TRI-agonists of the GLP-1, GIP, and amylin receptors and uses thereof

Abstract

The present invention provides a GLP-1- / GIP- / amylin-receptor triple agonist having a balanced efficacy ratio across all three receptors and / or improved pharmacokinetic properties. The present invention also provides a pharmaceutical composition comprising such a GLP-1- / GIP- / amylin-receptor triple agonist, as well as its use as a medicine for the treatment of subjects with overweight, obesity, and associated comorbidities.

Description

Technology Field

[0001] A composition comprising the said compound for use as a GLP-1- / GIP- / amylin-receptor triple agonist and a pharmaceutical. Background Technology

[0002] Overweight and obesity are the abnormal or excessive accumulation of body fat that poses a risk to an individual's overall health. The WHO considers the Body Mass Index (BMI) to be the most convenient and widely accepted 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 Grade I (BMI 30 to 34.9), Grade II (BMI 35 to 39.9), and Grade III (BMI > 40).

[0003] Obesity is a major risk factor for numerous serious conditions, including type 2 diabetes and its associated comorbidities, as well as for cardiovascular diseases such as heart disease and stroke, which are the leading causes of death worldwide. The World Health Organization (WHO) now recognizes obesity as a rapidly growing problem, even 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 were reported to be obese. According to the WHO, 422 million people worldwide suffer from diabetes, and 1.6 million people die annually from diabetes as a direct cause. Therefore, there are significant incentives for both individuals and society to prevent and / or treat obesity.

[0004] In cases where lifestyle changes such as diet and exercise alone are insufficient to sufficiently reduce the BMI of obese individuals to an acceptable level, treatment with pharmaceutical drugs such as liraglutide, orlistat, and naltrexone-bupropion has been shown to induce some weight loss. Nevertheless, this weight loss is often not sustained, and the reduction is too small for individuals with Grade II and Grade III obesity. In such cases, bariatric surgery has been proven necessary. While bariatric surgery is currently the most effective treatment for long-term weight loss, it is an invasive procedure that entails high risks and costs for the patient. Therefore, effective and minimally invasive treatments will significantly improve obesity care.

[0005] GLP-1 is a 30-amino acid or 31-amino acid polypeptide synthesized and secreted by intestinal endocrine 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), and its half-life is less than 2 minutes.

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

[0007] The following two commercially available finished products containing a GLP-1 receptor agonist as the active pharmaceutical ingredient are approved for use in individuals living with overweight and at least one weight-related comorbidity or living with obesity: liraglutide (Saxenda®) and semaglutide (Wegovy®). The maximum efficacy achievable with GLP-1 receptor agonists is limited by tolerability. When the dosage is increased, side effects such as nausea and vomiting become increasingly prominent.

[0008] Native human GIP is a 42-amino acid polypeptide synthesized and secreted by specific intestinal endocrine K-cells. These cells are primarily concentrated in the duodenum and proximal jejunum, but can also be found throughout the intestine. The primary stimulant for GIP secretion is the consumption of a diet rich in carbohydrates and lipids. Following intake, circulating plasma GIP levels increase ten to twentyfold. Like GLP-1, GIP is an incretin hormone, and in healthy humans, it appears to be a more potent incretin than GLP-1. However, in individuals with type 2 diabetes, GIP has lost its incretin effect. The half-life of intact GIP is estimated to be approximately 7 minutes in healthy subjects and about 5 minutes in individuals with type 2 diabetes.

[0009] Long-acting (or extended) GIP analogs have been shown to lower body weight and improve blood glucose control. Regarding weight loss, these effects are relatively lower compared to long-acting GLP-1 analogs in rodent models (Mroz et al. [Mol Metab, 2019, 20: 51-62]). Additionally, GIP analogs act additively or synergistically with long-acting GLP-1 analogs to induce weight loss when administered in combination with GLP-1 analogs (Finan et al. [Sci Transl Med, 2013, 5 (209): 209ra151]; Norregaard et al. [Diabetes Obes Metab, 2018, 20 (1): 60-68]), making them representative candidates suitable for amplifying GLP-1-based pharmacology. GIPR agonists can be included as partners for GLP-1 receptor agonists as single-molecule co-agonists that amplify GLP-1-induced weight loss and blood glucose control, as demonstrated in preclinical animal models (Finan et al. [Sci Transl Med, 2013, 5(209): 209ra151]; Coskun et al. [Mol Metab, 2018, 18:3-14]). Two different peptides (MAR709 and LY3298176, the latter known as tyrzepatide) with high efficacy against both GLP-1R and GIPR were tested in a multi-dose clinical trial. Clinical results showed that greater blood glucose control and weight improvement were achieved than with similar doses 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]), which demonstrates the translational and therapeutic benefits of co-targeting GLP-1 and GIP receptors.

[0010] Since the compound tirzepatide was approved for the treatment of diabetes in 2022, this concept of co-targeting GLP-1 and GIP receptors as a GLP-1 / GIP co-agonist has recently been demonstrated. Furthermore, tirzepatide is also useful for the treatment of obesity, as shown in a Phase 3 clinical trial where a high dose of tirzepatide (15 mg) helped patients lose 20.9% (average) of body weight after 72 weeks of treatment, including a 20-week dose escalation period (Literacy by AM Jastreboff, LJ Aronne, NN Ahmad, et al. [N Engl J Med 2022; 387:205-216]). Tirzepatide was recently approved for weight management in individuals with a BMI >30 or BMI >27 and at least one weight-related comorbidity (Trademark: Zepbound®).

[0011] In addition to tyrzepatide described in WO 2016 / 111971 A1, GLP-1 / GIP co-agonists and their potential medical uses are described in several patent applications such as WO 2006 / 086769, WO 2010 / 011439, WO 2013 / 164483, WO 2014 / 192284, WO 2015 / 067715, WO 2015 / 022420, WO 2015 / 086728, WO 2015 / 086729, WO 2016 / 111971, WO 2020 / 023386, US 2014 / 162945, US 2014 / 357552, and WO 2022 / 018186.

[0012] Amylin is a 37-amino acid polypeptide hormone produced by pancreatic beta (β) cells and co-secreted from the pancreas along with insulin. Amylin has a half-life of 15 to 20 minutes. It exerts effects on several different organ systems and acts primarily through the amylin receptor 1-3 (AMYR1-3). Amylin is an important regulator of energy metabolism in healthy individuals and patients, inhibiting glucagon secretion, delaying gastric emptying, signaling satiety, and suppressing appetite. Other actions of amylin, such as those on the cardiovascular system and bone, have also been reported.

[0013] Clinical studies have shown that amylin receptor agonists may be useful in the treatment of overweight, obesity, type 1 diabetes, and / or type 2 diabetes. Currently, one finished pharmaceutical product (Symlin®) containing an amylin receptor agonist (pramlintide acetate) as the active pharmaceutical ingredient is commercially available. Symlin®, a liquid pharmaceutical composition for subcutaneous administration, is approved for use in patients with type 1 or type 2 diabetes who use basal insulin and mealtime insulin and have not achieved desired glycemic control despite optimal insulin therapy. Clinical trials for pramlintide have also been conducted for use in overweight and obese individuals. Pramlintide has a short half-life (less than 1 hour) and must be administered three times daily. Consequently, plasma concentrations of pramlintide vary significantly throughout the day.

[0014] There has been a similar need to extend the action of amylin, and co-targeting of amylin receptors and GLP-1 receptors has been described. Amylin receptor agonists and their potential medical uses are described in several patent applications, e.g., WO 2012 / 168432, WO 2016 / 034604, WO 2022 / 129254, WO 2022 / 063925, or US 2022 / 0288168.

[0015] Fixed-dose combination therapy of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide is currently in clinical trials for the treatment of overweight and obesity (Lancet literature [2021; 397: 1736-48]). The finished product in clinical trials is a separate liquid pharmaceutical composition for subcutaneous use. The clinical trials demonstrated that the combination of cagrilintide and semaglutide in obese individuals induced greater weight loss than the maximum approved dose of semaglutide monotherapy. No worsening of the adverse effect profile was observed. Co-agonists of GLP-1 and amylin receptors, and their potential medical uses, are described in several patent applications, such as WO 2022 / 129526 A1. This discloses a peptide co-agonist of human GLP-1R and amylin receptors, which is potent and balanced (i.e., similar levels of activation in both receptor systems) and demonstrates oral bioavailability. Another example is WO 2007 / 022123, which describes a hybrid polypeptide containing exendin covalently bonded to amylin. However, to date, no co-agonists of GLP-1 and amylin receptors have obtained market approval.

[0016] Finally, WO 2023 / 288313 and WO 2024 / 015922 disclose multi-acting peptides useful as agents for the treatment and prevention of metabolic diseases and disorders, particularly diabetes and obesity. WO 2023 / 288313 discloses a peptide comprising two or more component peptides including amylin, GIP, GLP-1, and / or calcitonin. Specifically, the disclosed peptide is a triple agonist of GLP-1, GIP, and amylin receptors and exhibits activity on all three receptors in animals and a reduction in food intake and body weight.

[0017] While current treatment options and investigational drugs may be promising, individuals living with overweight, obesity, and / or related comorbidities may at this point in time best hope to be treated with injectable pharmaceutical formulations or medicines that possess some efficacy. There is still a need in the industry for more effective medicines that are effective in vitro and for weight loss, without causing proportionally increased levels of side effects, have improved pharmacokinetics and chemical stability, and are suitable for once-weekly administration or oral administration in humans.

[0018] The present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0019] Z1 - L1 - Z2 (I),

[0020] In the formula, Z1 is a peptide GLP-1- / GIP-receptor co-agonist, L1 is a peptide linker, Z2 is a peptide amylin-receptor agonist, and the peptide according to chemical formula (I) contains one lysine (Lys, K).

[0021] In one embodiment, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0022] Z1―L1―Z2 (I),

[0023] The above peptide includes one lysine (Lys, K) residue, wherein:

[0024] · Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[0025] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX33 X 34 (III),

[0026] During the meal

[0027] X2 represents Aib,

[0028] X 12 represents Ile(I) or Lys(K), and

[0029] X 20 represents Arg(R) or Gln(Q), and

[0030] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0031] X 27 represents Leu(L) or Ile(I),

[0032] X 28 represents Ala(A) or Gln(Q), and

[0033] X 30 represents Gly(G) or Ala(A), and

[0034] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0035] X 33 represents Glu(E) or Ser(S),

[0036] X 34 represents Gly(G) or Glu(E);

[0037] · L1 is a peptide linker and;

[0038] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0039] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72PRTETGSGSP (VI),

[0040] During the meal

[0041] X 52 represents Gly(G) or Ser(S),

[0042] X 53 represents Gln(Q), Glu(E), or His(H), and

[0043] X 58 represents Ala(A) or Gln(Q), and

[0044] X 59 represents Leu(L) or Thr(T),

[0045] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0046] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0047] X 72 represents Leu(L) or Glu(E).

[0048] 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), and X 28 is Ala(A) and X 30 is Gly(G) or Ala(A), and X 31 is Gly(G), Ala(A), or Pro(P), and X 33 is Ser(S), and X 34 is Gly(G).

[0049] In some embodiments of peptide Z2, X 52 is Ser(S), and X 53 is Glu(E) or His(H), and X 58is Ala(A) or Gln(Q), and X 59 is Leu(L) or Thr(T), and X 60 is Gly(G) or Gln(Q), and X 68 is Gln(Q), Glu(E), or Lys(K), and X 72 is Leu(L).

[0050] In some embodiments, the GLP-1- / GIP- / amylin-receptor triple agonist has an amino acid sequence comprising or consisting of the following:

[0051] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAQLGRLSAELHQLATLPRTETGSGSP (Sequence No. 230), or

[0052] YX2EGTFTSDYSILLEEIAAREFIEWLLAGGASSGAGEAPGEAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (Sequence No. 243), or

[0053] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (Sequence No. 244), or

[0054] YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (Sequence No. 246), or

[0055] YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence No. 250), or

[0056] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGGSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence No. 251), or

[0057] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence No. 252) (wherein each X2 is Aib).

[0058] In some embodiments, the GLP-1- / GIP- / amylin-receptor triple agonist is, for example, at position 12 of Z1 (X 12 ) or position 18(X of Z2 68 It includes an extension moiety that increases the half-life of peptide Z1-L1-Z2, attached via lysine residues in ).

[0059] In a second aspect, the present invention relates particularly to a pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist and one or more pharmaceutically acceptable excipients, for use in the treatment of a subject having an initial BMI of 27 or more, e.g. 30 or more, and optionally at least one weight-related comorbidity. The invention also relates to the medical use of said triple agonist.

[0060] In a third aspect, the present invention relates to a balanced GLP-1- / GIP- / amylin-receptor triple agonist capable of selectively activating or "functioning" all three of the GLP-1 receptor, GIP receptor, and amylin receptor to similar levels.

[0061] Also or alternatively, in a fourth aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist having improved pharmacokinetic properties.

[0062] Also or alternatively, in a fifth aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist suitable for once-weekly administration.

[0063] Also or alternatively, in a sixth aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist suitable for oral administration.

[0064] Also or alternatively, in a seventh aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist that reduces food intake.

[0065] Also or alternatively, in the eighth aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist with improved chemical stability.

[0066] The present invention can also solve additional problems that will become apparent from the disclosure of exemplary embodiments and aspects. Specific details for implementing the invention

[0067] The present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0068] Z1 - L1 - Z2 (I),

[0069] In the formula, Z1 is a peptide GLP-1- / GIP-receptor co-agonist, L1 is a peptide linker, Z2 is a peptide amylin-receptor agonist, and the peptide according to chemical formula (I) contains one lysine (Lys, K).

[0070] The compounds disclosed herein are referred to as "GLP-1- / GIP- / amylin-receptor tri-agonist" or "GLP-1 receptor-GIP receptor-amylin receptor tri-agonist" or "GLP-1- / GIP- / amylin-receptor triple agonist" or "GLP-1 receptor-GIP receptor-amylin receptor triple agonist".

[0071] The GLP-1- / GIP- / amylin-receptor triagonist comprises peptide Z1, a GLP-1- / GIP receptor co-agonist, peptide linker L1, and peptide Z2, an amylin receptor agonist. The GLP-1- / GIP- / amylin-receptor triagonist is a compound that binds to each of the three GLP-1, GIP, and amylin receptors and can activate each receptor, GLP-1R, GIPR, and amylin receptor, thereby inducing a response at each receptor.

[0072] The compounds disclosed herein are agonists at the receptors GLP-1, GIP, and amylin, respectively. Thus, the compounds of the present invention are GLP-1 receptor agonists, GIP receptor agonists, and amylin receptor agonists. This is a "GLP-1- / GIP- / amylin-receptor triple agonist" capable of activating or "functioning" all three of the GLP-1 receptor, GIP, and amylin receptors. The GLP-1- / GIP- / amylin-receptor triple agonist can provide similar levels of activation to all three GLP-1, GIP, and amylin receptors; then, this is referred to as a "balanced GLP-1- / GIP- / amylin-receptor triple agonist" or simply a "balanced triple agonist."

[0073] "Receptor agonist" or "agonist" may be defined as a ligand, such as a compound, that binds to a biological receptor and activates it to produce a biological response. A complete agonist may be defined as one that induces a response of the same magnitude as a natural ligand (see, for example, the literature ["Principles of Biochemistry", AL Lehninger, DL Nelson, MM Cox, Second Edition, Worth Publishers, 1993, page 763]). Receptors may be activated by endogenous agonists (e.g., endogenous hormones) or exogenous agonists (e.g., pharmaceutical drugs).

[0074] 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 that each bind to a given biological receptor and produce a biological response characteristic of a natural ligand. In a similar manner, 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 that each bind to a given biological receptor and produce a biological response characteristic of a natural ligand.

[0075] "GLP-1 receptor agonists" can be defined as compounds capable of binding to and activating GLP-1 receptors. "Complete" GLP-1 receptor agonists can be defined as GLP-1 receptor agonists capable of inducing a GLP-1 receptor response similar to that of natural glucagon, such as peptide 1 (GLP-1). Semaglutide disclosed in Example 4 of WO 2006 / 097537 is an example of an exogenous GLP-1 receptor agonist.

[0076] "GIP receptor agonists" can be defined as compounds capable of binding to and activating GIP receptors. "Complete" GIP receptor agonists can be defined as GIP receptor agonists capable of inducing a GIP receptor response similar to that of natural glucose-dependent insulin-secreting polypeptides (GIP).

[0077] "GLP-1 / GIP receptor co-agonists" can be defined as compounds that can bind to both GLP-1 receptors and GIP receptors and activate both receptors. An example of a GLP-1 / GIP co-agonist is tyrzepatide, described in WO 2016 / 111971.

[0078] "Amylin receptor agonists" may be defined as chemicals capable of binding to and activating the amylin receptor (AMYR) and the calcitonin receptor (CTR). The amylin receptor consists of a heterodimer of the following two components: the calcitonin receptor (CTR); and one of three receptor-activating-modifying proteins (RAMP1-3) that produce the three complex AMYR1-3. Unless otherwise specified herein, "amylin receptor" refers to at least the amylin receptor 3 (AMYR3). Nevertheless, some incidental activity toward other receptors may be expected. "Full" amylin receptor agonists may be defined as amylin receptor agonists capable of inducing an amylin receptor response to a degree similar to that of natural amylin. Amylin receptor agonists will often also be calcitonin receptor agonists. Examples of amylin receptor agonists are human amylin, framlintide, and cagrilintide (disclosed in WO 2012 / 168432). It should be noted that all headings and subheadings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0079] Any of the embodiments provided herein, or the use of exemplary language (e.g., “such as”), is merely intended to better describe the invention and does not limit the scope of the invention unless otherwise claimed.

[0080] For a better understanding of the present invention, certain terms are defined first.

[0081] In the following, Greek letters may be represented by symbols or corresponding names (e.g., α = alpha; β = beta; γ = gamma; ε = epsilon; ω = omega; etc.). Additionally, the Greek letter μ may be represented as "u" (e.g., μl = ul, or μM = uM).

[0082] Unless otherwise stated in this specification, terms presented in the singular form generally include the plural form. The term "one (a or an)" is intended to mean "one or more."

[0083] The term "comprising" (comprise and its variations, comprises and comprising) when modifying a step or element is intended to imply that additional steps or elements may exist at any time and are not excluded. As disclosed herein, open-form terms such as "comprising" ("comprises" and "comprising") may be replaced with closed-form terms such as "consisting of" ("consisting of," "consisting of," etc.).

[0084] The term “about” is used herein to mean approximately, roughly, or nearly. When the term “about” is used with a numerical range, it modifies the range by extending the boundaries above and below the presented numerical value. Generally, the term “about” can modify the numerical value by about 10% above or below the indicated value (higher or lower).

[0085] Amino acids are molecules containing an amine group and a carboxylic acid group, and optionally contain one or more additional groups, often referred to as side chains.

[0086] The term "amino acid" includes (genetically encoded) canonical amino acids and non-proteogenic amino acids. Non-limiting examples of non-proteogenic amino acids are Aib (α-aminoisobutyric acid or 2-aminocisobutyric acid) and D-isomers of canonical amino acids. Any amino acid residue in a peptide, for which an optical isomer is not mentioned, should be understood to mean an L-isomer in this document unless otherwise specified.

[0087] As used herein, "amino acid substitution" or "substitution" refers to one or more amino acid(s) that are replaced by an equal number of amino acid(s) in the peptide backbone. Substitutions may be conservative substitutions, but are not limited thereto. For example, amino acids can be substituted with amino acids having similar biochemical properties; for example, basic amino acids can be substituted with another basic amino acid (e.g., lysine to arginine), acidic amino acids can be substituted with another acidic amino acid (e.g., glutamate to aspartate), neutral amino acids can be substituted with another neutral amino acid (e.g., threonine to serine), charged amino acids can be substituted with another charged amino acid (e.g., glutamate to lysine), hydrophilic amino acids can be substituted with another hydrophilic amino acid (e.g., asparagine to glutamine), hydrophobic amino acids can be substituted with another hydrophobic amino acid (e.g., alanine to valine), polar amino acids can be substituted with another polar amino acid (e.g., serine to threonine), and aromatic amino acids can be substituted with another aromatic amino acid (e.g., phenylalanine to tryptophan). It can be, and an aliphatic amino acid can be substituted with another aliphatic amino acid (e.g., from leucine to isoleucine).

[0088] As used herein, the term "excipient" broadly refers to any component other than the active pharmaceutical ingredient (API).

[0089] As known in the art, the term "identity" or "sequence identity" refers to the relationship between the sequences of two or more polypeptides as determined by comparing the sequences. In the art, "identity" also refers to the degree of sequence relatedness between polypeptides as determined by the number of matches between strings of two or more amino acid residues. "Identity" is the measurement of the percentage of identity match between the smaller of two or more sequences using gap alignment (if present), which is handled by a specific mathematical model or computer program ("algorithm"). The identity of related polypeptides can be easily calculated by known methods, for example, using Needleman in EMBOSS-6.6.0 (Needleman et al. [J. Mol. Biol. 1970; 48: 443-453]) with parameters of 10 and 0.5 for gap opening and gap extension, respectively (gapopen = 10, gapextend = 0.5). It may be used or calculated by: (1) comparing a comparison window (e.g., length of a longer sequence, length of a shorter sequence, a specific window, etc.); (2) determining the number of positions containing the same monomer (e.g., the same amino acid occurring in both sequences); (3) dividing the number of matching positions within the comparison window (e.g., length of a longer sequence, length of a shorter sequence, a specific window) by the total number of positions; and (4) multiplying the result by 100 to calculate the percentage "sequence identity". For example, if both peptides A and B are 20 amino acids long and have the same amino acid at all positions except one, peptides A and B have 95% sequence identity.

