preferably, the EC is less than 50 pM. 50 A GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding alternative embodiments, which is activated by [unspecified action].

[0502] 54. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding alternative embodiments, which in vitro activates human GIP receptor, human GLP-1 receptor, and human amyrin receptor when measured without HSA in the assay described in Example 4, and has a potency ratio of less than 50.

[0503] 55. A GLP-1 / GIP / amyrin receptor triple agonist according to alternative embodiment 54, wherein the potency ratio is less than 20.

[0504] 56. A GLP-1 / GIP / amyrin receptor triple agonist according to alternative embodiment 54 or 55, wherein the potency ratio is less than 15, most preferably less than 11.

[0505] 57. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 21 to 41, having improved pharmacokinetic properties.

[0506] 58. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 21 to 41, having an extended half-life.

[0507] 59. The GLP-1 / GIP / amyrin receptor triple agonist according to alternative embodiment 58, which has an increased half-life of 40 to 145 hours, preferably 90 to 140 hours, and more preferably 85 to 125 hours, when determined in miniature pigs.

[0508] 60. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 21 to 59, having improved chemical stability.

[0509] 61. The GLP-1 / GIP / amyrin receptor triple agonist according to alternative embodiment 60, having improved chemical stability and a purity loss of 6.0 percent or less per week, as determined by Example 7 described herein, etc., preferably less than 3.0 percent per week, as determined by Example 7 described herein, etc.

[0510] 62. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 21 to 61, having an in vivo effect of reducing food intake in normal-weight rats, as determined by an experimental protocol for efficacy testing on appetite, such as Example 5 described herein.

[0511] 63. A pharmaceutically acceptable salt of a GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding alternative embodiments.

[0512] 64. A pharmaceutical composition comprising a GLP-1 / GIP / amyrin receptor triple agonist described in any one of the preceding alternative embodiments, and one or more pharmaceutically acceptable excipients.

[0513] 65. The pharmaceutical composition according to alternative embodiment 64 for oral or subcutaneous administration.

[0514] 66. A pharmaceutical composition according to alternative embodiment 64 or 65, which is a solid pharmaceutical composition.

[0515] 67. A solid pharmaceutical composition according to alternative embodiment 66, which is a tablet.

[0516] 68. A solid pharmaceutical composition according to alternative embodiment 66 or 67, comprising a salt of N-[8-(2-hydroxybenzoyl)amino]caprylate, preferably sodium N-(8-(2-hydroxybenzoyl)amino)caprylate and magnesium stearate.

[0517] A solid pharmaceutical composition according to any one of the alternative embodiments 66 to 68, comprising 69.75 to 600 mg of sodium N-(8-(2-hydroxybenzoyl)amino)caprylate and 7 to 8.5 mg of magnesium stearate.

[0518] 70. A pharmaceutical composition according to any one of the alternative embodiments 64 to 69, for administration approximately once a day, for example, once every 12 to 36 hours, for example, once every 18 to 30 hours, for example, once every 24 hours, or for administration approximately once a week, for example, once every 6 to 8 days.

[0519] 71. An injection device comprising a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63, or a pharmaceutical composition according to any one of Embodiments 64 to 70.

[0520] 72. A GLP-1 / GIP / amyrin receptor triple agonist peptide according to any of the alternative embodiments 1 to 19, for use as an intermediate in the production of a GLP-1 / GIP / amyrin receptor triple agonist peptide derivative according to any of embodiments 22 to 64.

[0521] 73. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 1 to 63, or a pharmaceutical composition according to any one of the embodiments 64 to 70, for use as a pharmaceutical.

[0522] 74. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63, or a pharmaceutical composition according to any one of Embodiments 64 to 70, for use in the treatment of type 2 diabetes, obesity, metabolic dysfunction-associated steatohepatitis (MASH), and / or cardiovascular disease.

[0523] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63, or a pharmaceutical composition according to any one of Embodiments 64 to 70, for use in the treatment of subjects having an initial body mass index (BMI) of 75.25 or higher, 27 or higher, 28 or higher, or 30 or higher.

[0524] A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63, or a pharmaceutical composition according to any one of Embodiments 64 to 70, for use in the treatment of subjects having an initial body mass index (BMI) of 76.25 or higher, 27 or higher, or 28 or higher, or 30 or higher, in the presence of at least one weight-related comorbidity.

[0525] 77. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63, or a pharmaceutical composition according to any one of Embodiments 64 to 70, for use as an adjunct to a low-calorie diet and increased physical activity for chronic weight management in adult subjects suffering from obesity, i.e., an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher, or in adult subjects suffering from overweight, i.e., an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher.

[0526] 78. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63, or a pharmaceutical composition according to any one of Embodiments 64 to 70, for use as an adjunct to a low-calorie diet and increased physical activity for chronic weight management in adult subjects who are obese, i.e., have an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 30 or higher, in the presence of at least one weight-related comorbidity, or in adult subjects who are overweight, i.e., have an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher.

[0527] 79. Use according to Alternative Embodiment 76 or Alternative Embodiment 78, wherein at least one weight-related comorbidity is selected from the group consisting of hypertension, dysglycemic disorder (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, and obstructive sleep apnea.

[0528] 80. Use of a GLP-1 / GIP / amyrin receptor triple agonist as described in any one of Alternative Embodiments 1 to 63 in the manufacture of a pharmaceutical product for the treatment of type 2 diabetes, obesity, metabolic dysfunction-associated steatohepatitis (MASH), and / or cardiovascular disease.

[0529] 81. Use of a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63 in the manufacture of a pharmaceutical product for the treatment of subjects having an initial body mass index (BMI) of 25 or greater, 27 or greater, or 28 or greater, or 30 or greater, in the presence of at least one weight-related comorbidity of any choice.

[0530] 82. Use of a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63 in the manufacture of a pharmaceutical product for the treatment of an adult subject suffering from obesity, i.e., having an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher, or an adult subject suffering from overweight, i.e., having an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher, in the presence of at least one weight-related comorbidity of any choice.

[0531] 83. Use of a GLP-1 / GIP / amyrin receptor triple agonist according to any one of Alternative Embodiments 1 to 63 in the manufacture of a pharmaceutical product for chronic weight management in adult subjects who are obese, i.e., have an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher, or who are overweight, i.e., have an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher, in the presence of at least one weight-related comorbidity of any choice.