[0090] As used herein, the terms “polypeptide” or “peptide” refer to a short chain of amino acids linked by one or more amide (or peptide) bonds, including oligopeptides. The terms “polypeptide” and “peptide” will be used interchangeably herein.

[0091] As used herein, the term “half-life” or “plasma half-life” refers to the time required for half of an amount of a substance administered to a person to be metabolized or removed from the person’s serum or plasma by normal biological processes.

[0092] As used herein, the term “treatment” and variations thereof refer to medical therapy for any human subject requiring such treatment. The term includes administering a therapeutically effective amount of a peptide as disclosed herein, sufficient to reduce or eliminate at least one symptom of a disorder in question. However, “treatment” is not necessarily a cure. The timing and purpose of said treatment may vary from person to person depending on the subject’s current health condition. Accordingly, said treatment may be preventive, palliative, symptomatic, and / or curative. In the context of the present invention, preventive, palliative, symptomatic, and / or curative treatment may represent distinct aspects of the present invention.

[0093] As used herein, the term "prevention" (preventing, prevent, or prevention) or variations thereof refers to protecting a subject from the occurrence of at least one symptom of a disease or reducing the severity of symptoms of disability.

[0094] The term “compound” is used herein to refer to a molecular entity, and thus, a “compound” may have different structural components in addition to the minimum component defined for each compound in the group of compounds. This means that, insofar as the compound contains the defined structural and / or functional elements, the compound may be a peptide or a derivative thereof. The term “compound” also means a pharmaceutically related form thereof, namely, a compound as defined herein or a pharmaceutically acceptable salt, amide, or ester thereof.

[0095] The compounds disclosed herein may be potent GLP-1 receptor agonists.

[0096] The compounds disclosed herein may be potent GIP receptor agonists.

[0097] The compounds disclosed herein may be potent amylin receptor agonists.

[0098] The in vitro efficacy of the agent can be measured as described in the assay of Example 4. The term "efficacy" is used to describe the effect of a given compound in an assay where a sigmoid relationship between the log concentration and the effect of the compound is established. Additionally, the response must be variable from 0 to 100%. The efficacy of the compound is its EC (effective concentration) 50 It can be described by the value. EC 50 represents the concentration of the compound at which 50% of the maximum effect of the compound is observed in the assay, as described in Example 4. EC 50 The lower the value, the stronger the compound.

[0099] The compounds disclosed herein can provide similar levels of activation to all three GLP-1, GIP, and amylin receptors; that is, they can be "balanced" and are referred to as "balanced GLP-1- / GIP- / amylin-receptor triple agonists" or simply "balanced triple agonists." Relatively "balanced" receptor activation is advantageous because the relative ratios of the GLP-1, GIP, and amylin receptor agonist activities of the compound are fixed for the molecule; it is not possible to titrate the three receptor agonists against one another. Ultimately, when the molecule is "balanced," the molecule can be administered to activate all three hormonal systems without side effects that outweigh the benefits.

[0100] The lowest efficacy (i.e., the highest value of EC) 50 The efficacy (A) of the receptor having the value) is the highest efficacy (i.e., the lowest EC value). 50 A triple agonist having an efficacy ratio (A / B) divided by the efficacy (B) of a receptor having a value of less than 50, preferably less than 30, is defined as a "balanced triple agonist" or a "balanced GLP-1- / GIP- / amylin-receptor triple agonist" (Example 4 Table 11 and Table 12 As shown in [figure], based on the assay in the absence of human serum albumin (HSA). For example, Compound 183 has an EC of 14.7 pM for the GLP-1 receptor. 50 , EC of 2.17 pM for GIP receptors 50 , and an EC of 7.08 pM for amylin receptors 50It has the lowest efficacy for hGLP-1 (where (A) corresponds to 14.7 pM) and the highest efficacy for GIP receptors (where (B) corresponds to 2.17 pM). Therefore, the efficacy ratio (A / B) is the value obtained by dividing 14.7 pM (A) by 2.17 pM (B), i.e., a value of 7 (rounded), which means that compound 183 is a "balancing triple agonist".

[0101] Compounds that are potent for one receptor and much less potent for the other become "unbalanced" compounds. Such "unbalanced triple agonists" are defined as compounds having an efficacy ratio (A / B) of 50 or greater, or alternatively, an efficacy ratio (A / B) of 30 or greater. For example, Reference Compound 1 has an efficacy ratio (A / B) of 256 (i.e., 1680 pM (= A) divided by 6.55 pM (= B) and rounded). For example, this reference compound is potent for the amylin receptor (i.e., EC 50 value <30 pM), less potent for GIP receptors (i.e., EC 50 (value 221 pM), much less potent against GLP-1 receptors (i.e., EC 50 (Value 1680 pM), optimal efficacy will not be achieved in all three of these hormone systems.

[0103] GLP-1 / GIP-receptor co-agonist - Z1 peptide

[0104] The present invention relates to a peptide according to Formula I comprising peptide Z1, which is a GLP-1- / GIP-receptor co-agonist.

[0105] In one embodiment, Z1, a GLP-1- / GIP-receptor co-agonist, is a peptide having up to 5 amino acid substitutions compared to Formula II (Sequence No. 1):

[0106] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0107] In the formula, the amino acid at position X2 is Aib.

[0108] In one embodiment, the GLP-1- / GIP-receptor co-agonist is a peptide comprising or composed of an amino acid sequence according to formula (III) (SEQ ID NO. 168):

[0109] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0110] During the meal

[0111] X2 represents Aib,

[0112] X 12 represents Ile(I) or Lys(K), and

[0113] X 20 represents Arg(R) or Gln(Q), preferably Arg(R), and

[0114] X 24 represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E), and

[0115] X 27 represents Leu(L) or Ile(I),

[0116] X 28 represents Ala(A) or Gln(Q), preferably Ala(A), and

[0117] X 30 represents Gly(G) or Ala(A), and

[0118] X 31 ... represents Gly(G), Gln(Q), Ala(A), or Pro(P), preferably Pro(P) or Ala(A), and

[0119] X 33It represents Glu(E) or Ser(S), preferably Ser(S), and

[0120] X 34 represents Gly(G) or Glu(E), preferably Gly(G).

[0121] In some embodiments, the peptide Z1 disclosed herein may have up to five amino acid substitutions relative to Formula II (Sequence No. 1), said substitution(s) may occur at any one of positions 1 to 34, preferably said substitution(s) may occur at positions 12, 17, 20, 24, 27, 28, 30, 31, 33, and / or 34, more preferably at positions 12, 17, 27, 30, 31, and / or 33. The present invention comprises a variant of a GLP-1- / GIP- / amylin-receptor triagonist as disclosed herein, said peptide Z1 may have one, two, three, four, or five amino acid substitution(s) relative to Formula II (Sequence No. 1).

[0122] Desirable substitutions include conservative substitutions that involve amino acids or structural analogs of amino acid residues with similar biochemical properties instead of the amino acid residues appearing in the sequence.

[0123] In one embodiment, the Z1 peptide according to formula III has up to 5 substitutions compared to formula II (sequence number 1), that is, compared to formula II.

[0124] In one embodiment, Z1, a GLP-1- / GIP-receptor co-agonist, is a peptide having up to 5 substitutions compared to formula (II) (SEQ ID NO. 1):

[0125] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0126] In the formula, X2 is Aib and

[0127] Z1 comprises or consists of an amino acid sequence according to chemical formula (III) (SEQ ID No. 168):

[0128] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0129] During the meal

[0130] X2 represents Aib,

[0131] X 12 represents Ile(I) or Lys(K), and

[0132] X 20 represents Arg(R) or Gln(Q), preferably Arg(R), and

[0133] X 24 represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E), and

[0134] X 27 represents Leu(L) or Ile(I),

[0135] X 28 represents Ala(A) or Gln(Q), preferably Ala(A), and

[0136] X 30 represents Gly(G) or Ala(A), and

[0137] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), preferably Ala(A), Gly(G), or Pro(P), and

[0138] X 33 It represents Glu(E) or Ser(S), preferably Ser(S), and

[0139] X 34represents Gly(G) or Glu(E), preferably Gly(G).

[0140] In one embodiment, Z1, a GLP-1- / GIP-receptor co-agonist, is a peptide having up to four substitutions compared to formula (II) (SEQ ID NO. 1):

[0141] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0142] In the formula, X2 is Aib and

[0143] Z1 comprises or consists of an amino acid sequence according to chemical formula (VII) (SEQ ID No. 162):

[0144] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII),

[0145] During the meal

[0146] X2 represents Aib,

[0147] X 12 represents Ile(I) or Lys(K), and

[0148] X 20 represents Arg(R) or Gln(Q), and

[0149] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0150] X 27 represents Leu(L) or Ile(I),

[0151] X 28 represents Ala(A) or Gln(Q), and

[0152] X 34 represents Gly(G) or Glu(E).

[0153] In one embodiment, the Z1 peptide comprises or consists of an amino acid sequence according to Formula IV (SEQ ID NO. 169):

[0154] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGX 30 X 31 SSG (IV),

[0155] During the meal

[0156] X2 represents Aib,

[0157] X 12 represents Ile(I) or Lys(K), and

[0158] X 27 represents Leu(L) or Ile(I),

[0159] X 30 represents Gly(G) or Ala(A), and

[0160] X 31 represents Ala(A), Gly(G), or Pro(P).

[0161] In one embodiment, the Z1 peptide comprises or consists of a peptide having an amino acid sequence selected from the group consisting of the sequences shown in Table 1:

[0162]

[0163] In one embodiment, the Z1 peptide comprises or consists of SEQ ID NO. 22. In one embodiment, the Z1 peptide comprises or consists of SEQ ID NO. 29. In one embodiment, the Z1 peptide comprises or consists of SEQ ID NO. 31. In one embodiment, the Z1 peptide comprises or consists of SEQ ID NO. 34.

[0165] L1 peptide linker

[0166] The GLP-1- / GIP- / amylin-receptor triagonist peptide backbone according to Formula I as disclosed herein comprises a peptide linker L1, which may comprise 1 to 14 amino acid residues, in particular canonical amino acid residues. The peptide linker may comprise 1 to 10 amino acid residues, in particular canonical amino acid residues, e.g., 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 include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues, particularly canonical amino acid residues.

[0167] Peptide linker L1 can be represented by the chemical formula VIIIa and:

[0168] 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),

[0169] X in food 141-154 Any one of them is independently selected from any naturally occurring amino acid residue(s) or canonical amino acid residue(s), wherein X 142-154 One of them may be absent.

[0170] The peptide backbone of the GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein comprises a peptide linker L1, wherein the peptide linker L1 comprises or consists of an amino acid sequence according to Formula VIIIa. Accordingly, the GLP-1- / GIP- / amylin-receptor triple agonist may comprise or consist of a peptide according to the amino acid sequence of SEQ ID NO. 5.

[0171] X 141-154 Any one of them can be selected from any non-aromatic amino acid residue. X 141-154 One of them may be a charged amino acid. X 141-154 One of them may be a polar amino acid. X 141-154 One of them may be a hydrophobic amino acid.

[0172] X 141-154 Any one of them may be independently selected from the group consisting of alanine (Ala, A), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), leucine (Leu, L), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), valine (Val, V), and asparagine (Asn, N). Preferably, X 141-154 Any one of them 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).

[0173] In one embodiment, the peptide linker L1 may be represented by the formula VIIIa, or may include or be composed of an amino acid sequence according to the formula IV:

[0174] X 141 X 142 X 143 X 144 X 145 X 146 X 147 X 148 X 149 X150 X 151 X 152 X 153 X 154 (VIIIa),

[0175] During the meal

[0176] X 141 represents Ala(A), Glu(E), and Gly(G),

[0177] X 142 represents or is absent of Gln(Q), Glu(E), Gly(G), Leu(L), and Pro(P),

[0178] X 143 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Pro(P),

[0179] X 144 is represented by or absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Pro(P),

[0180] X 145 is represented by or absent from Glu(E), Gly(G), Pro(P), Ser(S), and Thr(T),

[0181] X 146 ... represents or is absent from Glu(E), Gly(G), Leu(L), and Gln(Q),

[0182] X 147 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Phe(F),

[0183] X 148 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), Thr(T), Pro(P), Val(V), and

[0184] X 149 is represented by or absent from Glu(E), Asn(N), Pro(P), and Thr(T),

[0185] X 150... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), Val(V), and

[0186] X 151 represents Ala(A) or is absent,

[0187] X 152 represents Gln(Q) or is absent,

[0188] X 153 represents Thr(T) or is absent,

[0189] X 154 represents or is absent from Leu(L).

[0190] In one embodiment, the peptide linker L1 may comprise or consist of 1 to 10 amino acid residues and may be represented by the formula VIII:

[0191] X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII),

[0192] X in food 41-50 Any one of them is independently selected from any naturally occurring amino acid residue(s) or canonical amino acid residue(s), wherein X 42-50 One of them may be absent.

[0193] The peptide backbone of the GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein comprises a peptide linker L1, wherein the peptide linker L1 comprises or consists of an amino acid sequence according to Formula VIII. Accordingly, the GLP-1- / GIP- / amylin-receptor triple agonist may comprise or consist of a peptide according to the amino acid sequence of SEQ ID NO. 10.

[0194] X 41-50Any one of them can be selected from any non-aromatic amino acid residue. X 41-50 One of them may be a charged amino acid. X 41-50 One of them may be a polar amino acid. X 41-50 One of them may be a hydrophobic amino acid.

[0195] X 41-50 Any one of them may be independently selected from the group consisting of alanine (Ala, A), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), leucine (Leu, L), proline (Pro, P), serine (Ser, S), and valine (Val, V). Preferably, X 41-50 One of them may be selected from the group consisting of alanine (Ala, A), glutamic acid (Glu, E), glycine (Gly, G), and proline (Pro, P).

[0196] In one embodiment, the peptide linker L1 may be represented by Formula VIII, or may include or be composed of an amino acid sequence according to Formula VIII:

[0197] X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII),

[0198] During the meal

[0199] X 41 represents Ala(A), Glu(E), or Gly(G), and

[0200] X 42 represents or is absent from Glu(E) and Gly(G),

[0201] X 43 ... represents Glu(E), Gly(G), Gln(Q), or is absent,

[0202] X44 represents Ala(A), Glu(E), Gly(G), or is absent,

[0203] X 45 represents or is absent of Glu(E), Gly(G), and Pro(P),

[0204] X 46 ... represents or is absent from Glu(E) and Gly(G),

[0205] X 47 is Gln(Q) or Glu(E) and is absent,

[0206] X 48 ... represents or is absent from Ala(A) and Glu(E),

[0207] X 49 is indicative of or absent Glu(E) and Pro(P),

[0208] X 50 It represents or is absent from Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), and Val(V).

[0209] In one embodiment, the peptide linker L1 may be represented by Formula VIII, or may include or be composed of an amino acid sequence according to Formula VIII:

[0210] X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII),

[0211] During the meal

[0212] X 41 represents Ala(A) or Glu(E),

[0213] X 42 represents or is absent from Glu(E) and Gly(G),

[0214] X 43... represents Glu(E), Gly(G), Gln(Q), or is absent,

[0215] X 44 represents Ala(A), Glu(E), Gly(G), or is absent,

[0216] X 45 represents or is absent of Glu(E), Gly(G), and Pro(P),

[0217] X 46 ... represents or is absent from Glu(E) and Gly(G),

[0218] X 47 is Gln(Q) or Glu(E) and is absent,

[0219] X 48 ... represents or is absent from Ala(A) and Glu(E),

[0220] X 49 is indicative of or absent Glu(E) and Pro(P),

[0221] X 50 It represents or is absent from Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), and Val(V).

[0222] In one embodiment, the peptide linker (L1) may be any one of the peptide linkers represented by SEQ ID NOs 125 to 159. The peptide linker (L1) is Table 2 It may be any one of the peptide linkers listed in ).

[0223]

[0224] In one embodiment, the peptide linker L1 may be selected from the group consisting of: A, E, G, AE, GE, AG, AGGGG (SEQ No. 142), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), AGEAPGQAPG (SEQ No. 143), AGEAPGEAPG (SEQ No. 144), AGQAPGQAPA (SEQ No. 145), AGQAPGQAPE (SEQ No. 146), AGQAPGQAPP (SEQ No. 147), AGQAPGQAPS (SEQ No. 148), AGQAPGQAPV (SEQ No. 149), EGQAPGQAPG (SEQ No. 150), AGQEPGQAPG (SEQ No. 151), AGQAEGQAPG (SEQ No. 152), AGQAPEQAPG (Sequence No. 153), AGQAPGEAPG (Sequence No. 154), AGQAPGQEPG (Sequence No. 155), AGQAPGQAEG (Sequence No. 156), AGQEPGQEPG (Sequence No. 157), AGQAPGQAP (Sequence No. 158), and AGQAPGEAPL (Sequence No. 159).

[0225] In one embodiment, the peptide linker L1 may be selected from the group consisting of: E, AE, AG, AGGGG (SEQ No. 142), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), AGEAPGQAPG (SEQ No. 143), AGEAPGEAPG (SEQ No. 144), AGQAPGQAPA (SEQ No. 145), AGQAPGQAPE (SEQ No. 146), AGQAPGQAPP (SEQ No. 147), AGQAPGQAPS (SEQ No. 148), AGQAPGQAPV (SEQ No. 149), EGQAPGQAPG (SEQ No. 150), AGQEPGQAPG (SEQ No. 151), AGQAEGQAPG (SEQ No. 152), AGQAPEQAPG (SEQ No. 153), AGQAPGEAPG (SEQ No. 154), AGQAPGQEPG (SEQ No. 155), AGQAPGQAEG (SEQ No. 156), AGQEPGQEPG (SEQ No. 157), AGQAPGQAP (SEQ No. 158), and AGQAPGEAPL (SEQ No. 159).

[0226] In a preferred embodiment, the peptide linker L1 may be AG or AGEAPGEAPG (SEQ ID NO. 144).

[0227] In one embodiment, linker L1 comprises or consists of 1 to 10 amino acid residues. In a preferred embodiment, the linker comprises or consists of 1, 2, 5, 9, or 10 amino acid residues, more preferably 2 or 10 amino acid residues.

[0229] Amylin-receptor agonist - Z2 peptide

[0230] The present invention relates to a peptide according to formula I comprising peptide Z2, which is an amylin-receptor agonist.

[0231] In one embodiment, Z2, an amylin-receptor agonist, is a C-terminal amide and has up to 10 amino acid substitutions compared to formula V (SEQ ID NO. 2):

[0232] ASELSTAALGRLSAELHELATLPRTETGSGSP (V).

[0233] In one embodiment, the amylin-receptor agonist is a peptide comprising or composed of an amino acid sequence according to Formula VI (SEQ ID NO. 165):

[0234] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0235] During the meal

[0236] X 52 represents Gly(G) or Ser(S),

[0237] X 53 represents Gln(Q), Glu(E), or His(H), and

[0238] X 58 represents Ala(A) or Gln(Q), and

[0239] X 59 represents Leu(L) or Thr(T),

[0240] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0241] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0242] X 72 represents Leu(L) or Glu(E).

[0243] In one embodiment, Z2, an amylin-receptor agonist, is a C-terminal amide and has up to 10 amino acid substitutions compared to formula V (SEQ ID NO. 2):

[0244] ASELSTAALGRLSAELHELATLPRTETGSGSP (V)

[0245] Z2 comprises or consists of an amino acid sequence according to chemical formula VI (SEQ ID NO. 165):

[0246] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0247] During the meal

[0248] X 52 represents Gly(G) or Ser(S),

[0249] X 53 represents Gln(Q), Glu(E), or His(H), and

[0250] X 58 represents Ala(A) or Gln(Q), and

[0251] X 59 represents Leu(L) or Thr(T),

[0252] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0253] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0254] X 72 represents Leu(L) or Glu(E).

[0255] In a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of the prior embodiments, Z2 is a C-terminal amide and comprises or consists of an amino acid sequence according to Formula IX (SEQ ID NO. 61):

[0256] ASX 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATLPRTETGSGSP (IX),

[0257] During the meal

[0258] X 53 represents Glu(E) or His(H),

[0259] X 58 represents Ala(A) or Gln(Q), and

[0260] X 59 represents Leu(L) or Thr(T),

[0261] X 60 represents Gly(G) or Gln(Q), and

[0262] X 68 represents Gln(Q), Glu(E), or Lys(K).

[0263] The peptide Z2 disclosed herein may have up to 10 amino acid substitutions relative to Formula V (SEQ No. 2), said substitution(s) may occur at any one of positions 1 to 32, preferably said substitution(s) occur at positions 2, 3, 7, 8, 9, 10, 15, 18, 20, 21, 22, 24, and / or 31, more preferably at positions 3, 8, 9, 10, and / or 18. The present invention comprises a variant of a GLP-1- / GIP- / amylin-receptor triagonist as disclosed herein, said peptide Z2 may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitution(s) relative to Formula V (SEQ No. 2). Preferred substitutions include conservative substitutions as described above.