[0532] 84. The use of the pharmacopoeia according to an alternative embodiment 82, in which the pharmacopoeia is an adjunct to a low-calorie diet and increased physical activity for chronic weight management in adult subjects suffering from obesity or overweight.

[0533] 85. A method for treating type 2 diabetes, obesity, metabolic dysfunction-associated steatohepatitis (MASH), and / or cardiovascular disease, comprising administering a pharmaceutically appropriate amount of a GLP-1 / GIP / amyrin receptor triple agonist described in any one of Alternative Embodiments 1 to 63 to a person in need thereof.

[0534] 86. A method for treating a human subject whose initial body mass index (BMI) is 25 or greater, 27 or greater, 28 or greater, or 30 or greater, comprising administering to the human subject a pharmaceutically appropriate amount of a GLP-1 / GIP / amyrin receptor triple agonist described in any one of Alternative Embodiments 1 to 63.

[0535] 87. A method for reducing excess body weight in a human subject, comprising administering to the human subject a pharmaceutically appropriate amount of a GLP-1 / GIP / amyrin receptor triple agonist described in any one of Alternative Embodiments 1 to 63, in combination with a low-calorie diet and increased physical activity.

[0536] 88. The method of alternative embodiment 86 or alternative embodiment 87, wherein the human subject is an adult subject suffering from overweight and has an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher.

[0537] 89. The method of alternative embodiment 86 or alternative embodiment 87, wherein the human subject is an adult subject suffering from obesity and has an initial body mass index (BMI) of 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher.

[0538] 90. The method according to any one of the alternative embodiments 86 to 89, wherein the human subject has at least one weight-related comorbidity selected from the group consisting of hypertension, glycemic disorder (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, and obstructive sleep apnea.

[0539] 91. A method for preparing a GLP-1 / GIP / amyrin receptor triple agonist according to any one of the alternative embodiments 1 to 63.

[0540] 92. The method according to the alternative embodiment 91, comprising a step of solid-phase peptide synthesis.

[0541] A specific second alternative embodiment 1. A GLP-1 / GIP / amyrin receptor triple agonist, comprising a peptide conforming to formula I: Including Z1-L1-Z2(I), The peptide contains one lysine (Lys, K) residue, in the formula: Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or Ile (I), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34This is a peptide containing or consisting of Gly(G) or Glu(E), L1 is a peptide linker, and Z2 follows the amino acid sequence of formula VI (sequence number 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 GLP-1 / GIP / amyrin receptor triple agonists are peptides containing or comprising a C-terminal amide (representing Leu(L) or Glu(E)), Or a pharmaceutically acceptable salt thereof.

[0542] 2. Z1 is given by equation II (sequence number 1): YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II) (In the formula, the amino acid at position X2 represents Aib) is a peptide having up to 5 amino acid substitutions, and Z1 follows the amino acid sequence of formula III (sequence number 168): YX2EGTFTSDYSX 12 LLEEIAAX 20EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 20 This represents Arg(R) or Gln(Q), X 24 This represents Ala (A), Glu (E), or Gln (Q), X 27 This represents Leu (L) or I (Ile), X 28 This represents Ala(A) or Gln(Q), X 30 This represents Gly (G) or Ala (A), X 31 This represents Gly (G), Gln (Q), Ala (A), or Pro (P), X 33 This represents Glu (E) or Ser (S), X 34 This includes or consists of Gly (G) or Glu (E), L1 is a peptide linker, and Z2 is a peptide containing a C-terminal amide, and Z2 has an amino acid sequence that follows formula VI (SEQ ID NO: 165): AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP(VI) (In the formula, X 52 This represents Gly (G) or Ser (S), X 53 This represents Gln(Q), Glu(E), or His(H), X 58This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Ala (A), Gly (G), or Gln (Q), X 68 This represents Gln(Q), Glu(E), or Lys(K), X 72 A GLP-1 / GIP / amyrin receptor triple agonist according to a specific second alternative embodiment 1, comprising or consisting thereof (where is Leu(L) or Glu(E)).

[0543] 3. Z1 has an amino acid sequence that follows formula IV (sequence number 169): YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGX 30 X 31 SSG(IV) (In the formula, X2 represents Aib, X 12 This represents Ile (I) or Lys (K), X 27 This represents Leu (L) or I (Ile), X 30 This represents Gly (G) or Ala (A), X 31 A GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding specific second alternative embodiments, comprising or consisting thereof (where (G) represents Gly(G), Ala(A), or Pro(P)).

[0544] 4. The amino acid sequence of Z2 follows formula IX (sequence number 61): ASX 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATLPRTETGSGSP(IX) (In the formula, X 53This represents Glu (E) or His (H), X 58 This represents Ala(A) or Gln(Q), X 59 This represents Leu (L) or Thr (T), X 60 This represents Gly(G) or Gln(Q), X 68 A GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding specific second alternative embodiments, comprising or consisting thereof (where represents Gln(Q), Glu(E), or Lys(K)).

[0545] 5. The amino acid sequence of peptide linker L1 follows formula VIII: X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII) (In the formula, X 41 This represents Ala (A), Gly (G), or Glu (E), X 42 This represents Glu(E), Gly(G), or does not exist. X 43 This represents Glu(E), Gly(G), Gln(Q), or does not exist. X 44 This represents Ala(A), Glu(E), Gly(G), or does not exist. X 45 This represents Glu(E), Gly(G), Pro(P), or does not exist. X 46 This represents Glu(E), Gly(G), or does not exist. X 47 This represents Gln(Q), Glu(E), or does not exist. X 48 This represents Ala(A), Glu(E), or does not exist. X 49 This represents Glu(E), Pro(P), or does not exist. X 50 A GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding specific second alternative embodiments, comprising or consisting of (wherein represents Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(s), Val(V), or not present).

[0546] 6. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding specific second alternative embodiments, wherein peptide Z1-L1-Z2 comprises or consists of an amino acid sequence selected from the group comprising SEQ ID NOs. 170-252.

[0547] 7. Peptides Z1-L1-Z2 are YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAQLGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 230), YX2EGTFTSDYSILLEEIAAREFIEWLLAGGASSGAGEAPGEAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 243), YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 244), YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 246), YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (SEQ ID NO: 250), YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGGSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence ID 251), and A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding specific second alternative embodiments, comprising or consisting of an amino acid sequence selected from the group consisting of YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence ID 252) (wherein X2 is Aib).