[0264] 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:

[0265]

[0266] In one embodiment, the Z2 peptide comprises or consists of SEQ ID NO. 2. In one embodiment, the Z2 peptide comprises or consists of SEQ ID NO. 40. In one embodiment, the Z2 peptide comprises or consists of SEQ ID NO. 53. In one embodiment, the Z2 peptide comprises or consists of SEQ ID NO. 59.

[0268] GLP-GLP-1- / GIP- / amylin-receptor triple agonist peptide

[0269] In one embodiment, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist, which is a peptide also referred to as a "GLP-1- / GIP- / amylin-receptor triple agonist peptide." The GLP-1- / GIP- / amylin-receptor triple agonist comprises or consists of a peptide, namely Z1-L1-Z2, which includes peptide Z1, a peptide linker L1, and peptide Z2.

[0270] Peptide Z1 is a GLP-1 / GIP receptor co-agonist capable of binding to both GLP-1 and GIP receptors and activating both receptors. The C-terminus of peptide Z1 is attached to peptide linker L1 via a peptide bond.

[0271] L1 is a peptide linker. Its N-terminus is attached to the C-terminus of Z1, and its C-terminus is attached to the N-terminus of Z2 via a peptide bond.

[0272] Peptide Z2 is an amylane receptor agonist capable of binding to and activating at least an amylane receptor. The N-terminus of Z2 is attached to the C-terminus of L1 via a peptide bond. The C-terminus of Z2 is modified into an amide group considered essential for biological activity. In a preferred embodiment, the amine group of the C-terminal amide is NH2.

[0273] The molecular format may be a short-chain peptide backbone containing one lysine (Lys, K) residue. One lysine (Lys, K) residue may be present in the peptide Z1 portion of the peptide backbone, or one lysine (Lys, K) residue may be present in the peptide Z2 portion of the peptide backbone.

[0274] In one embodiment, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0275] Z1―L1―Z2 (I),

[0276] The above peptide includes one lysine (Lys, K) residue, wherein:

[0277] · Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[0278] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0279] During the meal

[0280] X2 represents Aib,

[0281] X 12 represents Ile(I) or Lys(K), and

[0282] X 20 represents Arg(R) or Gln(Q), and

[0283] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0284] X 27 represents Leu(L) or Ile(I),

[0285] X 28represents Ala(A) or Gln(Q), and

[0286] X 30 represents Gly(G) or Ala(A), and

[0287] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0288] X 33 represents Glu(E) or Ser(S),

[0289] X 34 represents Gly(G) or Glu(E);

[0290] · L1 is a peptide linker and;

[0291] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0292] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0293] During the meal

[0294] X 52 represents Gly(G) or Ser(S),

[0295] X 53 represents Gln(Q), Glu(E), or His(H), and

[0296] X 58 represents Ala(A) or Gln(Q), and

[0297] X 59 represents Leu(L) or Thr(T),

[0298] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0299] X68 represents Gln(Q), Glu(E), or Lys(K), and

[0300] X 72 represents Leu(L) or Glu(E).

[0301] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0302] Z1―L1―Z2 (I),

[0303] The above peptide includes one lysine (Lys, K) residue, wherein:

[0304] · Z1 comprises or consists of an amino acid sequence according to chemical formula XVII (SEQ No. 62):

[0305] YX2EGTFTSDYSX 12 LLEEIAAREFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (XVII),

[0306] During the meal

[0307] X2 represents Aib,

[0308] X 12 represents Ile(I) or Lys(K), and

[0309] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0310] X 27 represents Leu(L) or Ile(I),

[0311] X 28 represents Ala(A) or Gln(Q), and

[0312] X 30 represents Gly(G) or Ala(A), and

[0313] X 31represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0314] X 33 represents Glu(E) or Ser(S),

[0315] X 34 represents Gly(G) or Glu(E);

[0316] · L1 is a peptide linker and;

[0317] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0318] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0319] During the meal

[0320] X 52 represents Gly(G) or Ser(S),

[0321] X 53 represents Gln(Q), Glu(E), or His(H), and

[0322] X 58 represents Ala(A) or Gln(Q), and

[0323] X 59 represents Leu(L) or Thr(T),

[0324] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0325] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0326] X 72 represents Leu(L) or Glu(E).

[0327] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0328] Z1―L1―Z2 (I),

[0329] The above peptide includes one lysine (Lys, K) residue, wherein:

[0330] · Z1 is a peptide containing up to 5 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0331] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0332] In the formula, the amino acid at position X2 represents Aib;

[0333] · L1 is a peptide linker and;

[0334] · Z2 is a C-terminal amide and a peptide containing up to 10 amino acid substitutions relative to formula V (SEQ No. 2):

[0335] ASELSTAALGRLSAELHELATLPRTETGSGSP (V).

[0336] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0337] Z1―L1―Z2 (I),

[0338] The above peptide includes one lysine (Lys, K) residue, wherein:

[0339] · Z1 is a peptide containing up to 5 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0340] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0341] In the formula, the amino acid at position X2 represents Aib, and

[0342] Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[0343] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0344] During the meal

[0345] X2 represents Aib,

[0346] X 12 represents Ile(I) or Lys(K), and

[0347] X 20 represents Arg(R) or Gln(Q), preferably Arg(R), and

[0348] X 24 represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E).

[0349] X 27 represents Leu(L) or Ile(I),

[0350] X 28 represents Ala(A) or Gln(Q), and

[0351] X 30 represents Gly(G) or Ala(A), and

[0352] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0353] X 33 represents Glu(E) or Ser(S),

[0354] X 34 represents Gly(G) or Glu(E);

[0355] · L1 is a peptide linker and;

[0356] · Z2 is a C-terminal amide and a peptide containing up to 10 amino acid substitutions relative to formula V (SEQ No. 2):

[0357] ASELSTAALGRLSAELHELATLPRTETGSGSP (V),

[0358] Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0359] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0360] During the meal

[0361] X 52 represents Gly(G) or Ser(S),

[0362] X 53 represents Gln(Q), Glu(E), or His(H), and

[0363] X 58 represents Ala(A) or Gln(Q), and

[0364] X 59 represents Leu(L) or Thr(T),

[0365] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0366] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0367] X 72 represents Leu(L) or Glu(E).

[0368] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0369] Z1―L1―Z2 (I),

[0370] The above peptide includes one lysine (Lys, K) residue, wherein:

[0371] · Z1 is a peptide having up to 4 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0372] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0373] In the formula, the amino acid at position X2 represents Aib, and

[0374] Z1 comprises or consists of an amino acid sequence according to chemical formula VII (SEQ ID NO. 162):

[0375] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII),

[0376] During the meal

[0377] X2 represents Aib,

[0378] X 12 represents Ile(I) or Lys(K), and

[0379] X 20 represents Arg(R) or Gln(Q), and

[0380] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0381] X 27 represents Leu(L) or Ile(I),

[0382] X 28 represents Ala(A) or Gln(Q), and

[0383] X 34 represents Gly(G) or Glu(E);

[0384] · L1 is a peptide linker and;

[0385] · Z2 is a peptide containing a C-terminal amide and having up to 10 amino acid substitutions compared to formula V (SEQ No. 2):

[0386] ASELSTAALGRLSAELHELATLPRTETGSGSP (V),

[0387] Z2 comprises or consists of an amino acid sequence according to chemical formula VI (SEQ ID NO. 165):

[0388] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0389] During the meal

[0390] X 52 represents Gly(G) or Ser(S),

[0391] X 53 represents Gln(Q), Glu(E), or His(H), and

[0392] X 58 represents Ala(A) or Gln(Q), and

[0393] X 59 represents Leu(L) or Thr(T),

[0394] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0395] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0396] X 72 represents Leu(L) or Glu(E).

[0397] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention may comprise an amino acid sequence according to formula VX (SEQ ID NO. 167) or a peptide Z1 composed thereof, and:

[0398] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGGPSSX 34 (VX),

[0399] During the meal

[0400] X2 represents Aib,

[0401] X 12 represents Ile(I) or Lys(K), and

[0402] X 27 represents Leu(L) or Ile(I),

[0403] X 34 represents Gly(G) or Glu(E);

[0404] Peptide Z2 comprises or consists of the amino acid sequence according to SEQ ID NO. 40:

[0405] ASHLSTAQTQRLSAELHKLATLPRTETGSGSP.

[0406] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention may comprise an amino acid sequence according to Formula IV (SEQ ID NO. 169) or a peptide Z1 composed thereof, and:

[0407] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGX 30 X 31 SSG (IV),

[0408] During the meal

[0409] X2 represents Aib,

[0410] X 12 represents Ile(I) or Lys(K), and

[0411] X 27 represents Leu(L) or Ile(I),

[0412] X 30 represents Gly(G) or Ala(A), and

[0413] X 31 represents Ala(A), Gly(G), or Pro(P);

[0414] Peptide Z2 comprises or consists of an amino acid sequence according to Chemical Formula IX (SEQ No. 61):

[0415] ASX 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATLPRTETGSGSP (IX),

[0416] During the meal

[0417] X 53 represents Glu(E) or His(H),

[0418] X 58 represents Ala(A) or Gln(Q), and

[0419] X 59 represents Leu(L) or Thr(T),

[0420] X 60 represents Gly(G) or Gln(Q), and

[0421] X 68 represents Gln(Q), Glu(E), or Lys(K).

[0422] In one embodiment, the backbone of peptide Z1-L1-Z2 comprises or consists of 66 to 80 amino acid residues, for example, 66 to 76 amino acid residues.

[0423] In one embodiment, the backbone of peptide Z1-L1-Z2 comprises or consists of 67, 68, 71, 75, or 76 amino acid residues.

[0424] In a preferred embodiment, the backbone of peptide Z1-L1-Z2 comprises or consists of 68 or 76 amino acid residues.

[0425] In one embodiment, the backbone of peptide Z1-L1-Z2 comprises or consists of the amino acid sequence according to SEQ ID NO. 10. In one embodiment, the backbone of peptide Z1-L1-Z2 comprises or consists of the amino acid sequence according to SEQ ID NO. 5.

[0426] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist comprises a peptide according to Formula I: Z1-L1-Z2, said peptide Table 4 It comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs 170 to 252 shown in:

[0427]

[0428]

[0429]

[0430]

[0431] In a specific embodiment, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist, wherein the peptide comprises or consists of an amino acid sequence selected from the following list: 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.

[0432] 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 (Sequence 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 (Sequence No. 2).

[0433] In some embodiments of the present invention, the GLP-1- / GIP- / amylin-receptor triagonists disclosed herein do not contain cysteine ​​(Cys, C) residues and / or do not contain disulfide crosslinks. In relation to human amylin and analogs thereof, the term “disulfide crosslink” refers to a functional group having the structure RSS-R’ and may also be referred to as an “SS-bond”.

[0434] GLP-1- / GIP- / amylin-receptor triple agonists can exhibit various properties useful as medicines, as described herein.

[0436] Extended Mobility

[0437] In one embodiment, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist that may further comprise an extension moiety. In this case, the triple agonist is referred to as a "peptide derivative" or a "GLP-1- / GIP- / amylin-receptor triple agonist derivative." Accordingly, the addition of the term "derivative" implies the presence of an extension moiety, and compounds or compounds comprising an extension moiety are referred to as "derivatives" or "derivatives."

[0438] The molecular format may be a short-chain peptide backbone containing one lysine (Lys, K) residue. One lysine (Lys, K) residue may be present in the peptide Z1 portion of the peptide backbone, or one lysine (Lys, K) residue may be present in the peptide Z2 portion of the peptide backbone. One lysine residue may be covalently bonded to an extension moiety, which is described herein as "L P It can be referred to as -P", where "L P " is an arbitrary linker and "P" is a protractor. The peptide backbone of the GLP-1- / GIP- / amylin-receptor triagonist of the present invention generally comprises about 66 to about 76 amino acid residues linked together by peptide bonds.

[0439] As used herein, the term "extension moiety" has a half-life extension characteristic and is "extensor P" and any "linker L" P Refers to a moiety containing ", and the general formula "L P It can be expressed as -P", where L P is the above arbitrary linker and P is the above extender.

[0440] As used herein, the term “extending moiety” refers to a molecule that can increase the plasma half-life of a peptide attached to the peptide. Thus, the term “extending” refers to the extension of the half-life, and the terms “extending moiety,” “extending moiety,” or “half-life extending moiety” serve the purpose of extending the plasma half-life of a peptide as disclosed herein.

[0441] In addition, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention has a long plasma half-life relative to the dosing interval, thereby reducing the variability of steady-state exposure and thus enabling once-weekly administration. Since the compounds disclosed herein may be available for oral bioavailability, they may be suitable for oral administration to subjects requiring this. Both the peptide backbone and the extended moiety are engineered and purified to achieve a compound having all of the aforementioned characteristics.

[0442] Each extended moiety L P- P is covalently attached to the epsilon-amino group of a lysine residue in the peptide backbone of the GLP-1- / GIP- / amylin-receptor triagonist of the present invention. The attachment site is generally referred to as R1.

[0443] In one embodiment, the extended moiety 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 extension moiety L P -P is a lysine (Lys, K) residue within the peptide Z1 portion of the peptide backbone ("Z1" in Z1-L1-Z2), e.g., the Z1 peptide (X) of formula III (SEQN 168), formula IV (SEQN 169), formula VII (SEQN 162), formula XV (SEQN 167), or formula XVII (SEQN 62). 12 It can be attached to the epsilon position (i.e., amino group) of the lysine (Lys, K) residue at position 12 of ). In one embodiment, the extended moiety L P -P can be attached to the epsilon position (i.e., amino group) of the lysine (Lys, K) residue of SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 27, SEQ ID NO. 30 to 34, preferably SEQ ID NO. 22 or SEQ ID NO. 31.

[0444] In one embodiment, the extended moiety L P-P is a lysine (Lys, K) residue within the peptide Z2 portion of the peptide backbone ("Z2" in Z1-L1-Z2), e.g., at position 18 (X) of formula VI (SEQ No. 165), formula IX (SEQ No. 61), formula X (SEQ No. 166), or formula XIV (SEQ No. 4). 68 It can be attached to the epsilon position (i.e., amino group) of a lysine (Lys, K) residue in ). In one embodiment, the extended moiety L P -P can be attached to the epsilon position (i.e., amino group) of the lysine (Lys, K) residue of SEQ ID NO. 40, SEQ ID NO. 45 to 51, or SEQ ID NO. 58, preferably SEQ ID NO. 40.

[0445] In one embodiment, the extended moiety L P -P can be attached to the epsilon position (i.e., amino group) of the lysine (Lys, K) residue of the GLP-1- / GIP- / amylin-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.

[0446] Arbitrary linker L P If exists, extended moiety L P -P is the linker L P It is covalently attached to the peptide backbone through linker L P In the absence of , P is covalently attached to the peptide backbone.

[0447] As disclosed herein, the GLP-1- / GIP- / amylin-receptor triagonist of the present invention comprises or consists of a peptide containing a single lysine (Lys, K) residue, to which a single extension moiety is covalently attached / conjugated (at the epsilon-amino group) to the peptide. The extension moiety may consist of a single extender P. The extension moiety consists of a single linker L P and may include one extender P. The extension moiety is one linker L Pand may include two or more extension groups (in which case referred to as P1, P2, or P3, etc.). The two extension groups (P1 and P2) may be identical, or the two extension groups (P1 and P2) may not be identical. When the peptide derivative includes two or three extension groups (P1, P2, P3), the extension groups are preferably similar, more preferably substantially identical, or most preferably identical.

[0448] In the context of chemical moiety, such as the extension moiety disclosed herein, similarity and / or identity may be determined using any suitable computer program and / or known algorithm known in the art.

[0449] The extension moiety binds non-covalently to albumin, which can promote the circulation of peptide derivatives in the bloodstream and extend their plasma half-life. Therefore, those skilled in the art may refer to the extension moiety as an "albumin-binding moiety."

[0450] Extension device P

[0451] The extender P may include an acyl group. The acyl group may be branched or unbranched. The acyl group may be saturated or unsaturated. The extender P may include 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.

[0452] The extension group P may include a distal carboxylic acid group.

[0453] The extension group P may include a fatty acid group.

[0454] The extender P may include fatty acid groups and amide groups.

[0455] The extender P may include a distal carboxylic acid group and an amide group.

[0456] The extender P may include an alkyl group.

[0457] The extension group P may include an aryl group.

[0458] The extender P may include a tetrazole group.

[0459] The extender P may include a sulfonic acid group.

[0460] The extension phase P may include the phenoxy phase.

[0461] The extension group P may include a benzoic acid group.

[0462] The extender P may include a phosphonic acid group.

[0463] An extension may include a unit defined by the following:

[0464] Chemical formula 1a: HOOC-(CH2) n -CO-* (where n is an integer in the range of 6 to 30)(this is C (n+2) Discrete (e.g., C 18 It can be referred to as discrete), or (this is C (n+2) Discrete (e.g., C 18 (can be referred to as discrete), or

[0465] Chemical formula 1b: (In the formula, n is an integer in the range of 6 to 30). An asterisk (*) indicates the attachment point of the radical.

[0466] The extender P may contain 8 to 32 carbon atoms. The extender 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.

[0467] The extender P may include 6 to 30 consecutive -CH2- groups. The extender P may include 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.

[0468] The extender P may include 12 to 26 carbon atoms. The extender P may include 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 carbon atoms.

[0469] The extender P may include 10 to 26 consecutive -CH2- groups. The extender P may include a carbon chain containing 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 consecutive -CH2- groups.

[0470] The extender P may include 16 to 22 carbon atoms. The peptide derivative of the present invention may include a single extender moiety having an extender P comprising a side-chain carbon chain containing 16, 17, 18, 19, 20, 21, or 22 carbon atoms.

[0471] The extender P may include 14 to 20 consecutive -CH2- groups. The extender P may include a carbon chain containing 14, 15, 16, 17, 18, 19, or 20 consecutive -CH2- groups.

[0472] The extender P may contain 16 to 22 consecutive carbon atoms and 14 to 20 consecutive -CH2- groups.

[0473] The extender P can contain 16 consecutive carbon atoms and 14 consecutive -CH2- groups. The extender P is C 16It can be a discrete, which has the chemical formula HOOC-(CH2) 14 It can be defined as -CO-*.

[0474] The extender P can contain 18 consecutive carbon atoms and 16 consecutive -CH2- groups. The extender P is C 18 It can be a discrete, which has the chemical formula HOOC-(CH2) 16 It can be defined as -CO-*.

[0475] The extender P can contain 20 consecutive carbon atoms and 18 consecutive -CH2- groups. The extender P is C 20 It can be a discrete, which has the chemical formula HOOC-(CH2) 18 It can be defined as -CO-*.

[0476] The extender P can contain 22 consecutive carbon atoms and 20 consecutive -CH2- groups. The extender P is C 22 It can be a discrete, which has the chemical formula HOOC-(CH2) 20 It can be defined as -CO-*.

[0477] The term "fatty acid" refers to an aliphatic mono-carboxylic acid or dicarboxylic acid having 4 to 28 carbon atoms, which may be branched or unbranched, preferably unbranched, and may be saturated or unsaturated, preferably saturated.

[0478] As previously mentioned, the peptide derivative disclosed herein has one lysine (Lys, K) residue and one extension moiety therefrom (L P -P) is included, wherein the extension moiety is attached to the peptide backbone described herein through the epsilon position (i.e., amino group) of a lysine (Lys, K) residue (through an amide bond formed between the carboxylic acid group in the extension moiety and the epsilon amino group of the lysine residue). The extension moiety may be attached to the epsilon position of one lysine (Lys, K) residue within the peptide backbone.

[0479] In one embodiment, the extension moiety may be attached to the epsilon position of a lysine (Lys, K) residue in peptide Z1 ("Z1" in Z1-L1-Z2) of the peptide backbone. In particular, the extension moiety is attached to position X of formula III (SEQ No. 168) or formula VII (SEQ No. 162) of peptide Z1. 12 It can be attached to the epsilon position of lysine (Lys, K). In particular, the elongation moiety can be attached to the epsilon position of lysine (Lys, K) at position 12 of peptide Z1.

[0480] In one embodiment, the extension moiety may be attached to the epsilon position of a lysine (Lys, K) residue in the linker L1 portion ("L1" in Z1-L1-Z2) of the peptide backbone.

[0481] In one embodiment, the extension moiety may be attached to the epsilon position of a lysine (Lys, K) residue in peptide Z2 ("Z2" in Z1-L1-Z2) of the peptide backbone. In particular, the extension moiety is attached to position X of formula VI (SEQ ID NO. 165) of peptide Z2. 68 It can be attached to the epsilon position of lysine (Lys, K). In particular, the extension moiety can be attached to the epsilon position of the lysine (Lys, K) residue at position 18 of peptide Z2. In a preferred embodiment, the extension moiety can be attached to the epsilon position of the lysine (Lys, K) residue at position 18 of peptide Z2.

[0482] In some embodiments, a GLP-1- / GIP- / amylin-receptor triple agonist comprising the peptide derivative disclosed herein Table 5 It may include an extension P selected from any one of the ones shown in.

[0483] R1 is (a) the backbone of a peptide derivative, more specifically the epsilon-amino group of lysine, or (b) this optional linker L PIndicates the attachment site for. Based on the disclosure of the present invention, those skilled in the art may also determine, optionally after some limited routine experiments, other chemical moiety for use as an extender in certain peptide derivatives as disclosed herein.

[0484]

[0485]

[0486] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist is C 12 -C 20 It includes a peptide derivative containing a diacidic extension group P.

[0487] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist is C 16 Dispersal, C 18 Discrete, and C 20 It includes a peptide derivative comprising an extender P selected from the group consisting of diacids.

[0488] In a preferred embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist is C 18 Discrete acid (Chemical Formula 5), ​​C 20 Discrete acid (Chemical Formula 6), or C 19 It includes a peptide derivative containing an extending group P which is phosphonic acid (Chemical Formula 32).

[0489] Linker Lp

[0490] In one embodiment, the extender is directly, i.e., the linker L P It is attached / conjugated to the backbone of a peptide derivative without using (i.e., through covalent bonds (e.g., amide bonds)).

[0491] In another embodiment, the extender is a linker L P Since it is covalently conjugated to a peptide derivative using, as mentioned above, the extension moiety (L P -P) is arbitrarily linked L P Includes linker L PIt may include several "linker elements." The linker elements may be selected to improve the overall exposure profile after the compound is orally administered, by improving the overall properties of the molecule, for example, oral bioavailability, switching of half-life, or extension effect.

[0492] Linker L P It may include Ado, Aeep or Aeeep, Ahx, Ala, ε-Lys, Glu, γGlu, Gly, Ser, sulfonamide, Thr, and / or Trx.

[0493] Linker L P It may include at least one moiety that can be represented by the following chemical formula (where an asterisk (*) in the formula indicates a radical attachment site):

[0494] Chemical formula 9a: *-NH-(CH2)2-(O-(CH2)2) k -O-(CH2) n -CO-*

[0495] Chemical formula 9b: ,

[0496] In the expression, k is an integer in the range of 1 to 5, and n is an integer in the range of 1 to 5.

[0497] When k=1 and n=1, the linker element can be designated as Ado or 8-amino-3,6-dioxaoctanoyl, which can be represented by the following chemical formula:

[0498] Chemical formula 10a: *-NH-(CH2)2-O-(CH2)2-O-CH2-CO-*

[0499] or

[0500] Chemical formula 11b: .

[0501] When k=1 and n=2, the linker element can be designated as Aeep, which can be represented by the following chemical formula:

[0502] Chemical formula 12a: *-NH-(CH2)2-O-(CH2)2-O-(CH2)2-CO-*

[0503] or

[0504] Chemical formula 12b: .

[0505] When k=2 and n=2, the linker element can be designated as Aeeep, which can be represented by the following chemical formula:

[0506] Chemical formula 13a: *-NH-(CH2) 2- O-(CH2)2O-(CH2)2-O-(CH2)2-CO-*

[0507] or

[0508] Chemical formula 13b: .

[0509] Linker L P It may include a sulfonamide-C4 moiety. The sulfonamide-C4 group is a sulfonamide group attached to a 4-butanoyl group and has the following chemical formula:

[0510] Chemical formula 14a: *-NH-S(O)2-CH2-CH2-CH2-CO-*

[0511] or

[0512] Chemical formula 14b: .

[0513] Linker L P It may contain Trx. Trx is also referred to as tranexamic acid or trans-4-(aminomethyl)cyclohexanecarboxylic acid and has the following chemical formula:

[0514] Chemical formula 15a: *-NH-CH2-(C6H 10 )-CO-*

[0515] or

[0516] Chemical formula 15b: .

[0517] Linker L P It may contain Ahx. Ahx is also referred to as aminocaproic acid or 6-aminohexanoic acid and has the following chemical formula:

[0518] Chemical formula 16a: *-NH-(CH2)5-CO-*

[0519] or

[0520] Chemical formula 16b: .

[0521] Linker L P It may include epsilon-lysine (ε-Lys).

[0522] Linker L P It may include Lys.

[0523] Linker L P It may contain alanine (Ala).

[0524] Linker L P It may contain glycine (Gly).

[0525] Linker L P It may contain serine.

[0526] Linker L P It may contain glutamic acid (Glu).

[0527] Linker L P It may contain the following Glu D-radicals:

[0528] Chemical formula 17: ,

[0529] In the formula, the Glu D-radical may be included p times, where p is an integer in the range of 1 to 3. Linker L P As or linker L P Any of the aforementioned amino acids used as part of the product may be used as an L-isomer or a D-isomer.

[0530] Chemical formula 17 is the gamma-carboxyl group of the amino acid glutamic acid, which is also referred to as gamma-glu or simply γGlu because it is used to link with the epsilon-amino group of lysine. As previously mentioned, other linker elements may be, for example, other Glu residues or Ado molecules. The amino group of Glu forms an amide bond in turn with the carboxyl group of the extension moiety, or with the carboxyl group of, for example, the Ado molecule (if present), or with, for example, the gamma-carboxyl group of another Glu (if present).

[0531] The peptide derivatives disclosed herein are as follows: Table 6 A linker L selected from any one of those shown in P It may include. R1 represents a residue of the peptide backbone to which the extension moiety is attached, and P represents the extension group.

[0532] In some embodiments, the peptide derivative comprises an extension moiety, wherein the extension group is Formula 4 or Formula 5 or Formula 6 or Formula 32 as follows Table 6 In L 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 a linker designated as 6.

[0533] In some embodiments, the peptide derivative comprises an extension moiety, wherein the extension group, Formula 5, is as follows Table 6 In L 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 a linker designated as 6, and thus the extension moiety is formed by linker L of Formula 18, Formula 19, Formula 20, Formula 21, Formula 33, or Formula 34. PAs such, chemical formula 5 is included as the extender P.

[0534] In some embodiments, the peptide derivative comprises an extension moiety, wherein the extension group, Formula 6, is as follows Table 6 In L 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 a linker designated as 6, and thus the extension moiety is formed by linker L of Formula 18, Formula 19, Formula 20, Formula 21, Formula 33, or Formula 34. P As such, chemical formula 6 is included as the extender P.

[0535] In some embodiments, the peptide derivative comprises an extension moiety, wherein the extension group, Formula 32, is as follows Table 6 In L 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 a linker designated as 6, and thus the extension moiety is formed by linker L of Formula 18, Formula 19, Formula 20, Formula 21, Formula 33, or Formula 34. P As such, chemical formula 32 is included as the extender P.

[0536] In a preferred embodiment, the peptide derivative comprises an extension moiety, wherein the extension moiety is a linker L of Formula 20 or Formula 21. P As such, it includes Chemical Formula 5 or Chemical Formula 6 as the extender P.

[0537] In a preferred embodiment, the peptide derivative comprises an extension moiety, wherein the extension group, Formula 5, is L in Table 6 below. P It is attached to the peptide backbone using a linker designated as 3, and thus the extension moiety is linked by linker L of formula 20. PAs such, chemical formula 5 is included as the extender P.

[0538] In a preferred embodiment, the peptide derivative comprises an extension moiety, wherein the extension group, Formula 6, is L in Table 6 below. P It is attached to the peptide backbone using a linker designated as 3, and thus the extension moiety is linked by linker L of formula 20. P As such, chemical formula 6 is included as the extender P.

[0539] Based on the disclosure of the present invention, those skilled in the art may find the optimal L for use in specific peptide derivatives as disclosed herein. P The linker can be determined arbitrarily after some limited routine experiments.

[0540]

[0541]

[0542] In some embodiments, the peptide derivative comprises an extension moiety selected from the group presented in Table 7. R1 represents a residue of the peptide backbone to which the extension moiety is attached.

[0543]

[0544]

[0545]

[0546] In one embodiment, the extension moiety is selected from the list consisting of Formula 27, Formula 35, Formula 36, ​​and Formula 36. In a preferred embodiment, the extension moiety is Formula 27.

[0547] In one embodiment, glass lysine is one C 16It can act as a binding site for attaching a dioxide gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamin)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]), and thus the peptide derivative of the present invention comprises an extension moiety, wherein the extension moiety is C 16 It is a diacid(S) gamma-Glu 2xAdo fatty acid moiety.

[0548] In one embodiment, glass lysine is one C 18 It can act as a binding site for attaching a dilute gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamin)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]), and thus the peptide derivative of the present invention comprises an extension moiety, wherein the extension moiety is C 18 It is a diacid(S) gamma-Glu 2xAdo fatty acid moiety.

[0549] In one embodiment, glass lysine is one C 20 It can act as a binding site for attaching a dioxide gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamin)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]), and thus the peptide derivative of the present invention comprises an extension moiety, wherein the extension moiety is C 20 It is a diacid(S) gamma-Glu 2xAdo fatty acid moiety.

[0550] In one embodiment, glass lysine is one C 18It can act as a binding site for attaching a diacetyl gamma-Glu fatty acid moiety (IUPAC name [(4S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butanoyl]), and thus the peptide derivative of the present invention comprises an extension moiety, wherein the extension moiety is C 18 It is a diacid(S) gamma-Glu fatty acid moiety.

[0551] In one embodiment, glass lysine is one C 20 It can act as a binding site for attaching a diacetyl gamma-Glu fatty acid moiety (IUPAC name [(4S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butanoyl]), and thus the peptide derivative of the present invention comprises an extension moiety, wherein the extension moiety is C 20 It is a diacid(S) gamma-Glu fatty acid moiety.

[0552] In a preferred embodiment, free lysine is one C 18 It can act as a binding site for attaching a dioxide gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(17-carboxypentadecanoylamin)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]), and thus the peptide derivative of the present invention comprises an extension moiety, wherein the extension moiety is C 18 It is a diacid(S) gamma-Glu 2xAdo fatty acid moiety.

[0553] In a preferred embodiment, free lysine is one C 20It can act as a binding site for attaching a dioxide gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]), and thus the peptide derivative of the present invention comprises an extension moiety, wherein the extension moiety is C 20 It is a diacid(S) gamma-Glu 2xAdo fatty acid moiety.

[0554] In the most preferred embodiment, free lysine is one C 18 It can act as a binding site for attaching a dioxide gamma-Glu 2xAdo fatty acid moiety (IUPAC name [2-[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamin)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]), and thus the peptide derivative of the present invention comprises an extension moiety, wherein the extension moiety is C 18 It is a diacid(S) gamma-Glu 2xAdo fatty acid moiety.

[0556] GLP-1 / GIP / amylin-receptor triple agonist derivatives

[0557] As described above, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention may comprise a peptide linker and may further comprise an extension moiety. Accordingly, in another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0558] Z1―L1―Z2 (I),

[0559] The above peptide includes one lysine (Lys, K) residue, wherein:

[0560] · Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[0561] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0562] During the meal

[0563] X2 represents Aib,

[0564] X 12 represents Ile(I) or Lys(K), and

[0565] X 20 represents Arg(R) or Gln(Q), and

[0566] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0567] X 27 represents Leu(L) or Ile(I),

[0568] X 28 represents Ala(A) or Gln(Q), and

[0569] X 30 represents Gly(G) or Ala(A), and

[0570] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0571] X 33 represents Glu(E) or Ser(S),

[0572] X 34 represents Gly(G) or Glu(E);

[0573] · L1 is a peptide linker and;

[0574] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0575] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0576] During the meal

[0577] X 52 represents Gly(G) or Ser(S),

[0578] X 53 represents Gln(Q), Glu(E), or His(H), and

[0579] X 58 represents Ala(A) or Gln(Q), and

[0580] X 59 represents Leu(L) or Thr(T),

[0581] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0582] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0583] X 72 represents Leu(L) or Glu(E),

[0584] The above peptide is Table 7 It is a peptide derivative containing an extension moiety selected from.

[0585] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0586] Z1―L1―Z2 (I),

[0587] The above peptide includes one lysine (Lys, K) residue, wherein:

[0588] · Z1 is a peptide comprising or composed of an amino acid sequence according to chemical formula XVII (SEQ No. 62):

[0589] YX2EGTFTSDYSX 12 LLEEIAAREFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (XVII),

[0590] During the meal

[0591] X2 represents Aib,

[0592] X 12 represents Ile(I) or Lys(K), and

[0593] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0594] X 27 represents Leu(L) or Ile(I),

[0595] X 28 represents Ala(A) or Gln(Q), and

[0596] X 30 represents Gly(G) or Ala(A), and

[0597] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0598] X 33 represents Glu(E) or Ser(S),

[0599] X 34 represents Gly(G) or Glu(E);

[0600] · L1 is a peptide linker and;

[0601] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0602] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0603] During the meal

[0604] X 52 represents Gly(G) or Ser(S),

[0605] X 53 represents Gln(Q), Glu(E), or His(H), and

[0606] X 58 represents Ala(A) or Gln(Q), and

[0607] X 59 represents Leu(L) or Thr(T),

[0608] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0609] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0610] X 72 represents Leu(L) or Glu(E),

[0611] The above peptide is Table 7 It is a peptide derivative containing an extension moiety selected from.

[0612] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0613] Z1―L1―Z2 (I),

[0614] The above peptide includes one lysine (Lys, K) residue, wherein:

[0615] · Z1 is a peptide containing up to 5 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0616] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0617] In the formula, the amino acid at position X2 represents Aib, and

[0618] Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[0619] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0620] During the meal

[0621] X2 represents Aib,

[0622] X 12 represents Ile(I) or Lys(K), and

[0623] X 20 represents Arg(R) or Gln(Q), preferably Arg(R), and

[0624] X 24 represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E).

[0625] X 27 represents Leu(L) or Ile(I),

[0626] X 28 represents Ala(A) or Gln(Q), and

[0627] X 30 represents Gly(G) or Ala(A), and

[0628] X 31represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0629] X 33 represents Glu(E) or Ser(S),

[0630] X 34 represents Gly(G) or Glu(E);

[0631] · L1 is a peptide linker and;

[0632] · Z2 is a peptide comprising a C-terminal amide and comprising or consisting of an amino acid sequence according to Formula VI (SEQ ID NO. 165):

[0633] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0634] During the meal

[0635] X 52 represents Gly(G) or Ser(S),

[0636] X 53 represents Gln(Q), Glu(E), or His(H), and

[0637] X 58 represents Ala(A) or Gln(Q), and

[0638] X 59 represents Leu(L) or Thr(T),

[0639] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0640] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0641] X 72 represents Leu(L) or Glu(E),

[0642] The above peptide is Table 7 It is a peptide derivative containing an extension moiety selected from.

[0643] In another aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0644] Z1―L1―Z2 (I),

[0645] The above peptide includes one lysine (Lys, K) residue, wherein:

[0646] · Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[0647] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0648] During the meal

[0649] X2 represents Aib,

[0650] X 12 represents Ile(I) or Lys(K), and

[0651] X 20 represents Arg(R) or Gln(Q), preferably Arg(R), and

[0652] X 24 represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E), and

[0653] X 27 represents Leu(L) or Ile(I),

[0654] X 28 represents Ala(A) or Gln(Q), preferably Ala(A), and

[0655] X 30 represents Gly(G) or Ala(A), and

[0656] X 31 ... represents Gly(G), Gln(Q), Ala(A), or Pro(P), preferably Pro(P) or Ala(A), and

[0657] X 33 It represents Glu(E) or Ser(S), preferably Ser(S), and

[0658] X 34 represents Gly(G) or Glu(E); preferably Gly(G),

[0659] · L1 is a peptide linker selected from the group consisting of: E, AE, AG, AGGGG (SEQ No. 142), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), AGEAPGQAPG (SEQ No. 143), AGEAPGEAPG (SEQ No. 144), AGQAPGQAPA (SEQ No. 145), AGQAPGQAPE (SEQ No. 146), AGQAPGQAPP (SEQ No. 147), AGQAPGQAPS (SEQ No. 148), AGQAPGQAPV (SEQ No. 149), EGQAPGQAPG (SEQ No. 150), AGQEPGQAPG (SEQ No. 151), AGQAEGQAPG (SEQ No. 152), AGQAPEQAPG (SEQ NO. 153), AGQAPGEAPG (SEQ NO. 154), AGQAPGQEPG (SEQ NO. 155), AGQAPGQAEG (SEQ NO. 156), AGQEPGQEPG (SEQ NO. 157), AGQAPGQAP (SEQ NO. 158), and AGQAPGEAPL (SEQ NO. 159), preferably AG or AGEAPGEAPG (SEQ NO. 144);

[0660] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0661] AX52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0662] During the meal

[0663] X 52 represents Gly(G) or Ser(S),

[0664] X 53 represents Gln(Q), Glu(E), or His(H), and

[0665] X 58 represents Ala(A) or Gln(Q), and

[0666] X 59 represents Leu(L) or Thr(T),

[0667] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0668] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0669] X 72 represents Leu(L) or Glu(E),

[0670] The above peptide is Table 7 It is a peptide derivative selected from, preferably comprising an extension moiety of Formula 27.

[0671] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0672] Z1―L1―Z2 (I),

[0673] The above peptide includes one lysine (Lys, K) residue, wherein:

[0674] · Z1 comprises or consists of an amino acid sequence according to chemical formula XVII (SEQ No. 62):

[0675] YX2EGTFTSDYSX 12 LLEEIAAREFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (XVII),

[0676] During the meal

[0677] X2 represents Aib,

[0678] X 12 represents Ile(I) or Lys(K), and

[0679] X 24 represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E), and

[0680] X 27 represents Leu(L) or Ile(I),

[0681] X 28 represents Ala(A) or Gln(Q), preferably Ala(A), and

[0682] X 30 represents Gly(G) or Ala(A), and

[0683] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0684] X 33 It represents Glu(E) or Ser(S), preferably Ser(S), and

[0685] X 34 represents Gly(G) or Glu(E); preferably Gly(G);

[0686] · L1 is a peptide linker selected from the group consisting of: E, AE, AG, AGGGG (SEQ No. 142), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), AGEAPGQAPG (SEQ No. 143), AGEAPGEAPG (SEQ No. 144), AGQAPGQAPA (SEQ No. 145), AGQAPGQAPE (SEQ No. 146), AGQAPGQAPP (SEQ No. 147), AGQAPGQAPS (SEQ No. 148), AGQAPGQAPV (SEQ No. 149), EGQAPGQAPG (SEQ No. 150), AGQEPGQAPG (SEQ No. 151), AGQAEGQAPG (SEQ No. 152), AGQAPEQAPG (SEQ NO. 153), AGQAPGEAPG (SEQ NO. 154), AGQAPGQEPG (SEQ NO. 155), AGQAPGQAEG (SEQ NO. 156), AGQEPGQEPG (SEQ NO. 157), AGQAPGQAP (SEQ NO. 158), and AGQAPGEAPL (SEQ NO. 159), preferably AG or AGEAPGEAPG (SEQ NO. 144);

[0687] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0688] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0689] During the meal

[0690] X 52 represents Gly(G) or Ser(S), preferably Ser(S), and

[0691] X 53 represents Gln(Q), Glu(E), or His(H), and

[0692] X 58represents Ala(A) or Gln(Q), and

[0693] X 59 represents Leu(L) or Thr(T),

[0694] X 60 ... represents Ala(A), Gly(G), or Gln(Q), preferably Gly(G) or Gln(Q), and

[0695] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0696] X 72 represents Leu(L) or Glu(E), preferably Leu(L),

[0697] The above peptide is Table 7 It is a peptide derivative selected from, preferably comprising an extension moiety of Formula 27.

[0698] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0699] Z1―L1―Z2 (I),

[0700] The above peptide includes one lysine (Lys, K) residue, wherein:

[0701] · Z1 is a peptide containing up to 5 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0702] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0703] In the formula, the amino acid at position X2 represents Aib, and

[0704] Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[0705] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0706] During the meal

[0707] X2 represents Aib,

[0708] X 12 represents Ile(I) or Lys(K), and

[0709] X 20 represents Arg(R) or Gln(Q), preferably Arg(R), and

[0710] X 24 represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E), and

[0711] X 27 represents Leu(L) or Ile(I),

[0712] X 28 represents Ala(A) or Gln(Q), preferably Ala(A), and

[0713] X 30 represents Gly(G) or Ala(A), and

[0714] X 31 ... represents Gly(G), Gln(Q), Ala(A), or Pro(P), preferably Pro(P) or Ala(A), and

[0715] X 33 It represents Glu(E) or Ser(S), preferably Ser(S), and

[0716] X 34 represents Gly(G) or Glu(E), preferably Gly(G);

[0717] · L1 is a peptide linker selected from the group consisting of: E, AE, AG, AGGGG (SEQ No. 142), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), AGEAPGQAPG (SEQ No. 143), AGEAPGEAPG (SEQ No. 144), AGQAPGQAPA (SEQ No. 145), AGQAPGQAPE (SEQ No. 146), AGQAPGQAPP (SEQ No. 147), AGQAPGQAPS (SEQ No. 148), AGQAPGQAPV (SEQ No. 149), EGQAPGQAPG (SEQ No. 150), AGQEPGQAPG (SEQ No. 151), AGQAEGQAPG (SEQ No. 152), AGQAPEQAPG (SEQ NO. 153), AGQAPGEAPG (SEQ NO. 154), AGQAPGQEPG (SEQ NO. 155), AGQAPGQAEG (SEQ NO. 156), AGQEPGQEPG (SEQ NO. 157), AGQAPGQAP (SEQ NO. 158), and AGQAPGEAPL (SEQ NO. 159), preferably AG or AGEAPGEAPG (SEQ NO. 144);

[0718] · Z2 is a peptide comprising a C-terminal amide and comprising or consisting of an amino acid sequence according to Formula VI (SEQ ID NO. 165):

[0719] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0720] During the meal

[0721] X 52 represents Gly(G) or Ser(S), preferably Ser(S), and

[0722] X 53 represents Gln(Q), Glu(E), or His(H), preferably Glu(E) or His(H), and

[0723] X 58 represents Ala(A) or Gln(Q), and

[0724] X 59 represents Leu(L) or Thr(T),

[0725] X 60 ... represents Ala(A), Gly(G), or Gln(Q), preferably Gly(G) or Gln(Q), and

[0726] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0727] X 72 represents Leu(L) or Glu(E), preferably Leu(L);

[0728] The above peptide is Table 7 It is a peptide derivative selected from, preferably comprising an extension moiety of Formula 27.