[0548] 8. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding specific second alternative embodiments, wherein peptides Z1-L1-Z2 are peptide derivatives comprising an extended portion.

[0549] 9. Peptides Z1-L1-Z2 are peptide derivatives containing an extended portion, and the extended portion is C 12 ~C 20 A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the preceding specific second alternative embodiments, comprising protractor P, which is a diacid.

[0550] 10. Peptides Z1-L1-Z2 are peptide derivatives containing an extended portion, and the extended portion is a linker L P A GLP-1 / GIP / amyrin receptor triple agonist as described in any one of the preceding specific second alternative embodiments, further comprising:

[0551] 11. A GLP-1 / GIP / amyrin receptor triple agonist described in any one of the preceding specific second alternative embodiments, wherein the peptide Z1-L1-Z2 is a peptide derivative comprising an extended portion, the extended portion being selected from the group consisting of the following: [ka] (In the formula, R1 is the bond site of the epsilon-amino group of lysine (Lys, K).)

[0552] 12. A GLP-1 / GIP / amyrin receptor triple agonist, which is compound 104, compound 105, compound 107, compound 111, compound 112, compound 113, or compound 183.

[0553] 13. A pharmaceutical composition comprising a GLP-1 / GIP / amyrin receptor triple agonist described in any one of the specific second alternative embodiments 1 to 12, and one or more pharmaceutically acceptable excipients.

[0554] 14. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the specific second alternative embodiments 1 to 12, or a pharmaceutical composition according to the specific second alternative embodiment 13, for use as a pharmaceutical.

[0555] 15. A GLP-1 / GIP / amyrin receptor triple agonist according to any one of the specific second alternative embodiments 1 to 12, or a pharmaceutical composition according to the specific second alternative embodiment 13, for use in the treatment of subjects whose initial body mass index (BMI) is 25 or greater, 27 or greater, or 28 or greater, or 30 or greater, in the presence of at least one weight-related comorbidity.

[0556] Examples material and method List of Abbreviations The following abbreviations are used below, and they are listed in alphabetical order. Ado:8-amino-3,6-dioxaoctanoic acid A1: 2-aminoisobutyric acid amu: atomic mass unit BHK Baby Hamster Kidney Boc:t-butyloxycarbonyl 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 EC 50 : Maximum half-volume 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 amyrin 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 iv: intravenous LC-MS 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-compartment pharmacokinetics nd: Not decided OtBu:tert-butoxy Oxyma Pure (registered trademark): Cyano-hydroxyimino-ethyl acetate Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl PBS: Phosphate-buffered saline PK: Pharmacokinetics QD: Daily (once a day) QTof: Quadrupole time of flight RAMP3: Receptor-modified protein 3 RT: room temperature sc: subcutaneous SD: Sprague Dawley SEM: standard error SPPS: Solid-phase peptide synthesis tBu:tert-butyl TFA: Trifluoroacetic acid TIPS Triisopropylsilane TQ: Three-stage quadrupole Trt: Triphenylmethyl or Trityl UPLC: Ultra-high-performance liquid chromatography UV: Ultraviolet light

[0557] The building blocks of fatty acids and special amino acids Octadecanedioic acid mono-tert-butyl ester (C 18 For the synthesis of mono-tert-butyl dioxide, please refer to Patent Application No. WO2010 / 102886 (pages 27-28). 12 ~C 20 The corresponding mono-tert-butyl ester of the diacitic acid, in particular, C 16 Diacids and C 20 Diacids can be prepared based on them.

[0558] Fmoc-Leu-Ser(ψ Me , Me pro)-OH, Fmoc-Tyr(tBu)-Ser(ψ Me , Me pro)-OH and Fmoc-Gly-(DMB)Gly-OH are commercially available from TechnoComm Ltd.

[0559] General methods of peptide synthesis Peptide preparation (reference compounds and compounds of the present invention) was performed using Fmoc-based chemistry with a Protein Technologies Symphony X, Protein Technologies PurePep Chorus, CEM MultiPep 2, Vapourtec Vapourtec RS-500, or CSBio CS136XT via SPPS. The Fmoc-protected amino acids used in this method were the following standard recommended ones: e.g., Gyros Protein Technologies, Bachem, Iris 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 supplied by Biotech or NovabioChem H, 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. For example, the constituent units Fmoc-Leu-Ser(ψ) are commercially available from TechnoComm Ltd. Me,Me pro)-OH, Fmoc-Tyr(tBu)-Ser(ψ Me,Me pro)-OH and Fmoc-Gly-(DMB)Gly-OH were introduced where applicable.

[0560] Fmoc-PAL AM resin or Rink-Amide AM resin, both commercially available from NovabioChem, was used. Subsequent amino acids were introduced stepwise using a Symphony X peptide synthesizer according to the SPPS principle.

[0561] Fmoc deprotection was achieved with 20% piperidine in DMF containing 0.1 M Oxyma Pure for 2 × 10 minutes. Substitutions at the alpha position of the N-terminal amino acid (i.e., "protractor" P and optionally "linker L") were used. P The introduction of the extended portion (including the lysine (K) group) was achieved using standard Fmoc-protected amino acids. Peptide coupling was performed using DIC and colidine. An amino acid / Oxyma Pure solution (0.3 M / 0.3 M in DMF with a 5-10 molar excess) was first added to the resin. Then, the same molar equivalent of DIC (1.5 M in DMF) was added, followed by colidine (1.5 M in DMF). Most commonly, this was mixed for 1 hour. In some cases, the coupling time was extended, additional DIC was added, or the coupling step was repeated. Subsequently, a capping step was performed using 1 M acetic anhydride in DMF and colidine. The introduction of the extended portion of lysine (Lys, K) to the epsilon nitrogen in the sequence was achieved using Fmoc-Lys(Mtt)-OH. After the synthesis of the peptide backbone sequence, the Mtt group was removed by treatment with HFIP / DCM / TIPS (75:23:2) (5 minutes), followed by washing with DCM. Next, the resin was resuspended in HFIP / DCM / TIPS (75:23:2) (2 × 25 minutes), and then washed with DCM and DMF. The extended portion was then connected to Linker L P The protractor, the introduction of the fatty acid group, was achieved using a suitable protected structural unit, such as a standard Fmoc-protected amino acid like Fmoc-8-amino-3,6-dioxaoctanoic acid or Fmoc-Glu-OtBu, in the stepwise procedure described above.