[0729] In another aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to Formula I:

[0730] Z1―L1―Z2 (I),

[0731] The above peptide includes one lysine (Lys, K) residue, wherein:

[0732] · Z1 is a peptide having up to 4 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0733] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0734] In the formula, the amino acid at position X2 represents Aib, and

[0735] Z1 comprises or consists of an amino acid sequence according to chemical formula VII (SEQ ID NO. 162):

[0736] YX2EGTFTSDYSX 12 LLEEIAAX20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII),

[0737] During the meal

[0738] X2 represents Aib,

[0739] X 12 represents Ile(I) or Lys(K), and

[0740] X 20 represents Arg(R) or Gln(Q), and

[0741] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0742] X 27 represents Leu(L) or Ile(I),

[0743] X 28 represents Ala(A) or Gln(Q), and

[0744] X 34 represents Gly(G) or Glu(E);

[0745] · L1 is a peptide linker selected from the group consisting of E, GE, APPPSGGGE (SEQ No. 129), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137) and AGQAPGEAPG (SEQ No. 154);

[0746] · Z2 is a peptide containing a C-terminal amide and having up to 10 amino acid substitutions compared to formula V (SEQ No. 2):

[0747] ASELSTAALGRLSAELHELATLPRTETGSGSP (V),

[0748] Z2 comprises or consists of an amino acid sequence according to chemical formula VI (SEQ ID NO. 165):

[0749] AX 52 X 53 LSTAX58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0750] During the meal

[0751] X 52 represents Gly(G) or Ser(S),

[0752] X 53 represents Gln(Q), Glu(E), or His(H), and

[0753] X 58 represents Ala(A) or Gln(Q), and

[0754] X 59 represents Leu(L) or Thr(T),

[0755] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0756] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0757] X 72 represents Leu(L) or Glu(E);

[0758] The above peptide is a peptide derivative containing an extension moiety.

[0759] The GLP-1- / GIP- / amylin-receptor triple agonist of the present invention may be a peptide derivative comprising any one of the disclosed peptide Z1, any one of the disclosed peptide Z2, any one of the disclosed peptide linker L1, and any one of the disclosed extension moiety, and based on the disclosure of the present invention, a person skilled in the art may determine an optimal combination to arrive at a specific peptide derivative that is a potent GLP-1- / GIP- / amylin-receptor triple agonist having specific characteristics as described below.

[0760] The GLP-1- / GIP- / amylin-receptor triple agonists of the present invention may be selected from compounds No. 104 to 197 as described in Example 2 of the present invention. Preferred GLP-1- / GIP- / amylin-receptor triple agonists of the present invention are as follows:

[0761]

[0762]

[0763]

[0764]

[0766] Pharmaceutically acceptable salts

[0767] The compound of the present invention may be in the form of a pharmaceutically acceptable salt or amide.

[0768] Salts are formed by the chemical reaction between a base and an acid: 2NH3 + H2SO4 → (NH4)2SO4.

[0769] Salts can be basic salts or acidic salts, or neither (i.e., neutral salts). In water, basic salts produce hydroxide ions, and acidic salts produce hydronium ions.

[0770] The salts of the compounds of the present invention may be formed as addition cations or anions between anionic or cationic groups, respectively. These groups may be located within the peptide moiety and / or extension moiety of the compounds of the present invention.

[0771] Non-limiting examples of anionic groups of the compounds of the present invention include free carboxyl groups in the peptide backbone as well as in the extension moiety (if present). The peptide backbone may include free carboxyl groups in internal amino acid residues such as Asp(D) and Glu(E).

[0772] Non-limiting examples of cation groups within the peptide backbone include free amino groups at the N-terminus (if present), as well as any free amino groups of internal basic amino acid residues such as His(H), Arg(R), and Lys(K).

[0773] The amide of the compound 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 a substituted amine, or by the reaction of a free or substituted amino group with a carboxylic acid. Amidation formation may occur at any free carboxyl group in the extending moiety, a free amino group at the N-terminus of the peptide, and / or any free or substituted amino group in the peptide backbone.

[0774] 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.

[0776] Functional characteristics

[0777] In a first functional aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention has good efficacy at each of the GLP-1- / GIP- / amylin-receptors. Preferably, they are potent GLP-1- / GIP- / amylin-receptor agonists, as reflected by their ability to activate each of the GLP-1- / GIP- / amylin-receptors. Also, or alternatively, in a second functional aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention is a balanced triple agonist. Also, or alternatively, in a third functional aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention reduces food intake in vivo. Also, or alternatively, in a fourth functional aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention has improved pharmacokinetic properties. Also, or alternatively, in a fifth functional aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention is chemically stable.

[0779] Biological activity - In vitro efficacy

[0780] According to the first functional aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention is biologically active or potent in each of the GLP-1- / GIP- / amylin-receptor triple agonist peptides, namely the GLP-1- / GIPGLP-1 / amylin-receptor triple agonist peptides, which are capable of activating human GIP, GLP-1, and amylin receptors in vitro.

[0781] When tested as described in "GLP-1 Receptor Assay (in the absence of HSA)," the GLP-1- / GIP- / amylin-receptor triagonist disclosed herein has 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. 50It can have a value.

[0782] When tested as described in the "GIP Receptor Assay (in the absence of HSA)," the GLP-1- / GIP- / amylin-receptor triple-agonist peptide disclosed herein has 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 can have a value.

[0783] When tested as described in the Amylin Receptor Assay (in the absence of HSA), the GLP-1- / GIP- / Amylin-Receptor Triagonist peptide disclosed herein has 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- / amylin-receptor triple agonist disclosed herein acts on or activates the amylin receptor.

[0784] The GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein can be tested for GLP-1, GIP, and / or amylin activity as described in Example 4. .

[0785] The more potent the compound, the more EC 50 The value becomes even lower. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of about 100 pM or less in human GLP-1 receptor function assays (see Example 4). 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 90 pM or less in human GLP-1 receptor function assays. 50It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 80 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 75 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 70 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 60 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 50 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 40 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 30 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 25 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 20 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 15 pM or less in human GLP-1 receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 10 pM or less in human GLP-1 receptor function assays. 50It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 5 pM or less in human GLP-1 receptor function assays. 50 It may have. The GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein may have efficacy similar to semaglutide or tyrzepatide.

[0786] GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 125 pM or less in human GIP receptor function assays (see Example 4). 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of less than approximately 100 pM in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 90 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 80 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 75 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 70 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 60 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 50 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 40 pM or less in human GIP receptor function assays. 50It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 30 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 25 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 20 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 15 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of less than approximately 10 pM in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 9 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 8 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 7 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 6 pM or less in human GIP receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of less than approximately 5 pM in human GIP receptor function assays. 50 It may have. The GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein may have efficacy similar to tyrzepatide.

[0787] GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 125 pM or less in human amylin receptor function assays (see Example 4). 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 100 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 90 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 80 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 75 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 70 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 60 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 50 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 40 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 30 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 25 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 20 pM or less in human amylin receptor function assays.50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 15 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of less than approximately 10 pM in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 9 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 8 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 7 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 6 pM or less in human amylin receptor function assays. 50 It may have. GLP-1- / GIP- / amylin-receptor triple agonists have an EC of approximately 5 pM or less in human amylin receptor function assays. 50 It may have. The GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein may have efficacy similar to that of cagrilintide.

[0789] Biological Activity - Balanced GLP-1 / GIP / amylin-receptor triple agonist

[0790] In a second functional aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention activates human GIP, GLP-1, and amylin receptors in vitro when measured without HSA in the assay as described in Example 4, and has an efficacy ratio (A / B) of less than 50, preferably less than 30.

[0791] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist activates human GIP, GLP-1, and amylin receptors in vitro when measured without HSA in the assay as described in Example 4, and has an efficacy ratio (A / B) of less than 50. In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist activates human GIP, GLP-1, and amylin receptors in vitro when measured without HSA in the assay as described in Example 4, and has an efficacy ratio (A / B) of less than 30.

[0792] The balanced GLP-1- / GIP- / amylin-receptor triagonist of the present invention activates human GIP, GLP-1, and amylin receptors in vitro when measured without HSA in the assay as described in Example 4, and has an efficacy ratio (A / B) of less than 50, preferably less than 30, i.e., the efficacy of the receptor with the lowest efficacy (A) divided by the efficacy of the receptor with the highest efficacy (B). The triagonist disclosed herein may have an efficacy ratio (A / B) of less than 50, preferably less than 30 or less than 20, e.g., less than 19, less than 18, less than 17, less than 16, more preferably less than 15, e.g., less than 14, less than 13, less than 12, most preferably less than 11, e.g., less than 10, less than 9, less than 8, and less than 7.

[0794] Biological activity - In vivo pharmacology

[0795] In a third functional aspect, the GLP-1- / GIP- / amylin-receptor triagonist disclosed herein may reduce food intake in subjects, e.g., normal body weight rats or SD rats. Administration of the GLP-1- / GIP- / amylin-receptor triagonist disclosed herein may drastically reduce food intake. The in vivo effect of the GLP-1- / GIP- / amylin-receptor triagonist on food intake in rats can be evaluated as described in Example 5. A 100% (hypothetical value) reduction in food intake compared to the vehicle means that the rats do not eat.

[0796] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein can reduce food intake by at least 10% compared to the vehicle, preferably by at least 30% or 50% compared to the vehicle, e.g., by at least 70% compared to the vehicle, on day 1 (0 to 24 hours) after a single subcutaneous administration of 10 nmol / kg. The GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein can reduce food intake by 1% to 100% compared to the vehicle, e.g., by 15% to 95% compared to the vehicle, preferably by 40% to 85%, and more preferably by 50% to 80% compared to the vehicle, on day 1 (0 to 24 hours) after a single subcutaneous administration of 10 nmol / kg.

[0797] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein can reduce food intake by at least 15% compared to the vehicle, preferably by at least 30% or 50% compared to the vehicle, e.g., by at least 70% compared to the vehicle, on day 2 (24 to 48 hours) after a single subcutaneous administration of 10 nmol / kg. The GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein can reduce food intake by 1% to 100% compared to the vehicle, e.g., by 15% to 95% compared to the vehicle, preferably by 40% to 95%, and more preferably by 70% to 95% compared to the vehicle, on day 2 (24 to 48 hours) after a single subcutaneous administration of 10 nmol / kg.

[0798] In one embodiment, the GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein can reduce food intake by at least 15%, preferably by at least 35%, compared to the vehicle on day 1 (0 to 24 hours) after a single subcutaneous administration of 30 nmol / kg. The GLP-1- / GIP- / amylin-receptor triple agonist disclosed herein can reduce food intake by at least 15%, preferably by at least 35%, compared to the vehicle on day 2 (24 to 48 hours) after a single subcutaneous administration of 30 nmol / kg.

[0800] Pharmacokinetic profile

[0801] In a fourth functional aspect, the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention has improved pharmacokinetic properties, such as an increased terminal half-life.

[0802] Half-life is an important parameter because a longer half-life indicates that it may be possible to administer the compound at a lower frequency. Based on the disclosure of this application, those skilled in the art may determine an extension moiety for use with a specific peptide derivative as disclosed herein, optionally after some limited routine experiments. The GLP-1- / GIP- / amylin-receptor triple agonists or peptide derivatives of the present invention have a longer half-life relative to the dosing interval and thus reduce the variability of steady-state exposure.

[0803] The in vivo pharmacology of the GLP-1- / GIP- / amylin-receptor triple agonist described herein, including the half-life, can be evaluated as described in Example 6. In some embodiments, the half-life is the in vivo half-life (t) in a minipig or rat after IV administration, for example, as described in Example 6 of this application. 1 / 2The half-life of a GLP-1- / GIP- / amylin-receptor triple agonist in minipigs may be long, approximately 90 hours or more. The half-life of a GLP-1- / GIP- / amylin-receptor triple agonist in minipigs may be at least 80 hours, preferably at least 90 hours. The half-life of a GLP-1- / GIP- / amylin-receptor triple agonist in minipigs may be greater than 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 150, 160, or 170 hours. In minipigs, the half-life of a GLP-1- / GIP- / amylin-receptor triple agonist may be 80 to 200 hours, e.g. 90 to 190 hours, e.g. 95 to 185 hours. In rats, the half-life of a GLP-1- / GIP- / amylin-receptor triple agonist may be long, approximately 5 hours or more. In rats, the half-life of a GLP-1- / GIP- / amylin-receptor triple agonist may be at least 8 hours, preferably at least 10 hours. In rats, the half-life of a GLP-1- / GIP- / amylin-receptor triple agonist may be greater than 5, 6, 7, 8, 9, 10, 12, 14, 16, 20, or 25 hours. The half-life of GLP-1- / GIP- / amylin-receptor triple agonists in rats may be 5 to 50 hours, e.g. 10 to 35 hours, e.g. 12 to 30 hours.

[0804] In one embodiment, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist suitable for once-weekly administration. The GLP-1- / GIP- / amylin-receptor triple agonist or peptide derivative of the present invention has a long half-life relative to the administration interval, thereby reducing the variability of steady-state exposure and thus enabling once-weekly administration.

[0805] In one embodiment, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist suitable for oral administration. The GLP-1- / GIP- / amylin-receptor triple agonist may be bioavailable orally; that is, may be present in the bloodstream after oral administration. Thus, the compound is suitable for oral administration to a subject requiring it.

[0807] Chemical properties

[0808] In a fifth aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist having improved chemical stability. The term “chemical stability” refers to chemical (particularly, of covalent bonds) changes in the polypeptide structure that result in the formation of chemical degradation products, such as deamidation, isomerization, and hydrolysis products, which potentially have reduced biological efficacy and / or increased immunogenic effects compared to an intact polypeptide. Chemical stability can be determined, for example, by measuring the amount of chemical degradation products by SEC-HPLC, by measuring the loss of purity at various points in time after exposure to different environmental conditions, as described in Example 7 of the present invention. The GLP-1- / GIP- / amylin-receptor triple agonist of the present invention has a purity loss of less than 10.0% per week, preferably less than 5.0%, e.g. 4.0% or 3.0%, more preferably less than 2.0%, and most preferably less than 1.5%, when incubated at 37°C and as determined in Example 7 described herein.

[0810] Both the peptide backbone and the extension moiety are engineered and purified to achieve a peptide derivative having all of the aforementioned characteristics.

[0812] production method

[0813] The triple-acting agents disclosed herein may be produced by solid-phase peptide synthesis using classical peptide synthesis, e.g., t-Boc or Fmoc chemistry or other well-established techniques (see, e.g., the literature of Greene and Wuts ["Protective Groups in Organic Synthesis", John Wiley & Sons, 1999]; the literature of Florencio Zaragoza Dorwald ["Organic Synthesis on Solid Phase", Wiley-VCH Verlag GmbH, 2000]; and the literature of WC Chan and PD White (Eds.) ["Fmoc Solid Phase Peptide Synthesis", Oxford University Press, 2000]). In some embodiments, a method for preparing triple-acting agents is described herein. In some embodiments, a method for preparing triple-acting agents such as those described herein comprises the step of solid-phase peptide synthesis.

[0814] Alternatively, a compound, a peptide sequence, or a portion of a peptide sequence may be produced by a recombinant method, for example, by culturing a host cell capable of expressing the peptide containing a DNA sequence encoding a triple-acting agent peptide sequence in a suitable nutrient medium under conditions where peptide expression is possible. Non-limiting examples of host cells suitable for the expression of these peptides include E. coli cell lines, brewer's yeast ( Saccharomyces cerevisiae It is a mammalian BHK or CHO cell line as well as a ) cell line.

[0815] Triple agents containing non-natural amino acids and / or covalently attached substituents (extension moiety) can be produced as described in the experimental section under 'General methods for peptide synthesis'. Alternatively, refer, for example, to the literature by Hodgson et al. ["The synthesis of peptides and proteins containing non-natural amino acids", Chemical Society Reviews, vol. 33, no. 7 (2004), p. 422-430].

[0816] A triple agent as described herein containing an extension moiety can be produced, for example, as described in the 'General method for peptide synthesis' in the experimental part. In some embodiments, the extension moiety is constructed as part of solid-phase peptide synthesis or produced individually and attached via a single lysine residue after solid-phase peptide synthesis.

[0817] Specific examples of methods for manufacturing multiple triple agents as described herein are provided below.

[0818] A further aspect of the present invention relates to a method for manufacturing the receptor triple agonist described herein.

[0819] In one embodiment, a method for preparing a compound as described herein includes a step of solid-phase peptide synthesis. The extension moiety may be constructed sequentially as part of the solid-phase peptide synthesis, or may be produced separately and attached via a lysine residue after peptide synthesis.

[0821] Pharmaceutical composition

[0822] In a further aspect, the present invention relates to a pharmaceutical composition comprising the above-mentioned GLP-1- / GIP- / amylin-receptor triple agonist. A pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist as disclosed herein and one or more pharmaceutically acceptable excipients is disclosed herein. A pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist as described herein and one or more pharmaceutically acceptable excipients may be prepared using methods known to those skilled in the art.

[0823] The term “pharmaceuticalally acceptable excipient” refers to any component in a pharmaceutical composition that is not an active pharmaceutical ingredient or a GLP-1- / GIP- / amylin-receptor triple agonist as disclosed herein. The term “pharmaceutically acceptable excipient” means an excipient useful for preparing a pharmaceutical composition comprising an excipient that is generally safe, non-toxic, and acceptable for human pharmaceutical use. Such excipients may be, for example, solid, liquid, or semi-solid.

[0824] Excipients may be functional or inert and may be used for various purposes, e.g., as buffers, isotonic agents, carriers, vehicles, fillers, binders, lubricants, lubricants, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, or combinations thereof, or may be used to improve the administration and / or absorption of active pharmaceutical ingredient(s). The amount of each excipient used may vary within the usual range in the art.

[0825] Techniques and excipients that may be used are described in the following literature: for example, literature [ Handbook of Pharmaceutical Excipients (For example, 8 thedition, Sheskey et al., Eds., American Pharmaceuticals Association and Pharmaceutical Press publications, department of the Royal Pharmaceutical Society of Great Britain (2017) and later editions) and literature [ Remington: The Science and Practice of Pharmacy (e.g., Remington and Allen, Eds., Pharmaceutical Press (2021): 23rd edition, and subsequent revisions)].

[0826] A pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist as disclosed herein may be for oral administration.

[0827] A pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist as disclosed herein may be a solid pharmaceutical composition (e.g., tablet or capsule) containing the active pharmaceutical ingredient as, for example, a lyophilized composition or a spray-dried composition, and may be used as is, dissolved before use, or combined into a formulation with excipients.

[0828] The pharmaceutical composition is a compound disclosed herein, as described in the art, N Salt of -[8-(2-hydroxybenzoyl)amino]caprylate, preferably N It may be a solid pharmaceutical composition comprising -(8-(2-hydroxybenzoyl)amino)caprylate sodium and one or more additional excipients. For example, the solid pharmaceutical composition may be as described in WO 2012 / 080471, WO 2013 / 139694, WO 2013 / 189988, WO 2019 / 149880, WO 2019 / 215063, WO 2021 / 219710 or WO 2023 / 012263 A1.

[0829] Alternatively, a pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist as disclosed herein may be a liquid composition, such as an aqueous composition. Such a liquid composition may be suitable for oral administration or parenteral administration, e.g., intravenously, intramuscularly, or subcutaneously.

[0830] Liquid compositions suitable for injection may be prepared using conventional techniques of the pharmaceutical industry, said techniques comprising appropriately dissolving and mixing components to obtain a desired finished pharmaceutical product. Thus, according to one procedure, the compounds described herein are dissolved in a suitable buffer solution of an appropriate pH. The composition is sterilized, for example, by sterile filtration. Techniques and excipients that may be used to prepare liquid formulations are described in the following literature: for example, literature [ Handbook of Pharmaceutical Excipients (e.g., 8th edition, Sheskey et al., Eds., American Pharmaceuticals Association and Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2017) and later editions) and literature [ Remington: The Science and Practice of Pharmacy (e.g., Remington and Allen, Eds., Pharmaceutical Press (2021): 23rd edition, and subsequent revisions)]. Preferably, in an embodiment where the pharmaceutical composition is in a liquid formulation, the liquid formulation provides improved stability.

[0831] A pharmaceutical composition is generally administered to a subject already suffering from a disease such as the indications described below in an amount sufficient to cure, alleviate, or partially stop the disease or its complications. The amount appropriate to achieve this is defined as the "therapeutically effective amount." As understood by those skilled in the art, the amount effective for this purpose depends on the severity of the disease as well as the subject's body weight and overall condition.

[0832] In some embodiments, the dosage of the compound delivered by subcutaneous administration may be about 0.1 mg to 500 mg of the compound daily, depending on the severity of the condition, or preferably about 0.5 mg to 150 mg daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, or weekly.

[0833] The appropriate dosage may be adjusted according to the characteristics of the compound, including its in vivo half-life or average residence time and biological activity, for a specific compound. For example, the compound to be delivered may be administered once a day in one embodiment, or once a week in another embodiment. Thus, the pharmaceutical composition may be used for administration approximately once a day, e.g., once every 12 to 36 hours, e.g., once every 18 to 30 hours, e.g., once every 24 hours, or for administration approximately once a week, e.g., once every 6 to 8 days.

[0834] In one embodiment, the present invention relates to an injection device comprising the above pharmaceutical composition.

[0836] Pharmacological indications

[0837] In a further aspect, the present invention relates to a GLP-1- / GIP- / amylin-receptor triple agonist as disclosed herein for use as a medicine.

[0838] GLP-1- / GIP- / amylin-receptor triple agonists as disclosed herein

[0839] It may be used for the following medical treatments or indications:

[0840] (i) Prevention and / or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (adult-onset diabetes mellitus in minors), gestational diabetes, and / or reduced HbA1c;

[0841] (ii) delay or prevention of the progression of diabetic disease, such as the progression of type 2 diabetes, delay of the progression of impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delay of the progression of non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes;

[0842] (iii) prevention and / or treatment of eating disorders (e.g., obesity) by, for example, reducing food intake, weight loss, appetite suppression, or inducing satiety; treatment or prevention of binge eating disorder, food cravings, bulimia nervosa, and / or obesity induced by the administration of psychotropic drugs or steroids; reduction of gastric motility; and / or delay of gastric fasting;

[0843] (iv) Weight maintenance after successful weight loss (drug-induced or through diet and exercise)—i.e., prevention of weight gain after successful weight loss;

[0844] (v) Prevention and / or treatment of cardiovascular disease, e.g., delay or reduction of major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, hospitalization due to unstable angina, and hospitalization due to heart failure;

[0845] (vi) Prevention and / or treatment of non-alcoholic fatty liver disease (NAFLD, metabolic dysfunction-associated fatty liver disease, known as MAFLD) and / or non-alcoholic steatohepatitis (NASH, metabolic dysfunction-associated steatohepatitis, known as MASH);

[0846] (vii) Prevention and / or treatment of cognitive impairment such as that caused by Alzheimer's disease;

[0847] (viii) Prevention and / or treatment of chronic kidney disease;

[0848] (ix) Prevention and / or treatment of obstructive sleep apnea.

[0850] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In additional 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.

[0851] As used herein, the term "treatment" refers to a medical therapy for any human or other vertebrate subject in need. The subject has likely undergone a physical examination by a physician or veterinarian, and it is expected that the physician or veterinarian has issued a tentative or definite diagnosis indicating that the use of the specific therapeutic agent is beneficial to the health of the human or other vertebrate. The timing and purpose of the treatment may vary individually depending on the subject's current health condition. Accordingly, the treatment may be prophylactic, palliative, symptomatic, and / or curative.

[0852] In some embodiments, the indications are (i) and (iii). In some embodiments, the indications are (ii) and (iii).

[0853] The World Health Organization (WHO) defines overweight and obesity as the abnormal or excessive accumulation of body fat that poses a risk to an individual's overall health. Generally, all individuals suffering from obesity are also considered to be overweight. Obese individuals can be human beings, such as adults or children, where "children" includes infants, children, and adolescents. In this field, the term "pre-obesity" is also used instead of "overweight." The WHO considers the Body Mass Index (BMI) to be the most convenient and widely accepted measure of overweight and obesity. BMI is a measure of body fat based on height and weight. The calculation formula is BMI = Weight (kg) / Height (m²). 2 )am.

[0854] 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.

[0855] For children, the WHO considers age when defining overweight and obesity. For children under 5 years of age, overweight means that the weight-to-height ratio exceeds the WHO median standard for child growth by more than 2 standard deviations; obesity means that the weight-to-height ratio exceeds the WHO median standard for child growth by more than 3 standard deviations. For children aged 5 to 19 years, overweight and obesity are defined as follows: overweight means that the age-specific BMI exceeds the WHO median standard for growth by more than 1 standard deviation; obesity means that the age-specific BMI exceeds the WHO median standard for growth by more than 2 standard deviations.

[0856] Nevertheless, for adults, as shown in Table 8 below, diagnostic criteria for underweight, normal range, pre-obesity / overweight, and obesity may vary between countries / populations.

[0857]

[0858] Guidelines for Asian populations were published in the literature by Misra A et al. [J Assoc Physicians India. 2009; 57:163-70]. Guidelines for Chinese populations were published in the literature compiled by the Chinese Working Group on Obesity [ Guidelines for Prevention and Control of Overweight and Obesity in Chinese Adults It was published as the 2006 revised edition. Guidelines for the Japanese population were based on literature by the Japanese Society for the Study of Obesity (JASSO) in 2016 [ Guidelines for the management of obesity disease It was published as ]. Guidelines for the Taiwanese population were published in 2023 by the Health Promotion Administration (HPA) of the Ministry of Health and Welfare of the Taiwanese government in the literature[" Evidence-Based Guideline on Adult Obesity Prevention and Management It was published as the second revised edition of [].

[0859] In some embodiments, the obese subject is a human being such as an adult human or a pediatric human (including infants, children, and adolescents). Thus, the obese human subject may have a BMI of 25 or higher, 27 or higher, 28 or higher, or 30 or higher; such a subject may also be referred to as obese. Obesity may be Grade I, Grade II, Grade III, or Grade IV obesity (as defined in Table 8). In some embodiments, the obese human subject may have a BMI of 35 or higher or a BMI in the range of 30 or higher to less than 40. In some embodiments, obesity is severe obesity or morbid obesity, and the human subject may have a BMI of 40 or higher.

[0860] In some embodiments, the present invention relates to a method for treating or preventing overweight in the presence of optionally at least one weight-related comorbidity. In one embodiment, a GLP-1- / GIP- / amylin-receptor triple agonist as disclosed herein is intended for use in treating a subject having an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher; optionally in the presence of at least one weight-related comorbidity.

[0861] In some embodiments, the present invention relates to the use of a formulation for the treatment or prevention of overweight in the presence of optionally at least one weight-related comorbidity. In some embodiments, the subject suffering from overweight is a human being such as an adult human or a pediatric human (including infants, children, and adolescents). In some embodiments, the adult human subject suffering from overweight may have a BMI of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher. In some embodiments, the human subject suffering from overweight has a BMI in the range of 24 to <27, 24 to <28, 25 to <30, or 27 to <30. In some embodiments, the weight-related comorbidity is selected from the group consisting of hypertension, dysglycemia (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, and obstructive sleep apnea.

[0862] In some embodiments, the triple agonist disclosed herein relates to a method for weight management. In some embodiments, the triple agonist disclosed herein relates to a method for reducing appetite. In some embodiments, the triple agonist disclosed herein relates to a method for reducing food intake. In some embodiments, the triple agonist disclosed herein relates to a method for preventing or treating overweight in a subject.

[0863] The term "weight loss" may include the treatment or prevention of obesity and / or overweight.

[0864] The administration of the compounds disclosed herein may be an adjunct to a reduced-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 28 or higher, or 30 or higher; 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; optionally in the presence of at least one weight-related comorbidity (e.g., hypertension, dysglycemia (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease, and obstructive sleep apnea).

[0866] Specific implementation example

[0867] 1. A GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to the following chemical formula I:

[0868] Z1―L1―Z2 (I),

[0869] The above peptide includes one lysine (Lys, K) residue, wherein:

[0870] · Z1 is a peptide containing up to 5 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0871] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0872] In the formula, the amino acid at position X2 represents Aib;

[0873] · L1 is a peptide linker and;

[0874] · Z2 is a C-terminal amide and a peptide containing up to 10 amino acid substitutions relative to formula V (SEQ No. 2):

[0875] ASELSTAALGRLSAELHELATLPRTETGSGSP (V).

[0876] 2. As a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to the following chemical formula I:

[0877] Z1―L1―Z2 (I),

[0878] The above peptide includes one lysine (Lys, K) residue, wherein:

[0879] · Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[0880] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0881] During the meal

[0882] X2 represents Aib,

[0883] X 12 represents Ile(I) or Lys(K), and

[0884] X 20 represents Arg(R) or Gln(Q), preferably Arg(R), and

[0885] X 24 represents Ala(A), Glu(E), or Gln(Q), preferably Glu(E), and

[0886] X 27 represents Leu(L) or Ile(I),

[0887] X 28 represents Ala(A) or Gln(Q), and

[0888] X 30 represents Gly(G) or Ala(A), and

[0889] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0890] X 33 represents Glu(E) or Ser(S),

[0891] X 34 represents Gly(G) or Glu(E);

[0892] · L1 is a peptide linker and;

[0893] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[0894] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0895] During the meal

[0896] X 52 represents Gly(G) or Ser(S),

[0897] X 53 represents Gln(Q), Glu(E), or His(H), and

[0898] X 58 represents Ala(A) or Gln(Q), and

[0899] X 59 represents Leu(L) or Thr(T),

[0900] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0901] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0902] X 72is a GLP-1- / GIP- / amylin-receptor triple agonist representing Leu(L) or Glu(E).

[0903] 3. In any one of the prior embodiments, comprising a peptide according to Formula I:

[0904] Z1―L1―Z2 (I),

[0905] The above peptide includes one lysine (Lys, K) residue, wherein:

[0906] · Z1 is a peptide having up to 5 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0907] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0908] In the formula, the amino acid at position X2 represents Aib, and

[0909] Z1 comprises or consists of an amino acid sequence according to Chemical Formula III (Sequence No. 168):

[0910] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[0911] During the meal

[0912] X2 represents Aib,

[0913] X 12 represents Ile(I) or Lys(K), and

[0914] X 20 represents Arg(R) or Gln(Q), and

[0915] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0916] X 27represents Leu(L) or Ile(I),

[0917] X 28 represents Ala(A) or Gln(Q), and

[0918] X 30 represents Gly(G) or Ala(A), and

[0919] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[0920] X 33 represents Glu(E) or Ser(S),

[0921] X 34 represents Gly(G) or Glu(E);

[0922] · L1 is a peptide linker and;

[0923] · Z2 is a peptide containing a C-terminal amide, and Z2 comprises or consists of an amino acid sequence according to Formula VI (SEQ ID NO. 165):

[0924] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0925] During the meal

[0926] X 52 represents Gly(G) or Ser(S),

[0927] X 53 represents Gln(Q), Glu(E), or His(H), and

[0928] X 58 represents Ala(A) or Gln(Q), and

[0929] X 59 represents Leu(L) or Thr(T),

[0930] X60 represents Ala(A), Gly(G), or Gln(Q), and

[0931] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0932] X 72 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Leu(L) or Glu(E).

[0933] 4. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein Z1 is a peptide having up to 4 amino acid substitutions compared to Formula II (Sequence No. 1).

[0934] 5. As a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to the following chemical formula I:

[0935] Z1―L1―Z2 (I),

[0936] The above peptide includes one lysine (Lys, K) residue, wherein:

[0937] · Z1 is a peptide having up to 4 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[0938] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[0939] In the formula, the amino acid at position X2 represents Aib, and

[0940]

[0941] Z1 comprises or consists of an amino acid sequence according to chemical formula VII (SEQ ID NO. 162):

[0942] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII),

[0943] During the meal​

[0944] X2 represents Aib,

[0945] X 12 represents Ile(I) or Lys(K), and

[0946] X 20 represents Arg(R) or Gln(Q), and

[0947] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[0948] X 27 represents Leu(L) or Ile(I),

[0949] X 28 represents Ala(A) or Gln(Q), and

[0950] X 34 represents Gly(G) or Glu(E);

[0951] · L1 is a peptide linker and;

[0952] · Z2 is a peptide containing a C-terminal amide and having up to 10 amino acid substitutions compared to formula V (SEQ No. 2):

[0953] ASELSTAALGRLSAELHELATLPRTETGSGSP (V),

[0954] Z2 comprises or consists of an amino acid sequence according to chemical formula VI (SEQ ID NO. 165):

[0955] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[0956] During the meal

[0957] X 52 represents Gly(G) or Ser(S),

[0958] X 53represents Gln(Q), Glu(E), or His(H), and

[0959] X 58 represents Ala(A) or Gln(Q), and

[0960] X 59 represents Leu(L) or Thr(T),

[0961] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[0962] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[0963] X 72 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Leu(L) or Glu(E).

[0964] 6. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein, in any one of the prior embodiments, one lysine (Lys, K) residue is present in peptide Z1 or peptide Z2.

[0965] 7. A GLP-1 / GIP- / amylin-receptor triple agonist, wherein, in any one of the prior embodiments, one lysine (Lys, K) residue is present in peptide Z1.

[0966] 8. A GLP-1 / GIP- / amylin-receptor triple agonist in any one of embodiments 1 to 6, wherein one lysine (Lys, K) residue is present in peptide Z2.

[0967] 9. In any one of the prior embodiments, a GLP-1- / GIP- / amylin-receptor triple agonist, wherein chemical formula I comprises one or fewer lysine (Lys, K) residues.

[0968] 10. In any one of the prior embodiments, the GLP-1- / GIP- / amylin-receptor triple agonist is a GLP-1- / GIP- / amylin-receptor triple agonist that does not contain a cysteine ​​(Cys, C) residue.

[0969] 11. In any one of the prior embodiments, the GLP-1- / GIP- / amylin-receptor triple agonist is a GLP-1- / GIP- / amylin-receptor triple agonist that does not contain a disulfide bridge.

[0970] 12. In any one of the prior embodiments, X 12 is a GLP-1- / GIP- / amylin-receptor triple agonist, Lys(K).

[0971] 13. In any one of Embodiments 1 to 11, X 12 is a GLP-1- / GIP- / amylin-receptor triple agonist that is Ile(I).

[0972] 14. In any one of the prior embodiments, X 20 is a GLP-1- / GIP- / amylin-receptor triple agonist that is Arg(R).

[0973] 15. In any one of Embodiments 1 to 13, X 20 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Gln(Q).

[0974] 16. In any one of the prior embodiments, X 24 is a GLP-1- / GIP- / amylin-receptor triple agonist, Glu(E).

[0975] 17. In any one of Embodiments 1 to 15, X 24 is an Ala(A) GLP-1- / GIP- / amylin-receptor triple agonist.

[0976] 18. In any one of Embodiments 1 to 15, X 24 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Gln(Q).

[0977] 19. In any one of the prior embodiments, X 27 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Leu(L).

[0978] 20. In any one of Embodiments 1 to 18, X27 is a GLP-1- / GIP- / amylin-receptor triple agonist that is Ile(I).

[0979] 21. In any one of the prior embodiments, X 28 is an Ala(A), a GLP-1- / GIP- / amylin-receptor triple agonist.

[0980] 22. In any one of Embodiments 1 to 20, X 28 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Gln(Q).

[0981] 23. In any one of the prior embodiments, X 30 is a GLP-1- / GIP- / amylin-receptor triple agonist, Gly(G).

[0982] 24. In any one of Embodiments 1 to 22, X 30 is an Ala(A), a GLP-1- / GIP- / amylin-receptor triple agonist.

[0983] 25. In any one of the prior embodiments, X 31 is a GLP-1- / GIP- / amylin-receptor triple agonist that is Pro(P).

[0984] 26. In any one of Embodiments 1 to 24, X 31 is an Ala(A), a GLP-1- / GIP- / amylin-receptor triple agonist.

[0985] 27. In any one of Embodiments 1 to 24, X 31 is a GLP-1- / GIP- / amylin-receptor triple agonist, Gly(G).

[0986] 28. In any one of Embodiments 1 to 24, X 31 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Gln(Q).

[0987] 29. In any one of the prior embodiments, X 33 is a GLP-1- / GIP- / amylin-receptor triple agonist that is Ser(S).

[0988] 30. In any one of Embodiments 1 to 28, X 33 A GLP-1 / GIP- / amylin-receptor triple agonist, which is Glu(E).

[0989] 31. In any one of the prior embodiments, X 34 is a GLP-1- / GIP- / amylin-receptor triple agonist that is Gly(G).

[0990] 32. In any one of Embodiments 1 to 30, X 34 is a GLP-1- / GIP- / amylin-receptor triple agonist, Glu(E).

[0991] 33. In any one of the prior embodiments, X 30 X 31 It is Gly-Pro(GP), a GLP-1- / GIP- / amylin-receptor triple agonist.

[0992] 34. In any one of Embodiments 1 to 32, X 30 X 31 It is Gly-Ala(GA), a GLP-1- / GIP- / amylin-receptor triple agonist.

[0993] 35. In any one of Embodiments 1 to 32, X 30 X 31 It is Ala-Pro(AP), a GLP-1- / GIP- / amylin-receptor triple agonist.

[0994] 36. In any one of Embodiments 1 to 32, X 30 X 31 It is a GLP-1- / GIP- / amylin-receptor triple agonist, Gly-Gly(GG).

[0995] 37. In any one of Embodiments 1 to 32, X 31 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Gly(G), Gln(Q), or Ala(A).

[0996] 38. In any one of the prior embodiments, Z1 comprises or is composed of an amino acid sequence according to Formula IV (SEQ ID NO. 169):

[0997] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGX 30 X 31 SSG (IV),

[0998] During the meal

[0999] X2 represents Aib,

[1000] X 12 represents Ile(I) or Lys(K), and

[1001] X 27 represents Leu(L) or Ile(I),

[1002] X 30 represents Gly(G) or Ala(A), and

[1003] X 31 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Ala(A), Gly(G), or Pro(P).

[1004] 39. In any one of the prior embodiments, Z1 comprises or is composed of an amino acid sequence according to the formula XI (SEQ ID NO. 163):

[1005] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLLAGGPSSG (XI),

[1006] During the meal

[1007] X2 represents Aib,

[1008] X 12 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Ile(I) or Lys(K).

[1009] 40. In any one of the prior embodiments, Z1 is a GLP-1- / GIP- / amylin-receptor triple agonist comprising or consisting of an amino acid sequence selected from the following list:

[1010]

[1011] 41. In any one of the prior embodiments, Z1 is a GLP-1- / GIP- / amylin-receptor triple agonist comprising or consisting of an amino acid sequence selected from the following list:

[1012]

[1013] 42. In any one of the prior embodiments, Z1 is a GLP-1- / GIP- / amylin-receptor triple agonist comprising or composed of the amino acid sequence according to SEQ ID NO. 22.

[1014] 43. A GLP-1- / GIP- / amylin-receptor triple agonist in any one of embodiments 1 to 41, wherein Z1 comprises or consists of the amino acid sequence according to SEQ ID NO. 29.

[1015] 44. A GLP-1- / GIP- / amylin-receptor triple agonist in any one of embodiments 1 to 41, wherein Z1 comprises or consists of the amino acid sequence according to SEQ ID NO. 31.

[1016] 45. A GLP-1- / GIP- / amylin-receptor triple agonist in any one of embodiments 1 to 41, wherein Z1 comprises or consists of the amino acid sequence according to SEQ ID NO. 34.

[1017] 46. ​​A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, the peptide linker L1 comprises 1 to 14, 1 to 10, or 2 to 9, or 5 amino acid residues.

[1018] 47. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, 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).

[1019] 48. In any one of the prior embodiments, the peptide linker L1 comprises or is composed of an amino acid sequence according to the formula VIIIa:

[1020] 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),

[1021] During the meal

[1022] X 141 represents Ala(A), Glu(E), and Gly(G),

[1023] X 142 represents or is absent of Gln(Q), Glu(E), Gly(G), Leu(L), and Pro(P),

[1024] X 143 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Pro(P),

[1025] X 144 is represented by or absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Pro(P),

[1026] X 145 is represented by or absent from Glu(E), Gly(G), Pro(P), Ser(S), and Thr(T),

[1027] X 146 ... represents or is absent from Glu(E), Gly(G), Leu(L), and Gln(Q),

[1028] X 147 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Phe(F),

[1029] X 148 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), Thr(T), Pro(P), Val(V), and

[1030] X 149 is represented by or absent from Glu(E), Asn(N), Pro(P), and Thr(T),

[1031] X 150 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), Val(V), and

[1032] X 151 represents Ala(A) or is absent,

[1033] X 152 represents Gln(Q) or is absent,

[1034] X 153 represents Thr(T) or is absent,

[1035] X 154 is a GLP-1- / GIP- / amylin-receptor triple agonist that represents or is absent from Leu(L).

[1036] 49. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, 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).