[0562] Common cutting methods The peptide was cleaved from the resin using TFA / TIPS / H2O / DTT (90:4:3:3) for 2-3 hours. The peptide was then transferred to cold diethyl ether and centrifuged. The ether was decanted, and the peptide precipitate was washed twice more with ether.

[0563] General methods for the purification and quantification of derivatives Crude peptides were dissolved in acetic acid / MeCN / Milli-Q water (45:10:45 or 40:20:40) and orthogonally purified by reversed-phase preparative HPLC (Waters Delta Prep 4000) on a column containing C18 silica gel. Initial elution was performed using a gradual increase in MeCN from 20% to 50% in Milli-Q water containing 1% ammonium bicarbonate. The relevant fractions were analyzed by UPLC. The fraction containing the target peptide was pooled and diluted with Milli-Q water (1:1) before the second reversed-phase preparative HPLC. The second elution was performed using a gradual increase in MeCN from 20% to 50% in Milli-Q water containing 0.1% TFA. The relevant fractions were analyzed by UPLC. The fraction containing the pure target peptide was pooled. The resulting solutions were analyzed (UPLC, LCMS), and peptide derivatives were quantified using a CAD-specific HPLC detector (Thermo-Fischer Vanquish HPLC-CAD). The product was dispensed into glass vials. The vials were capped with a Millipore glass fiber pre-filter. The derivative trifluoroacetate was obtained as a white solid by freeze-drying.

[0564] The compounds synthesized below were prepared using the method described above.

[0565] Example 1: Reference compound Reference compound 1 (GLP-1 / GIP / amyrin receptor triple agonist disclosed in WO2023 / 288313, Example 1, Peptide / Compound No. 16; SEQ ID NO: 11) [ka] Reference compound 2 (A triple agonist based on the conjugation of tilzepatide and caglilintide, SEQ ID NO: 12) [ka] Reference compound 3 (Triple agonist based on the conjugation of tilzepatide and amyrin receptor agonist disclosed in Example 21 of WO2016 / 034604, SEQ ID NO: 13) [ka] Reference compound 4 (WO2019 / 211451, Example 1, GIP receptor agonist disclosed in Compound 31, SEQ ID NO: 14) [ka] Reference compound 5 (GLP-1 / GIP synergistic agent tilzepatide, SEQ ID NO: 15) [ka] Reference compound 6 (Amyrin receptor agonist caglilintide, WO2012 / 168432, Example 53, SEQ ID NO: 16) [ka] Reference compound 7 (GLP-1 receptor agonist semaglutide, WO2006 / 097537, Example 4, SEQ ID NO: 17) [ka]

[0566] Example 2: GLP-1 / GIP / amyrin receptor triple agonist according to the present invention Compound 104: [ka] Compound 105: [ka] Compound 106:

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[0567] [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7] (In the equation, each X² is Aib.)

[0568] Example 3: LC-MS characterization of synthetic compounds LCMS Characterization Method LCMS analysis was performed using a setup consisting of a Waters Acquity UPLC H Class system and a Waters Xevo G2-XS QTof. Eluents: A: Milli-Q water, B: MeCN, C: Milli-Q water with 2% formic acid + 0.1% TFA.

[0569] The analysis was performed at RT (column temperature 60°C) by injecting an appropriate volume of sample into the column. The sample was eluted with a linear gradient of 5-95% B in A and a constant 5% C.

[0570] 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% to 95% B, and 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 to 5000 amu.

[0571] The monoisotopic masses of the synthetic compounds were recorded, and their measured and calculated values ​​are shown in [Table 18].

[0572] [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5]

[0573] Example 4: In vitro efficacy assay (high-throughput assay) of human GLP-1 receptor, human GIP receptor, and human amyrin receptor. GLP-1 receptor assay To determine the compound's ability to activate or activate the GLP-1 receptor, an in vitro efficacy assay was performed on baby hamster kidney (BHK) cells expressing the human GLP-1 receptor (hGLP-1R) as described below. To assess how receptor activation may 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, throughout this specification, references to the "GLP-1 receptor assay described in Example 4" refer to the assay procedure described herein in the absence of HSA (hGLP-1R assay).

[0574] Assay principle Activating the human GLP-1 receptor results in increased intracellular concentrations of cyclic AMP (cAMP) and transcriptional activation from a promoter containing multiple copies of the cAMP response element (CRE). Therefore, GLP-1 receptor activity can be measured using a CRE luciferase reporter gene introduced into baby hamster kidney (BHK) cells co-expressing the human GLP-1 receptor.

[0575] Cells and assay reagents Cell stocks were prepared by culturing cell lines that stably express the human GLP-1 receptor and contain a CRE-responsive luciferase (CRE-Luc) reporter gene (BHK 467-12A KZ-10, prepared according to a method known to those skilled in the art) in a growth medium consisting of 10% FBS (Gibco, 10100-147), 1% penicillin-streptomycin (Gibco, 15140-122), 1 mM Na-piruvate (Gibco, 11360-039), 0.5 mg / mL G418 (Gibco, 10131-027), and 240 nM methotrexate (Pfizer, 15936) in DMEM (Gibco, 61965-026). 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 and frozen in Recovery® Cell Culture Freezing Medium (Gibco 12648-010) for approximately 1.5 × 10⁶ cells. 6 The solution was diluted to cells / mL. The cells were divided equally and stored at -180°C until use.

[0576] The assay buffer consisted of DMEM supplemented with 1x GlutaMAX (Gibco, 35050-038), 10 mM HEPES (Gibco, 15630-056), 1% (w / v) ovalbumin (Sigma, A5503), and 0.1% (v / v) Pluronic F-68 (Gibco, 24040-032), without phenol red (Gibco, 11880-028), either with or without HSA (Sigma, A9511).

[0577] Procedure (hGLP-1R assay) To perform the assay, serial dilutions (7-fold dilution, 7 concentrations per compound, and one well containing only assay buffer) of the reference compound and the GLP-1 / GIP / amyrin receptor triple agonist were performed in assay buffer in a 96-well plate. The serial dilutions were transferred to a 384-well assay plate (Revvity, 6007688) and mixed with an equal volume (10 μL) of assay buffer, either containing or not containing 3% (w / v) HSA (Sigma, A9511). Frozen stocks of hGLP-1R BHK Cre-Luc cells were thawed in a 37°C water bath, washed once in PBS (Gibco 14190-094), and 1.5 × 10⁶ cells were thawed in assay buffer (without HSA). 5 Dilution to (1.5E+5) cells / mL was added to each well of a 384-well assay plate (10 μL). After brief centrifugation, the assay plate was incubated in 5% CO2 at 37°C for 3 hours, then equilibrated at room temperature for 10 minutes, after which 30 μL of steadylite plus® Revvity (6066759) was added per well. The plate was sealed and incubated at room temperature for 30 minutes with gentle shaking, protected from light. Luminescence was detected using a luminescence plate reader, e.g., Synergy 2 (BioTek). EC 50 The value [pM] was calculated by nonlinear curve fitting using a 4-parameter logistic model (hill slope = 1) with GraphPad Prism (GraphPad Software, Boston, MA, USA), or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA).

[0578] GIP receptor assay To determine the compound's ability to activate or activate the GIP receptor, an in vitro efficacy assay was performed on baby hamster kidney (BHK) cells expressing the human GIP receptor (hGIPR) as described below. To assess how receptor activation may 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, throughout this specification, references to the "GIP receptor assay described in Example 4" refer to the assay procedure described herein in the absence of HSA (hGIPR assay).

[0579] Assay principle Activating the human GIP receptor results in increased intracellular concentrations of cyclic AMP (cAMP) and transcriptional activation from a promoter containing multiple copies of the cAMP response element (CRE). Therefore, GIP receptor activity can be measured using a CRE luciferase reporter gene introduced into baby hamster kidney (BHK) cells co-expressing the human GIP receptor.

[0580] Cells and assay reagents Cell stocks were prepared by culturing cell lines that stably express the human GIP receptor and contain a CRE-responsive luciferase (CRE-Luc) reporter gene (hGIPR BHK Cre-Luc2p clone #5, prepared according to a method known to those skilled in the art) in growth medium consisting of 10% fetal bovine serum (Gibco, 10100-147), 0.5 mg / ml G418 (Gibco, 10131-027), 1% penicillin-streptomycin (Gibco, 15140-122), and 0.3 mg / ml hygromycin B (ThermoFisher, 10687010) at 5% CO2 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 frozen in Recovery Cell Culture Freezing Medium (Gibco 12648-010) for approximately 1.5-3.0 × 10⁶ cells. 6 Diluted to (1.5E+6~3.0E+6) cells / mL and stored at -180°C in suitable aliquots until use.

[0581] The assay buffer consisted of DMEM supplemented with 1x GlutaMAX (Gibco, 35050-038), 10 mM HEPES (Gibco, 15630-056), 1% (w / v) ovalbumin (Sigma, A5503), and 0.1% (v / v) Pluronic F-68 (Gibco, 24040-032), without phenol red (Gibco, 11880-028), either with or without HSA (Sigma, A9511).

[0582] Procedure (hGIPR assay) To perform the assay, serial dilutions (7-fold dilution, 7 concentrations per compound, and one well containing only assay buffer) of the reference compound and the GLP-1 / GIP / amyrin receptor triple agonist were prepared in assay buffer in a 96-well plate. The serial dilutions were transferred to a 384-well assay plate (Revvity, 6007688) and mixed with an equal volume (10 μL) of assay buffer, either containing or not containing 3% HSA (Sigma, A9511). Frozen stocks of hGIPR BHK Cre-Luc cells were thawed in a 37°C water bath, washed once in PBS (Gibco 14190-094), and 1.5 × 10⁶ cells in assay buffer (without HSA). 5 Dilution to (1.5E+5) cells / mL was added to each well of a 384-well assay plate (10 μL). After brief centrifugation, the assay plate was incubated in 5% CO2 at 37°C for 3 hours, then equilibrated at room temperature for 10 minutes, after which 30 μL of steadylite plus® (Revvity, 6066759) was added per well. The plate was sealed and incubated at room temperature for 30 minutes with gentle shaking, protected from light. Luminescence was detected using a luminescence plate reader, e.g., Synergy 2 (BioTek). EC 50 The value [pM] was calculated by nonlinear curve fitting using a 4-parameter logistic model (hill slope = 1) with GraphPad Prism (GraphPad Software, Boston, MA, USA), or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA).

[0583] Amyrin receptor assay To determine the compound's ability to activate or activate the amyrin receptor, an in vitro efficacy assay was performed on baby hamster kidney (BHK) cells expressing the human amyrin receptor (hAMYR3) as described below. To assess how receptor activation may 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, throughout this specification, references to the "amyrin receptor assay described in Example 4" refer to the assay procedure described herein in the absence of HSA (hAMYR3 assay).

[0584] Assay principle Activating the human amyrin 3 receptor results in an increase in intracellular cAMP concentration and transcriptional activation from a promoter containing multiple copies of the cAMP response element (CRE). Therefore, hAMYR3 activity can be measured using a CRE luciferase reporter gene introduced into baby hamster kidney (BHK) cells co-expressing hAMYR3.

[0585] Cells and assay reagents BHK cell lines were converted to human calcitonin receptors according to methods known to those skilled in the art (Hollex-1 cell line, obtained from Zymogentics as described in U.S. Patent No. 5,622,839) (a) The cell line was manipulated to stably express the CRE-responsive luciferase (CRE-Luc) reporter gene. The cell line was further transfected with human receptor-modified protein 3 (hRAMP3) using standard methods. The association of hRAMP3 with the human calcitonin receptor generates the human amyrin-3-(a) receptor (hAMYR3).

[0586] Cell stocks were prepared by culturing the hAMYR3 BHK Cre-Luc cell line in growth medium consisting of 10% FBS (Gibco, 10100-147), 1% penicillin-streptomycin (Gibco, 15140-122), 0.5 mg / mL gentisine (Gibco, 10131-027), 0.4 mg / mL hygromycin (ThermoFisher, 10687010), and 250 nM methotrexate (Sigma, A6770) supplemented with DMEM (Gibco, 31966-021). 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 (trademark) (Gibco, 12605-010). After centrifugation, the cell pellet was resuspended and frozen in Recovery (trademark) Cell Culture Freezing Medium (Gibco, 12648-010) for approximately 2.5-4.0 × 10⁶ times. 6 The solution was diluted to (2.5E+6~4.0E+6) cells / mL. The cells were divided equally and stored at -180°C until use.

[0587] The assay buffer consisted of DMEM without phenol red (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).