[1037] 50, in any one of the prior embodiments, the peptide linker L1 comprises or is composed of an amino acid sequence according to Formula VIII:

[1038] X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII),

[1039] During the meal

[1040] X 41 represents Ala(A), Gly(G), or Glu(E),

[1041] X 42 represents or is absent from Glu(E) and Gly(G),

[1042] X 43 ... represents Glu(E), Gly(G), Gln(Q), or is absent,

[1043] X 44 represents Ala(A), Glu(E), Gly(G), or is absent,

[1044] X 45 represents or is absent of Glu(E), Gly(G), and Pro(P),

[1045] X 46 ... represents or is absent from Glu(E) and Gly(G),

[1046] X 47 is Gln(Q) or Glu(E) and is absent,

[1047] X 48 ... represents or is absent from Ala(A) and Glu(E),

[1048] X 49 is indicative of or absent Glu(E) and Pro(P),

[1049] X 50is a GLP-1- / GIP- / amylin-receptor triple agonist having or lacking Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), or Val(V).

[1050] 51. In any one of the prior embodiments, the peptide linker L1 comprises or is composed of an amino acid sequence according to Formula VIII:

[1051] X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII),

[1052] During the meal

[1053] X 41 represents Ala(A) or Glu(E),

[1054] X 42 represents or is absent from Glu(E) and Gly(G),

[1055] X 43 ... represents Glu(E), Gly(G), Gln(Q), or is absent,

[1056] X 44 represents Ala(A), Glu(E), Gly(G), or is absent,

[1057] X 45 represents or is absent of Glu(E), Gly(G), and Pro(P),

[1058] X 46 ... represents or is absent from Glu(E) and Gly(G),

[1059] X 47 is Gln(Q) or Glu(E) and is absent,

[1060] X 48 ... represents or is absent from Ala(A) and Glu(E),

[1061] X49 is indicative of or absent Glu(E) and Pro(P),

[1062] X 50 is a GLP-1- / GIP- / amylin-receptor triple agonist having or lacking Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), or Val(V).

[1063] 52. In any one of the prior embodiments, the peptide linker L1 is a GLP-1- / GIP- / amylin-receptor triple agonist selected from the group consisting of: A, E, G, AE, AG, GE, APPE (SEQ No. 125), GGGE (SEQ No. 126), AGQAPG (SEQ No. 127), APPPSGGG (SEQ No. 128), APPPSGGGE (SEQ No. 129), APPPSGGGG (SEQ No. 130), ALAQTLAQTL (SEQ No. 131), ALAQTLFVNQ (SEQ No. 132), ALAQTLGTNE (SEQ No. 133), ALQAPGQAPG (SEQ No. 134), ALQAPGQAPL (SEQ No. 135), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (Sequence No. 137), GGGEGGGEGE (Sequence No. 138), GQAPGQAPGE (Sequence No. 139), GQEPGQEPGE (Sequence No. 140), APPPSLAQTLAQTL (Sequence No. 141), AGGGG (Sequence No. 142), AGEAPGQAPG (Sequence No. 143), AGEAPGEAPG (Sequence No. 144), AGQAPGQAPA (Sequence No. 145), AGQAPGQAPE (Sequence No. 146), AGQAPGQAPP (Sequence No. 147), AGQAPGQAPS (Sequence No. 148), AGQAPGQAPV (Sequence No. 149), EGQAPGQAPG (Sequence No. 150), AGQEPGQAPG (Sequence No. 151), AGQAEGQAPG (Sequence No. 152), AGQAPEQAPG (Sequence No. 153), AGQAPGEAPG (Sequence No. 154), AGQAPGQEPG (Sequence No. 155), AGQAPGQAEG (Sequence No. 156), AGQEPGQEPG (Sequence No. 157), AGQAPGQAP (Sequence No. 158), and AGQAPGEAPL (Sequence No. 159).

[1064] 53. In any one of the prior embodiments,

[1065] Peptide linker L1 is a GLP-1- / GIP- / amylin-receptor triple agonist selected from the group consisting of: A, E, G, AE, AG, GE, AGGGG (SEQ No. 142), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), AGEAPGQAPG (SEQ No. 143), AGEAPGEAPG (SEQ No. 144), AGQAPGQAPA (SEQ No. 145), AGQAPGQAPE (SEQ No. 146), AGQAPGQAPP (SEQ No. 147), AGQAPGQAPS (SEQ No. 148), AGQAPGQAPV (SEQ No. 149), EGQAPGQAPG (SEQ No. 150), AGQEPGQAPG (SEQ No. 151), AGQAEGQAPG (Sequence No. 152), AGQAPEQAPG (Sequence No. 153), AGQAPGEAPG (Sequence No. 154), AGQAPGQEPG (Sequence No. 155), AGQAPGQAEG (Sequence No. 156), AGQEPGQEPG (Sequence No. 157), AGQAPGQAP (Sequence No. 158), and AGQAPGEAPL (Sequence No. 159).

[1066] 54. In any one of the prior embodiments,

[1067] Peptide linker L1 is a GLP-1- / GIP- / amylin-receptor triple agonist selected from the group consisting of: E, AE, AG, AGGGG (SEQ No. 142), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), AGEAPGQAPG (SEQ No. 143), AGEAPGEAPG (SEQ No. 144), AGQAPGQAPA (SEQ No. 145), AGQAPGQAPE (SEQ No. 146), AGQAPGQAPP (SEQ No. 147), AGQAPGQAPS (SEQ No. 148), AGQAPGQAPV (SEQ No. 149), EGQAPGQAPG (SEQ No. 150), AGQEPGQAPG (SEQ No. 151), AGQAEGQAPG (Sequence No. 152), AGQAPEQAPG (Sequence No. 153), AGQAPGEAPG (Sequence No. 154), AGQAPGQEPG (Sequence No. 155), AGQAPGQAEG (Sequence No. 156), AGQEPGQEPG (Sequence No. 157), AGQAPGQAP (Sequence No. 158), and AGQAPGEAPL (Sequence No. 159).

[1068] 55. In any one of the prior embodiments, the peptide linker L1 is a GLP-1- / GIP- / amylin-receptor triple agonist selected from the group consisting of AG and AGEAPGEAPG (SEQ No. 144).

[1069] 56. In any one of the prior embodiments, X 52 is a GLP-1- / GIP- / amylin-receptor triple agonist that is Ser(S).

[1070] 57. In any one of Embodiments 1 to 55, X 52 is a GLP-1- / GIP- / amylin-receptor triple agonist that is Gly(G).

[1071] 58. In any one of the prior embodiments, X 53 A GLP-1 / GIP- / amylin-receptor triple agonist, which is Glu(E).

[1072] 59. In any one of Embodiments 1 to 57, X 53은 His(H), a GLP-1- / GIP- / amylin-receptor triple agonist.

[1073] 60. In any one of Embodiments 1 to 57, X 53 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Gln(Q).

[1074] 61. In any one of the prior embodiments, X 58 is an Ala(A), a GLP-1- / GIP- / amylin-receptor triple agonist.

[1075] 62. In any one of Embodiments 1 to 60, X 58 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Gln(Q).

[1076] 63. In any one of the prior embodiments, X 59 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Leu(L).

[1077] 64. In any one of Embodiments 1 to 62, X 59 is a Thr(T) GLP-1- / GIP- / amylin-receptor triple agonist.

[1078] 65. In any one of the prior embodiments, X 60 is a GLP-1- / GIP- / amylin-receptor triple agonist, Gly(G).

[1079] 66. In any one of Embodiments 1 to 64, X 60 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Gln(Q).

[1080] 67. In any one of Embodiments 1 to 64, X 60 is an Ala(A), a GLP-1- / GIP- / amylin-receptor triple agonist.

[1081] 68. In any one of the prior embodiments, X 68is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Gln(Q).

[1082] 69. In any one of Embodiments 1 to 67, X 68 A GLP-1 / GIP- / amylin-receptor triple agonist, which is Glu(E).

[1083] 70. In any one of Embodiments 1 to 67, X 68 Lys(K) is a GLP-1- / GIP- / amylin-receptor triple agonist.

[1084] 71. In any one of the prior embodiments, X 72 is a GLP-1- / GIP- / amylin-receptor triple agonist, which is Leu(L).

[1085] 72. In any one of Embodiments 1 to 70, X 72 is a GLP-1- / GIP- / amylin-receptor triple agonist, Glu(E).

[1086] 73. In any one of the prior embodiments, Z2 comprises or is composed of an amino acid sequence according to Formula IX (SEQ ID NO. 61):

[1087] ASX 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATLPRTETGSGSP (IX),

[1088] During the meal

[1089] X 53 represents Glu(E) or His(H),

[1090] X 58 represents Ala(A) or Gln(Q), and

[1091] X 59 represents Leu(L) or Thr(T),

[1092] X 60 represents Gly(G) or Gln(Q), and

[1093] X 68 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Gln(Q), Glu(E), or Lys(K).

[1094] 74. In any one of the prior embodiments, Z2 comprises or is composed of an amino acid sequence according to the chemical formula X (SEQ ID NO. 166):

[1095] ASX 53 LSTAQTQRLSAELHKLATLPRTETGSGSP(X),

[1096] During the meal

[1097] X 53 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Glu(E) or His(H).

[1098] 75. In any one of the prior embodiments, Z2 comprises or consists of an amino acid sequence selected from the following list, a GLP-1- / GIP- / amylin-receptor triple agonist:

[1099]

[1100] 76. In any one of the prior embodiments, Z2 is a GLP-1- / GIP- / amylin-receptor triple agonist comprising or consisting of an amino acid sequence selected from the following list:

[1101]

[1102] 77. In any one of the prior embodiments, Z2 is a GLP-1- / GIP- / amylin-receptor triple agonist comprising or consisting of the amino acid sequence according to SEQ ID NO. 59.

[1103] 78. A GLP-1- / GIP- / amylin-receptor triple agonist in any one of embodiments 1 to 76, wherein Z2 comprises or consists of the amino acid sequence according to SEQ ID NO. 40.

[1104] 79. A GLP-1- / GIP- / amylin-receptor triple agonist in any one of embodiments 1 to 76, wherein Z2 comprises or consists of the amino acid sequence according to SEQ ID NO. 53.

[1105] 80. A GLP-1- / GIP- / amylin-receptor triple agonist in any one of embodiments 1 to 76, wherein Z2 comprises or consists of an amino acid sequence according to SEQ ID NO. 2.

[1106] 81. In any one of the prior embodiments, the peptide Z1 - L1 - Z2 comprises or consists of the following amino acid sequence, a GLP-1- / GIP- / amylin-receptor triple agonist:

[1107] · Z1 is selected from the group consisting of the following:

[1108]

[1109] · L1 is selected from the group consisting of the following:

[1110] E, AE, AG, AGGGG(SEQ No. 142), AGQAPGQAPG(SEQ No. 136), AGQAPGQAPL(SEQ No. 137), AGEAPGQAPG(SEQ No. 143), AGEAPGEAPG(SEQ No. 144), AGQAPGQAPA(SEQ No. 145), AGQAPGQAPE(SEQ No. 146), AGQAPGQAPP(SEQ No. 147), AGQAPGQAPS(SEQ No. 148), AGQAPGQAPV(SEQ No. 149), EGQAPGQAPG(SEQ No. 150), AGQEPGQAPG(SEQ No. 151), AGQAEGQAPG(SEQ No. 152), AGQAPEQAPG(SEQ No. 153), AGQAPGEAPG (Sequence No. 154), AGQAPGQEPG (Sequence No. 155), AGQAPGQAEG (Sequence No. 156), AGQEPGQEPG (Sequence No. 157), AGQAPGQAP (Sequence No. 158), and AGQAPGEAPL (Sequence No. 159),

[1111] · Z2 is selected from the group consisting of the following:

[1112]

[1113] 82. In any one of the prior embodiments, the peptide Z1 - L1 - Z2 comprises or consists of the following amino acid sequence, a GLP-1- / GIP- / amylin-receptor triple agonist:

[1114] · Z1 is selected from the group consisting of the following:

[1115]

[1116] · L1 is selected from the group consisting of AG and AGEAPGEAPG (sequence number 144), and

[1117] · Z2 is selected from the group consisting of the following:

[1118]

[1119] 83. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, peptide Z1-L1-Z2 comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs 170 to 252.

[1120] 84. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is:

[1121] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAQLGRLSAELHQLATLPRTETGSGSP (Sequence No. 230), or

[1122] YX2EGTFTSDYSILLEEIAAREFIEWLLAGGASSGAGEAPGEAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (Sequence No. 243), or

[1123] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP(SEQ ID 244), or

[1124] YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (Sequence No. 246), or

[1125] YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence No. 250), or

[1126] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGGSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence No. 251), or

[1127] A sequence of amino acids selected from the group consisting of YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (SEQ No. 252), comprising or composed of such a sequence, wherein X2 is an Aib, a GLP-1- / GIP- / amylin-receptor triple agonist.

[1128] 85. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, the skeleton of peptide Z1-L1-Z2 comprises 66 to 80 amino acid residues, e.g., 66 to 76 amino acid residues or 67 to 75 amino acid residues.

[1129] 86. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein the skeleton of peptide Z1-L1-Z2 comprises 67, 68, 71, 75, or 76 amino acid residues in any one of the prior embodiments.

[1130] 87. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein the skeleton of peptide Z1-L1-Z2 comprises 68 amino acid residues in any one of the prior embodiments.

[1131] 88. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein the skeleton of peptide Z1-L1-Z2 comprises 76 amino acid residues in any one of the prior embodiments.

[1132] 89. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, peptide Z1-L1-Z2 is a peptide derivative comprising an extension moiety.

[1133] 90. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is C 12 -C 20 A GLP-1- / GIP- / amylin-receptor triple agonist comprising a discrete extender P.

[1134] 91. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, peptide Z1-L1-Z2 is a peptide derivative comprising an extension moiety, said extension moiety comprising an extension group P selected from the group consisting of the following:

[1135]

[1136]

[1137] 92. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is C 18 Dispersal, C 20 Discrete, and C 19 It comprises an extender P selected from the group consisting of phosphonic acids; preferably, the extender P is C 20A GLP-1- / GIP- / amylin-receptor triple agonist, which is a diacid (chemical formula 6).

[1138] 93. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is attached to the epsilon position of a single lysine (Lys, K) residue, a GLP-1- / GIP- / amylin-receptor triple agonist.

[1139] 94. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, said extension moiety is attached to the epsilon-amino group of one lysine (Lys, K) residue of peptide Z1 or attached to the epsilon-amino group of a lysine (Lys, K) residue of peptide Z2.

[1140] 95. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is position 12 (Z of peptide Z1). 12 A GLP-1- / GIP- / amylin-receptor triple agonist attached to the epsilon-amino group of one lysine (Lys, K) residue in ).

[1141] 96. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is at position 18 (X) of peptide Z2 68 A GLP-1- / GIP- / amylin-receptor triple agonist attached to the epsilon-amino group of one lysine (Lys, K) residue in ).

[1142] 97. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is a linker L selected from the group consisting of the following. P GLP-1- / GIP- / amylin-receptor triple agonists additionally containing:

[1143]

[1144]

[1145] 98. In any one of the prior embodiments, the peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is a linker L selected from the group consisting of the following. P A GLP-1- / GIP- / amylin-receptor triple agonist further comprising: Formula 20, Formula 33, and Formula 34, preferably the linker L P is chemical formula 20.

[1146] 99. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is a GLP-1- / GIP- / amylin-receptor triple agonist selected from the group consisting of:

[1147]

[1148]

[1149]

[1150] 100. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is selected from the group consisting of: GLP-1- / GIP- / amylin-receptor triple agonist: Formula 27, Formula 35, Formula 36, ​​and Formula 37.

[1151] 101. In any one of the prior embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is a GLP-1- / GIP- / amylin-receptor triple agonist of Formula 27.

[1152] 102. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, peptide Z1-L1-Z2 is a peptide derivative selected from the group consisting of compound numbers 104 to 197 of Example 2 of the present invention.

[1153] 103. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, peptide Z1-L1-Z2 is a peptide derivative selected from the group consisting of compounds No. 104-193 and 196-197 of Example 2 of the present invention.

[1154] 104. A GLP-1- / GIP- / amylin-receptor triple agonist, which is Compound 104 of Example 2 of the present invention, in any one of the prior embodiments.

[1155]

[1156] 105. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of embodiments 1 to 103, compound 105 of Example 2 of the present invention.

[1157]

[1158] 106. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of embodiments 1 to 103, compound 107 of Example 2 of the present invention.

[1159]

[1160] 107. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of embodiments 1 to 103, compound 111 of Example 2 of the present invention.

[1161]

[1162] 108. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of embodiments 1 to 103, compound 112 of Example 2 of the present invention.

[1163]

[1164] 109. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of embodiments 1 to 103, compound 113 of Example 2 of the present invention.

[1165]

[1166] 110. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of embodiments 1 to 103, compound 183 of Example 2 of the present invention.

[1167]

[1168] 111. In any one of the prior embodiments, the peptide is a GLP-1- / GIP- / amylin-receptor triple agonist having a C-terminal amide modification.

[1169] 112. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human GIP receptors in any one of the prior embodiments.

[1170] 113. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating the human GIP receptor in a assay in which the entire cell expresses the human GIP receptor, in any one of the prior embodiments.

[1171] 114. In any one of the prior embodiments, when measured in the absence of HSA in the test as described in Example 4, preferably less than 125 pM EC 50 , more preferably EC of less than 100 pM 50 , most preferably EC of less than 50 pM 50 A GLP-1 / GIP- / amylin-receptor triple agonist that in vivo activates human GIP receptors.

[1172] 115. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human GLP-1 receptors in any one of the prior embodiments.

[1173] 116. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating the human GLP-1 receptor in a assay in which the entire cell expresses the human GLP-1 receptor, in any one of the prior embodiments.

[1174] 117. In any one of the prior embodiments, when measured in the absence of HSA in the test as described in Example 4, preferably less than 125 pM EC 50 , more preferably EC of less than 100 pM 50 , most preferably EC of less than 50 pM 50 A GLP-1- / GIP- / amylin-receptor triple agonist that in vivo activates the human GIP-1 receptor.

[1175] 118. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human amylin receptors in any one of the prior embodiments.

[1176] 119. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating the human amylin receptor in a assay in which the entire cell expresses the human amylin receptor, in any one of the prior embodiments.

[1177] 120. In any one of the prior embodiments, when measured in the absence of HSA in the test as described in Example 4, preferably less than 125 pM EC 50 , more preferably EC of less than 100 pM 50 , most preferably EC of less than 50 pM 50 A GLP-1- / GIP- / amylin-receptor triple agonist that in vivo activates human amylin receptors.

[1178] 121. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human GIP, GLP-1, and amylin receptors in any one of the prior embodiments.

[1179] 122. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human GIP, GLP-1, and amylin receptors in a assay in which the entire cell expresses human GIP, GLP-1, and amylin receptors in any one of the prior embodiments.

[1180] 123. In any one of the prior embodiments, when measured in the absence of HSA as described in Example 4, preferably less than 125 pM EC 50 , more preferably EC of less than 100 pM 50 , most preferably EC of less than 50 pM 50 A GLP-1- / GIP- / amylin-receptor triple agonist that in vivo activates human GIP, GLP-1, and amylin receptors.

[1181] 124. A GLP-1- / GIP- / amylin-receptor triple agonist that, in any one of the prior embodiments, activates human GIP, GLP-1, and amylin receptors in vitro when measured in the absence of HSA as described in Example 4, and has an efficacy ratio of less than 50, e.g., less than 30.

[1182] 125. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein the efficacy ratio is less than 20 in any one of the prior embodiments.

[1183] 126. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior embodiments, the efficacy ratio is less than 15, most preferably less than 10.

[1184] 127. A GLP-1- / GIP- / amylin-receptor triple agonist having improved pharmacokinetic properties in any one of the prior embodiments.

[1185] 128. A GLP-1- / GIP- / amylin-receptor triple agonist having an increased half-life in any one of the prior embodiments.

[1186] 129. A GLP-1- / GIP- / amylin-receptor triple agonist having an increased half-life of 80 to 200 hours, preferably 90 to 190 hours, more preferably 95 to 185 hours, as determined in a minipig as described in Example 6, in any one of the prior embodiments.

[1187] 130. A GLP-1- / GIP- / amylin-receptor triple agonist having an increased half-life of 40 to 145 hours, preferably 90 to 140 hours, more preferably 85 to 125 hours, when determined in a minipig as described in Example 6, in any one of the prior embodiments.

[1188] 131. A GLP-1- / GIP- / amylin-receptor triple agonist having an increased half-life of 5 to 50 hours, preferably 10 to 35 hours, more preferably 12 to 30 hours, when determined in rats as described in Example 6, in any one of the prior embodiments.

[1189] 132. A GLP-1- / GIP- / amylin-receptor triple agonist having improved chemical stability in any one of the prior embodiments.

[1190] 133. A GLP-1- / GIP- / amylin-receptor triple agonist having improved chemical stability in any one of the prior embodiments, and having a purity loss of 5.0% or less per week, preferably less than 3.0% per week, more preferably less than 2.0% per week, as determined in Example 7 described herein.

[1191] 134. A GLP-1- / GIP- / amylin-receptor triple agonist having an in vivo effect of reducing food intake in normal-weight rats, as determined in the experimental protocol for an efficacy test on appetite, such as Example 5 described herein, in any one of the prior embodiments.

[1192] 135. A GLP-1- / GIP- / amylin-receptor triple agonist, which is a pharmaceutically acceptable salt of a GIP-1- / GLP- / amylin-receptor triple agonist in any one of the prior embodiments.

[1193] 136. A pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of the prior embodiments, and at least one pharmaceutically acceptable excipient.