[0588] Procedure (hAMYR3) To perform the assay, hAMYR3 BHK Cre-Luc cells were thawed, washed once with PBS (Gibco 14190-094), and the day before the experiment, 4.0 × 10⁶ cells were placed in 40 μL of growth medium in a white 384-well culture plate (Revvity, 6007688). 3Cells were seeded at a cell density of (4.0E+3) cells / well. The plates were incubated overnight at 37°C in 5% CO2. On the day of assay, serial dilutions of the reference compound and the GLP-1 / GIP / amyrin receptor triple agonist (7-fold dilution, 7 concentrations per compound, and one 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 containing either equal volumes (1:1:1 ratio) of assay buffer and assay buffer with or without 3% HSA (Sigma, A9511). 20 microliters of the solution mixture were transferred to cells that had been pre-washed once with PBS (Gibco 14190-094). After brief centrifugation, the assay plates were incubated at 37°C in 5% CO2 for 3 hours, equilibrated at room temperature for 10 minutes, and then 30 μL of steadylite plus® (Revvity, 6066759) per well was added. The plates were sealed and incubated at room temperature for 30 minutes with gentle shaking, protected from light. Luminescence was detected using a luminescence plate reader, e.g., Synergy 2 (BioTek). 50 The values ​​[pM] were calculated by nonlinear curve fitting using a four-parameter logistic model (hill slope = 1.5, shared lowest response within each plate) with GraphPad Prism (GraphPad Software, Boston, MA, USA), or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA).

[0589] result:

[0590] [Table 19]

[0591] The results in [Table 19] indicate that reference compounds 4–7 are agonists or co-agonists for one or two of the following receptors: GLP-1 receptor, GIP receptor, and amyrin receptor (hAMYR3).

[0592] As shown in [Table 19], the activity data for reference compound 2 demonstrate that linking the C-terminus of a potent GLP-1 / GIP co-agonist (tilzepatide) to the N-terminus of a potent amyrin receptor agonist (caglilintide) via a peptide linker does not result in a compound that is equally potent for these three receptors and can therefore function as a GLP-1 / GIP / amyrin receptor triple agonist (i.e., a compound according to the present invention). A comparison of reference compound 2 with reference compounds 5 (tilzepatide) and 6 (caglilintide) illustrates this point. Compared to the original compound, reference compounds 5 (tilzepatide) and 6 (caglilintide), reference compound 2 shows a significant loss of efficacy against the GLP-1 receptor and some further loss of efficacy against the amyrin receptor.

[0593] Reference compounds 1-3 exhibit functional activation of all three receptors, but their efficacy against one or more of the GLP-1 receptor, GIP receptor, and amyrin receptor is impaired compared to the GLP-1 / GIP / amyrin receptor triple agonist of the present invention. Therefore, reference compounds 1-3 are not potent and are unbalanced across all three receptors.

[0594] [Table 20-1] [Table 20-2] [Table 20-3]

[0595] The results in [Table 20] demonstrate 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 amyrin receptor (hAMYR3).

[0596] Most of the GLP-1 / GIP / amyrin receptor triple agonists of the present invention are comparable to the GIP, GLP-1, and amyrin receptor agonists, as well as the GLP-1 / GIP co-agonists disclosed herein as reference compounds 4-7. 50 The values ​​activate different receptors. Furthermore, the GLP-1 / GIP / amyrin receptor triple agonist of the present invention exhibits potent and balanced functional activation of all three receptors, as shown in [Table 20], and is a balanced GLP-1 / GIP / amyrin receptor triple agonist in contrast to reference compounds 1, 2, and 3.

[0597] [Table 21]

[0598] [Table 22-1] [Table 22-2] [Table 22-3]

[0599] Absolute EC generated in the presence of 1% HSA 50 The values ​​can vary significantly depending on the HSA batch used. Therefore, the absolute data itself cannot be used, but it should be compared to a reference compound run using the same HSA batch.

[0600] Example 5: Experimental protocol for efficacy testing of appetite using an ad libitum rat model Male Sprague Dawley (SD) rats from Taconic, Denmark were used in acute food ingestion experiments in accordance with the principles of laboratory animal management.

[0601] The rats weighed 250–350 g at the start of the experiment and had not received an obesity-inducing diet. To allow for acclimatization to the experimental setup, the rats arrived at least 7 days prior to the start of the experiment. Immediately upon arrival, the rats were changed to a reversed light cycle (dark from 11 am to 11 pm), and three rats were housed per cage in an automated food intake measurement system (HM2 system, MBRose; Faaborg, Denmark). The rats had free access to a 10% fat diet (research diet D12450B) and water and were housed at room temperature (approximately 22°C). To enable recording of individual food intake, ID chips were implanted in the rats during the acclimatization period. Since rats are normally active and consume most of their daily calories during the dark period, the rats were administered medication in the morning just before lights out. This setup resulted in the lowest data variability and highest test sensitivity. Each dose of the triple agonist was tested in groups of 5–8 rats. Each set of the study included vehicle groups of 5–8 rats. Each cage contained animals from three different treatment groups (primary read: to rule out the possibility of cage effects (e.g., cage failure) on food intake). Rats were administered a single subcutaneous (sc) dose of the compound of interest or vehicle according to the vehicle's body weight (10, 30, or 100 nmol / kg) using NovoPen® (Novo Nordisk, Bagsverd, Denmark). The injection volume was 0.5 mL / kg.

[0602] The compound of the present invention was formulated using the following vehicle: 8 mM phosphate, 250 mM glycerol, 0.007% polysorbate 20, pH 7.4.

[0603] After administration, the rats were returned to their home cages, where they were given free access to a 10% fat diet and water. Food consumption was continuously recorded using the HM2 system from 24 hours prior to administration of the test substance (baseline), and from 0 to 72 hours after administration of the test compound. The data recorded and acquired by the HM2 system was stored in the HMBase SQL database (Firebird® relational database management system) and processed by HM2Lab software (MBRose; Faaborg, Denmark) installed on an embedded computer. The feeding system is a highly sensitive system with a load resolution of 0.001 g. In addition to recording food intake, the system also 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, YD, 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.

[0604] Table 23 shows the acute food intake in normal-weight (lean) rats based on the protocol described above for efficacy testing of appetite. These results allow for 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 expressed as the mean inhibition rate against 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]), with food intake continuing for up to 72 hours in the rats. Food intake on each test day (e.g., Day 1) represents the cumulative food intake over the course of that day (i.e., a 24-hour period).

[0605] [Table 23-1] [Table 23-2]

[0606] If only one value is listed, the food intake is measured at a dose of 10 nmol / kg. "-X" means that the food intake is reduced by "X%" compared to the vehicle.

[0607] As can be inferred from the data presented in [Table 23], after administering the GLP-1 / GIP / amyrin receptor triple agonists of the present invention to rats, many were observed to cause significant inhibition of food intake compared to vehicle therapy. Generally, the compounds in [Table 23] showed similar or improved reductions in food intake at doses much lower than the 50 nmol / kg dose level of the disclosed reference compound 1 disclosed in WO2023 / 288313.

[0608] Example 6: Pharmacokinetic studies in miniature pigs and rats The purpose of this study is to determine the in vivo half-life (t) of the GLP-1 / GIP / amyrin receptor triple agonist of the present invention after intravenous (iv) administration to miniature pigs or rats. 1 / 2 This involves determining the residence time in the body and the duration of their effects. This is called the terminal phase half-life (t) of the compound or derivative in question. 1 / 2 This was determined in pharmacokinetic (PK) studies. Terminal phase half-life is the time it takes to halve a specific plasma concentration in the terminal elimination phase, and represents the duration of drug activity in the body.

[0609] Miniature pig experiment Female Göttingen minipigs were obtained from Ellegaard Göttingen Minipigs (Dalmose, Denmark) and used in the study if they were approximately 8-12 months old and weighed approximately 20-30 kg. The minipigs (pigs with permanent catheters) were individually housed in sheds filled with straw as bedding and were fed Altromin 9023 minipig feed (Altromin Spezialfutter GmbH & Co.KG) once a day on a restricted diet.

[0610] After a three-week acclimatization period, two permanent central venous catheters were implanted in the tail of each animal's vena cava. The animals were allowed to recover for at least 10 days post-surgery and then used for repeated pharmacokinetic studies with appropriate washout periods between consecutive drug administrations.

[0611] The compound of the present invention was formulated using the following vehicle: 8 mM phosphate, 250 mM glycerol, 0.007% polysorbate 20, pH 7.4 (40 nmol / ml).

[0612] Intravenous injections of the derivative (0.05 ml / kg and 2 nmol / kg / volume corresponding to the dose of the derivative) were administered through one catheter, and blood samples were collected at predetermined time points up to 14 days after administration (preferably from another catheter).

[0613] Blood samples (e.g., 1.3 ml) were collected in tubes coated with EDTA (1.3 ml tubes containing K3EDTA to obtain 1.6 mg of K3EDTA per 1 ml of blood), and then centrifuged at 4°C and 2000 × g for 10 minutes.

[0614] Sampling and analysis Plasma was pipetteed into Micronic tubes stored on dry ice within 30 minutes of centrifugation, and then kept at -20°C until the plasma concentration of the compound was analyzed using LC-MS.

[0615] The plasma concentrations of the peptides of the present invention were assayed by plasma protein precipitation and analyzed by LC-MS. Standards were prepared by spiking blank plasma from miniature pigs 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 a 20 nM internal standard (structurally similar analogues with different masses) to 1 volume of the sample, followed by centrifugation at 6200 rpm at 4°C for 10 minutes. 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 pharmacokinetics (NCA) using Phoenix v.6.4 (Pharsight Inc., Mountain View, CA, USA) to determine the resulting terminal phase half-lives (harmonic mean). LC-MS analysis was performed using a Thermo Fisher Scientific (Bremen, Germany) TurboFlow HPLC system coupled with either a Q Exactive Orbitrap or an Altis Triple Quadrupole (TQ) mass spectrometer. The LC mobile phase consisted of two phases: A: MQ water containing 5% organic solvent (50% methanol / 50% MeCN) and 1% formic acid, and B: MQ water containing 95% organic solvent (50% methanol / 50% MeCN) and 1% formic acid. A Thermo Fischer Scientific (Bremen, Germany) TurboFlow Cyclone 0.5 × 100 mm column was used for extraction, followed by analytical elution using an XBridge Peptide BEH C18 300 Å, 3.5 μm, 2.1 × 50 mm column, both operated at 60°C. Typically, 40–45%B and 75–80%B were used for packing and elution on the TurboFlow column, followed by linear gradient elution on the analytical column over 2.33 minutes, typically from approximately 45%B to 85%B.The Orbitrap mass spectrometer was operated in positive ionization mode at a spray voltage of 4.0 kV using Parallel Reaction Monitoring scan mode with a resolution of 35 K on the Orbitrap MS and a separation window of 5 m / z at the compound's most abundant charge state. The TQ mass spectrometer was operated in positive ionization mode at a spray voltage of 4.0 kV using Single Reaction Monitoring scan mode with Q1 and Q3 resolutions of 1.2 (FWHM).

[0616] For all compounds, the individual optimal fragmentation collision energy was found and used. The data was then used to calculate the concentration in the plasma sample using a linear calibration curve (1 / × 2 Data were processed using the Quan browser in Thermo Fisher Scientific's (Bremen, Germany) Xcalibur software by fitting the data to a weighted system. Quality control samples were included. The deviation between nominal and calculated concentrations in the reference material and quality control samples was less than 15%.

[0617] Rat study Male Sprague-Dawley rats (250–320g) were obtained from Charles River, Germany, or Janvier Labs France. Two animals were housed per cage, and they had free access to rodent food (Altromin 1324) and water throughout the experiment.

[0618] After a 12-day acclimatization period, a triple-acting compound formulated with 8 mM phosphate, 250 mM glycerol, and pH 7.4 was administered intravenously (50 nmol / 0.5 ml / kg), and blood samples were collected at various predetermined time points up to 72 hours after administration.

[0619] Sampling and analysis Blood samples (approximately 120 μl / sample) were collected in vials coated with K3EDTA and centrifuged at 2000 × g for 5 minutes at 4°C. Plasma samples (50–60 μl / sample) were transferred to micronic tubes, flash-frozen, and stored at -20°C until analysis of the plasma concentration of the compound using LC-MS. The plasma concentration of the peptide of the present invention was assayed by plasma protein precipitation and analyzed by LC-MS. Standards were prepared by spiking rat blank plasma with compounds in the typical range of 0.5–2000 nM. The LLoQ was typically in the range of 0.5–1 nM. Standards, plasma blanks, or test samples were prepared for LC-MS by protein precipitation by adding 6 volumes of methanol containing a 20 nM internal standard (structurally similar analogues with different masses) to 1 volume of sample, followed by centrifugation at 6400 rpm at 4°C for 10 minutes. The supernatant was diluted with 1 volume of Milli-Q water containing 1% formic acid and then injected into the LC-MS system. LC-MS analysis was performed using a Thermo Fisher Scientific (Bremen, Germany) TurboFlow or HPLC system coupled with either a Q Exactive Plus or Q Exactive HF Orbitrap mass spectrometer. The LC mobile phase consisted of A: MQ water containing 5% organic solvent (50% methanol / 50% MeCN) and 1% formic acid, and B: MQ water containing 95% organic solvent (50% methanol / 50% MeCN) and 1% formic acid. In the HPLC system, mobile phase A consisted of 99.9% Milli-Q water and 0.1% formic acid, and mobile phase B consisted of 99.9% MeCN and 0.1% formic acid. A TurboFlow Cyclone 0.5×100 mm column from Thermo Fischer Scientific (Bremen, Germany) was used for extraction, followed by analytical elution using an XBridge Peptide BEH C18 300 Å, 3.5 μm, 2.1×50 mm column, both performed at 60°C. An Accucore 150-C4 analytical column (2.1×100 mm, Thermo Fischer Scientific, 2.6 μM) was used in the HPLC system.Typically, 20%B and 75%B were used for packing and elution on the TurboFlow column, followed by linear gradient elution over 4 minutes on the analytical column, typically around 49%B–89%B. The HPLC gradient was in the range of 20–80%B. The Q Exactive Plus or Q Exactive HF Quadrap mass spectrometer was operated in positive ionization mode at a spray voltage of 4.0 kV, using single-ion monitoring (SIM) scan mode with a 5 m / z separation window at the compound's most abundant charge state, at resolutions of 35 K and 60 K, respectively, on the mass spectrometer. Data were processed using Quan Browser in Thermo Fisher Scientific (Bremen, Germany) Xcalibur software by fitting the data to a linear calibration curve (weighted 1 / ×2) used to calculate concentrations in plasma samples. Quality control samples were included. Deviations between nominal and calculated concentrations in the standard and quality control samples were less than 15%.

[0620] result:

[0621] [Table 24]

[0622] As shown in [Table 24], the GLP-1 / GIP / amyrin receptor triple agonist of the present invention tested had a very long half-life of at least 14 hours in rats or 95 hours in miniature pigs (t 1 / 2 ) has. Based on these half-lives in rats and miniature pigs, it is intended that the half-life in humans will be sufficient with administration at least once a week by liquid subcutaneous injection or at least once a day by oral tablet.

[0623] Example 7: Evaluation of chemical stability in the formulation Assays were performed to investigate the degree of in vitro chemical degradation over time after incubation at 37°C for two weeks.

[0624] Peptide solutions were prepared by dissolving lyophilized powder in 8 mM phosphate buffer at pH 7.4 to a target concentration 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 packed 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 two weeks, rapidly frozen at -80°C, and stored at -20°C until analysis.

[0625] Sample analysis was performed using a UPLC combining UV detection at 215 nm with MS (UPLC-UV-MS). 1 μL of sample was injected into a Waters Acquity UPLC equipped with a flow-through needle injection system and placed on a Waters Acquity CSH C18 column (1 × 150 mm) with a particle size of 1.7 μm, and maintained at 55°C. A flow rate of 100 μL / min was delivered using a two-component solvent control pump with 0.1% formic acid in water as solvent A and 0.1% formic acid in MeCN as solvent B. Gradient elution was performed using 20% ​​B at 0–2 minutes, followed by 20–50% B at 2–20 minutes, for a total run time of 30 minutes. Peptide attributes were confirmed by MS, and the peak purity and area % from the UV signal at 215 nm were plotted against time. The weekly purity loss was calculated using the slope from linear regression ([Table 25]).

[0626] [Table 25-1] [Table 25-2] [Table 25-3]

[0627] All GLP-1 / GIP / amyrin receptor triple agonists tested in this assay exhibit acceptable chemical stability with an acceptable degradation rate (less than 5% purity loss per week) in aqueous buffer (37°C). The majority of the tested GLP-1 / GIP / amyrin receptor triple agonists exhibit good chemical stability with a purity loss of less than 2.0% per week, or even better chemical stability (less than 1.5% purity loss per week). Therefore, the GLP-1 / GIP / amyrin receptor triple agonists of the present invention are considered chemically stable in solution.

[0628] While certain features of the present invention are illustrated and described herein, many modifications, substitutions, alterations, and equivalents will be conceivable to those skilled in the art. It should therefore be understood that the appended claims are intended to encompass all such modifications and alterations that fall within the true spirit of the present invention.

Claims

1. Compound 105: 【Chemistry 1】 Compound 107: 【Chemistry 2】 Compound 113: 【Transformation 3】 Compound 183: 【Chemistry 4】 A GLP-1 / GIP / amyrin receptor triple agonist selected from the group consisting of the following.

2. Compound 105: 【Transformation 5】 The GLP-1 / GIP / amyrin receptor triple agonist according to claim 1.

3. Compound 107: 【Transformation 6】 The GLP-1 / GIP / amyrin receptor triple agonist according to claim 1.

4. Compound 113: 【Transformation 7】 The GLP-1 / GIP / amyrin receptor triple agonist according to claim 1.

5. Compound 183: 【Transformation 8】 The GLP-1 / GIP / amyrin receptor triple agonist according to claim 1.

6. A pharmaceutical composition comprising a GLP-1 / GIP / amyrin receptor triple agonist according to any one of claims 1 to 5, and one or more pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 6, comprising the GLP-1 / GIP / amyrin receptor triple agonist according to claim 2 and one or more pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 6, comprising the GLP-1 / GIP / amyrin receptor triple agonist according to claim 3 and one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 6, comprising the GLP-1 / GIP / amyrin receptor triple agonist according to claim 4 and one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 6, comprising the GLP-1 / GIP / amyrin receptor triple agonist according to claim 5 and one or more pharmaceutically acceptable excipients.

11. A pharmaceutical composition according to claim 6, for use as a pharmaceutical.

12. The pharmaceutical composition according to claim 6, for use in the treatment of type 2 diabetes, obesity, metabolic dysfunction-related steatohepatitis (MASH), and / or cardiovascular disease.

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