[1194] 137. A pharmaceutical composition for oral or subcutaneous administration according to Embodiment 136.

[1195] 138. A pharmaceutical composition that is a solid pharmaceutical composition in either Embodiment 136 or 137.

[1196] 139. A solid pharmaceutical composition, which is a tablet, according to Embodiment 138.

[1197] 140. In either Embodiment 138 or Embodiment 139, N -[8-(2-hydroxybenzoyl)amino]caprylate salt, preferably sodium N A solid pharmaceutical composition comprising -(8-(2-hydroxybenzoyl)amino)caprylate, and magnesium stearate.

[1198] 141. In any one of embodiments 138 to 140, 75 to 600 mg of sodium N A solid pharmaceutical composition comprising -(8-(2-hydroxybenzoyl)amino)caprylate and 7 to 8.5 mg of magnesium stearate.

[1199] 142. A pharmaceutical composition for administering approximately once a day, for example, once every 12 to 36 hours, for example, once every 18 to 30 hours, for example, once every approximately 24 hours, or once a week, for example, once every 6 to 8 days, in any one of embodiments 136 to 141.

[1200] 143. An injection device comprising a GLP-1- / GIP- / amylin-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.

[1201] 144. A GLP-1- / GIP- / amylin-receptor triple agonist peptide according to any one of Examples 1 to 88 for use as an intermediate in the preparation of a GLP-1- / GIP- / amylin-receptor triple agonist peptide derivative according to any one of Examples 89 to 135.

[1202] 145. A GLP-1- / GIP- / amylin-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 medicine.

[1203] 146. A GLP-1- / GIP- / amylin-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 fatty liver hepatitis (MASH) and / or cardiovascular disease.

[1204] 147. A GLP-1- / GIP- / amylin-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 treating subjects having an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher.

[1205] 148. A GLP-1- / GIP- / amylin-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 treating a subject having an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher in the presence of at least one weight-related comorbidity.

[1206] 149. A GLP-1- / GIP- / amylin-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 adjuvant for a low-calorie diet and increased physical activity for chronic weight management in an adult subject suffering from obesity, i.e., an adult subject with 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., an adult subject with an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher.

[1207] 150. A GLP-1- / GIP- / amylin-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 an adult subject suffering from obesity, i.e., an adult subject with 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., an adult subject with 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.

[1208] 151. In Embodiment 148 or Embodiment 150, at least one weight-related comorbidity is selected from the group consisting of hypertension, dysglycemia (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease and obstructive sleep apnea.

[1209] 152. Use of a GLP-1- / GIP- / amylin-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 manufacturing a medicine for the treatment of type 2 diabetes, obesity, metabolic dysfunction-associated fatty liver hepatitis (MASH), and / or cardiovascular disease.

[1210] 153. Use of a GLP-1- / GIP- / amylin-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 manufacturing a medicine for treating a subject whose initial body mass index (BMI) is 25 or higher, 27 or higher, or 28 or higher, or 30 or higher; optionally in the presence of at least one weight-related comorbidity.

[1211] 154. Use of a GLP-1- / GIP- / amylin-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 manufacturing a medicine for treating an adult subject who is obese, i.e., an adult subject whose initial body mass index (BMI) is 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher; or an adult subject who is overweight, i.e., an adult subject whose initial body mass index (BMI) is 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher, optionally in the presence of at least one weight-related comorbidity.

[1212] 155. Use of a GLP-1- / GIP- / amylin-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 manufacturing a medicine for chronic weight management in an adult subject suffering from obesity, i.e., an adult subject with 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., an adult subject with an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher, optionally in the presence of at least one weight-related comorbidity.

[1213] 156. In Embodiment 154 or Embodiment 155, the medicine is used as an adjuvant for a low-calorie diet and increased physical activity for chronic weight management in an adult subject suffering from obesity or overweight.

[1214] 157. A method for treating type 2 diabetes, obesity, metabolic dysfunction-associated fatty liver hepatitis (MASH), and / or cardiovascular disease, comprising the step of administering a pharmaceutically relevant amount of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of embodiments 1 to 135 to a subject in need thereof.

[1215] 158. A method for treating a human subject having an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher, comprising the step of administering a pharmaceutically relevant amount of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of embodiments 1 to 135 to the human subject.

[1216] 159. A method for reducing excess weight in a human subject in combination with a reduced calorie diet and increased physical activity, comprising the step of administering a pharmaceutically relevant amount of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of embodiments 1 to 135 to said human subject.

[1217] 160. A method according to Embodiment 158 ​​or Embodiment 159, wherein the human subject is an adult subject who suffers 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.

[1218] 161. A method according to Embodiment 158 ​​or Embodiment 159, wherein the human subject is an adult subject who suffers 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.

[1219] 162. A method in 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, dysglycemia (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease and obstructive sleep apnea.

[1220] 163. A method for preparing a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of Embodiments 1 to 135.

[1221] 164. A method according to Embodiment 163, comprising a solid-phase peptide synthesis step.

[1223] Example of a specific alternative implementation

[1224] 1. A GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to the following chemical formula I:

[1225] Z1―L1―Z2 (I),

[1226] The above peptide includes one lysine (Lys, K) residue, wherein:

[1227] · Z1 is a peptide containing up to 4 amino acid substitutions compared to Formula II (Sequence No. 1):

[1228] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[1229] In the formula, the amino acid at position X2 represents Aib;

[1230] · L1 is a peptide linker and;

[1231] · Z2 is a C-terminal amide and a peptide containing up to 10 amino acid substitutions relative to formula V (SEQ No. 2):

[1232] ASELSTAALGRLSAELHELATLPRTETGSGSP (V).

[1233] 2. In Alternative Embodiment 1, 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 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 respect to Formula V (SEQ No. 2). GLP-1 / GIP / amylin-receptor triple agonist.

[1234] 3. A GLP-1- / GIP- / amylin-receptor triple agonist according to alternative embodiments 1 and 2, wherein one lysine (Lys, K) residue is present in peptide Z1 or peptide Z2.

[1235] 4. In alternative embodiments 1 to 3, the GLP-1- / GIP- / amylin-receptor triple agonist is a GLP-1- / GIP- / amylin-receptor triple agonist that does not contain a cysteine ​​(Cys, C) residue.

[1236] 5. In alternative embodiments 1 to 4, the GLP-1- / GIP- / amylin-receptor triple agonist is a GLP-1- / GIP- / amylin-receptor triple agonist that does not contain a disulfide bridge.

[1237] 6. In Alternative Embodiments 1 to 5:

[1238] · Z1 is a peptide having up to 4 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[1239] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[1240] In the formula, the amino acid at position X2 represents Aib, and

[1241] Z1 comprises or consists of an amino acid sequence according to chemical formula VII (SEQ ID NO. 162):

[1242] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII),

[1243] During the meal

[1244] X2 represents Aib,

[1245] X 12 represents Ile(I) or Lys(K), and

[1246] X 20 represents Arg(R) or Gln(Q), and

[1247] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[1248] X 27 represents Leu(L) or Ile(I),

[1249] X 28 represents Ala(A) or Gln(Q), and

[1250] X 34 represents Gly(G) or Glu(E);

[1251] · L1 is a peptide linker and;

[1252] · Z2 is a peptide containing a C-terminal amide and having up to 10 amino acid substitutions compared to formula V (SEQ No. 2):

[1253] ASELSTAALGRLSAELHELATLPRTETGSGSP (V),

[1254] Z2 comprises or consists of an amino acid sequence according to chemical formula VI (SEQ ID NO. 165):

[1255] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[1256] During the meal

[1257] X 52 represents Gly(G) or Ser(S),

[1258] X 53 represents Gln(Q), Glu(E), or His(H), and

[1259] X 58 represents Ala(A) or Gln(Q), and

[1260] X 59 represents Leu(L) or Thr(T),

[1261] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1262] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[1263] X 72is a GLP-1- / GIP- / amylin-receptor triple agonist representing Leu(L) or Glu(E).

[1264] 7. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of alternative embodiments 1 to 6, the peptide linker L1 comprises 1 to 14, 1 to 10, 4 to 10, or 9 to 10 amino acid residues.

[1265] 8. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of alternative embodiments 1 to 7, 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).

[1266] 9. In any one of alternative embodiments 1 to 8, the peptide linker L1 comprises or consists of an amino acid sequence according to formula VIIIa:

[1267] 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),

[1268] During the meal

[1269] X 141 represents Ala(A), Glu(E), and Gly(G),

[1270] X 142 represents or is absent of Gln(Q), Glu(E), Gly(G), Leu(L), and Pro(P),

[1271] X 143... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Pro(P),

[1272] X 144 is represented by or absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Pro(P),

[1273] X 145 is represented by or absent from Glu(E), Gly(G), Pro(P), Ser(S), and Thr(T),

[1274] X 146 ... represents or is absent from Glu(E), Gly(G), Leu(L), and Gln(Q),

[1275] X 147 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), and Phe(F),

[1276] X 148 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), Thr(T), Pro(P), Val(V), and

[1277] X 149 is represented by or absent from Glu(E), Asn(N), Pro(P), and Thr(T),

[1278] X 150 ... represents or is absent from Ala(A), Gln(Q), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), Val(V), and

[1279] X 151 represents Ala(A) or is absent,

[1280] X 152 represents Gln(Q) or is absent,

[1281] X 153 represents Thr(T) or is absent,

[1282] X 154 is a GLP-1- / GIP- / amylin-receptor triple agonist that represents or is absent from Leu(L).

[1283] 10. In any one of alternative embodiments 1 to 9,

[1284] GLP-1- / GIP- / amylin-receptor triple agonist, wherein peptide linker L1 comprises or consists of an amino acid sequence selected from the group consisting of: A, E, G, AE, AG, GE, APPE (SEQ No. 125), GGGE (SEQ No. 126), AGQAPG (SEQ No. 127), APPPSGGG (SEQ No. 128), APPPSGGGE (SEQ No. 129), APPPSGGGG (SEQ No. 130), ALAQTLAQTL (SEQ No. 131), ALAQTLFVNQ (SEQ No. 132), ALAQTLGTNE (SEQ No. 133), ALQAPGQAPG (SEQ No. 134), ALQAPGQAPL (SEQ No. 135), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), GGGEGGGEGE(Sequence No. 138), GQAPGQAPGE(Sequence No. 139), GQEPGQEPGE(Sequence No. 140), APPPSLAQTLAQTL(Sequence No. 141), AGGGG(Sequence No. 142), AGEAPGQAPG(Sequence No. 143), AGEAPGEAPG(Sequence No. 144), AGQAPGQAPA(Sequence No. 145), AGQAPGQAPE(Sequence No. 146), AGQAPGQAPP(Sequence No. 147), AGQAPGQAPS(Sequence No. 148), AGQAPGQAPV(Sequence No. 149), EGQAPGQAPG(Sequence No. 150), AGQEPGQAPG(Sequence No. 151), AGQAEGQAPG(Sequence No 152), AGQAPEQAPG (Sequence No. 153), AGQAPGEAPG (Sequence No. 154), AGQAPGQEPG (Sequence No. 155), AGQAPGQAEG (Sequence No. 156), AGQEPGQEPG (Sequence No. 157), AGQAPGQAP (Sequence No. 158), and AGQAPGEAPL (Sequence No. 159).

[1285] 11. In Alternative Implementation Example 10,

[1286] The peptide linker L1 is a GLP-1- / GIP- / amylin-receptor triple agonist selected from the group consisting of: E, GE, APPPSGGGE (SEQ No. 129), AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), and AGQAPGEAPG (SEQ No. 154).

[1287] 12. In any one of alternative embodiments 1 to 5 and 7 to 11,

[1288] Peptide Z2 comprises or consists of an amino acid sequence according to chemical formula XIV (SEQ No. 4):

[1289] ASX 53 LSTAX 58 X 59 X 60 RLSAX 65 LHX 68 LX 70 X 71 LPX 74 TETGSGX 81 P (XIV),

[1290] During the meal

[1291] X 53 represents Lys(K), and

[1292] X 58 represents Ala(A) or Gln(Q), and

[1293] X 59 represents Gln(Q), Leu(L), or Thr(T), and

[1294] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1295] X 65 represents Glu(E),

[1296] X 68 represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), and

[1297] X 70represents Ala(A), and

[1298] X 71 represents Asp(D) or Thr(T),

[1299] X 74 represents Arg(R), and

[1300] X 81 represents Ala(A) or Ser(S);

[1302] X 53 represents Gln(Q), Glu(E), or His(H), and

[1303] X 58 represents Ala(A) or Gln(Q), and

[1304] X 59 represents Gln(Q), Leu(L), or Thr(T), and

[1305] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1306] X 65 represents Lys(K), and

[1307] X 68 represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), and

[1308] X 70 represents Ala(A), and

[1309] X 71 represents Asp(D) or Thr(T),

[1310] X 74 represents Arg(R), and

[1311] X 81 represents Ala(A) or Ser(S);

[1312]

[1313] X 53 represents Gln(Q), Glu(E), or His(H), and​

[1314] X 58 represents Ala(A) or Gln(Q), and

[1315] X 59 represents Gln(Q), Leu(L), or Thr(T), and

[1316] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1317] X 65 represents Glu(E),

[1318] X 68 represents Lys(K), and

[1319] X 70 represents Ala(A), and

[1320] X 71 represents Asp(D) or Thr(T),

[1321] X 74 represents Arg(R), and

[1322] X 81 represents Ala(A) or Ser(S);

[1323]

[1324] X 53 represents Gln(Q), Glu(E), or His(H), and

[1325] X 58 represents Ala(A) or Gln(Q), and

[1326] X 59 represents Gln(Q), Leu(L), or Thr(T), and

[1327] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1328] X 65 represents Glu(E),

[1329] X 68 ​represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), and

[1330] X 70 represents Lys(K), and

[1331] X 71 represents Asp(D) or Thr(T),

[1332] X 74 represents Arg(R), and

[1333] X 81 represents Ala(A) or Ser(S);

[1334]

[1335] X 53 represents Gln(Q), Glu(E), or His(H), and

[1336] X 58 represents Ala(A) or Gln(Q), and

[1337] X 59 represents Gln(Q), Leu(L), or Thr(T), and

[1338] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1339] X 65 represents Glu(E),

[1340] X 68 represents Arg(R), Gln(Q), Glu(E), Gly(G), His(H), Thr(T), or Tyr(Y), and

[1341] X 70 represents Ala(A), and

[1342] X 71 represents Asp(D) or Thr(T),

[1343] X 74 represents Lys(K), and

[1344] X 81 ​is a GLP-1- / GIP- / amylin-receptor triple agonist representing Ala(A) or Ser(S).

[1345] 13. In Alternative Implementation Example 6,

[1346] Peptide Z1 comprises or consists of an amino acid sequence according to the chemical formula VX (SEQ No. 167):

[1347] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGGPSSX 34 (VX),

[1348] During the meal

[1349] X2 represents Aib,

[1350] X 12 represents Ile(I) or Lys(K), and

[1351] X 27 represents Leu(L) or Ile(I),

[1352] X 34 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Gly(G) or Glu(E).

[1353] 14. In Alternative Embodiment 6 or Alternative Embodiment 13, peptide Z2 comprises or consists of the following amino acid sequence, a GLP-1- / GIP- / amylin-receptor triple agonist:

[1354] ASHLSTAQTQRLSAELHKLATLPRTETGSGSP (Sequence No. 40).

[1355] 15. In any one of alternative embodiments 6, 13, or 14,

[1356] Peptide Z1 comprises or consists of an amino acid sequence according to the chemical formula XV (SEQ No. 167):

[1357] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGGPSSX 34(XV),

[1358] During the meal

[1359] X2 represents Aib,

[1360] X 12 represents Ile(I) or Lys(K), and

[1361] X 27 represents Leu(L) or Ile(I),

[1362] X 34 represents Gly(G) or Glu(E);

[1363] Peptide Z2 is an amino acid sequence

[1364] A GLP-1- / GIP- / amylin-receptor triple agonist comprising or composed of ASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ No. 40).

[1365] 16. In any one of alternative embodiments 6 or 13 to 15,

[1366] Peptide Z1 comprises or consists of an amino acid sequence according to chemical formula XI (SEQ No. 163):

[1367] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLLAGGPSSG (XI),

[1368] During the meal

[1369] X2 represents Aib,

[1370] X 12 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Ile(I) or Lys(K).

[1371] 17. In any one of alternative embodiments 6 or 13 to 16,

[1372] Peptide Z2 comprises or consists of an amino acid sequence according to chemical formula X (SEQ ID NO. 166):

[1373] ASX 59LSTAQTQRLSAELHKLATLPRTETGSGSP(X),

[1374] During the meal

[1375] X 59 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Glu(E) or His(H).

[1376] 18. In any one of alternative embodiments 1 to 5 and 7 to 11,

[1377] A GLP-1- / GIP- / amylin-receptor triple agonist, wherein peptide Z1-L1-Z2 comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs 170 to 242, and X2 represents Aib.

[1378] 19. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior alternative embodiments, the skeleton of peptide Z1-L1-Z2 comprises 66 to 80 amino acid residues.

[1379] 20. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior alternative embodiments, the skeleton of peptide Z1-L1-Z2 comprises 67, 68, 75, or 76 amino acid residues, preferably 76 amino acid residues.

[1380] 21. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein the peptide is a peptide derivative comprising an extension moiety in any one of the prior alternative embodiments.

[1381] 22. In any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is C 12 -C 20 A GLP-1- / GIP- / amylin-receptor triple agonist comprising a discrete extender P.

[1382] 23. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, said extension moiety comprising an extension group P selected from the group consisting of the following:

[1383]

[1384]

[1385] 24. In any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is C 16 Dispersal, C 18 Dispersal, C 20 Discrete, and C 19 It comprises an extender P selected from the group consisting of phosphonic acids; preferably, the extender P is C 18 Discrete or C 20 Dioxide, GLP-1- / GIP- / amylin-receptor triple agonist.

[1386] 25. In any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is attached to the epsilon position of a single lysine (Lys, K) residue, a GLP-1- / GIP- / amylin-receptor triple agonist.

[1387] 26. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, said extension moiety being attached to the epsilon position of a lysine (Lys, K) residue of peptide Z1 or attached to the epsilon position of a lysine (Lys, K) residue of peptide Z2.

[1388] 27. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, said extension moiety being attached to the epsilon position of a lysine (Lys, K) residue at position 12 or position 33 or position 34 of peptide Z1, preferably at position 12 or position 33 of peptide Z1.

[1389] 28. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, said extension moiety being attached to the epsilon position of a lysine (Lys, K) residue at positions 3, 15, 18, 20, or 24 of peptide Z2.

[1390] 29. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, said extension moiety being attached to the epsilon position of a lysine (Lys, K) residue at position 15 of peptide Z2 or position 18 of peptide Z2.

[1391] 30. In any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is a linker L selected from the group consisting of the following. P GLP-1- / GIP- / amylin-receptor triple agonists additionally containing:

[1392]

[1393]

[1394] 31. In any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is a linker L PA GLP-1- / GIP- / amylin-receptor triple agonist comprising Formula 20 or Formula 21 as the extender P, and Formula 5 or Formula 6.

[1395] 32. In any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is (i) Table 6 Linker L selected from the group presented in P and (ii) Table 5 It is composed of an extender P selected from the group presented in, and preferably, the extender moiety is Table 7 A GLP-1- / GIP- / amylin-receptor triple agonist selected from the group presented in.

[1396] 33. In any one of the prior alternative embodiments, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is C 18 Dioxide(S) gamma-Glu 2xAdo fatty acid moiety (Chemical Formula 28) or C 20 A GLP-1- / GIP- / amylin-receptor triple agonist, which is a diacid(S) gamma-Glu 2xAdo fatty acid moiety (Chemical Formula 27).

[1397] 34. In any one of Alternative Embodiments 1 to 33,

[1398] Peptide Z1 comprises or consists of an amino acid sequence according to Chemical Formula VII (SEQ No. 162):

[1399] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII),

[1400] During the meal

[1401] X2 represents Aib,

[1402] X 12 represents Ile(I) or Lys(K), and

[1403] X 20 represents Arg(R) or Gln(Q), and

[1404] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[1405] X 27 represents Leu(L) or Ile(I),

[1406] X 28 represents Ala(A) or Gln(Q), and

[1407] X 34 represents Gly(G) or Glu(E);

[1408] Peptide linker L1 comprises or is composed of an amino acid sequence selected from the group consisting of E, AG, AGQAPGQAPG (SEQ No. 136), AGQAPGQAPL (SEQ No. 137), AGGGG (SEQ No. 142), AGEAPGQAPG (SEQ No. 143), and AGQAPGEAPG (SEQ No. 154);

[1409] Peptide Z2 comprises or consists of an amino acid sequence according to chemical formula VI (SEQ ID NO. 165):

[1410] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[1411] During the meal

[1412] X 52 represents Gly(G) or Ser(S),

[1413] X 53 represents Gln(Q), Glu(E), or His(H), and

[1414] X 58 represents Ala(A) or Gln(Q), and

[1415] X 59 represents Leu(L) or Thr(T),

[1416] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1417] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[1418] X 72 represents Leu(L) or Glu(E);

[1419] The peptide is a GLP-1- / GIP- / amylin-receptor triple agonist, which is a peptide derivative containing an extension moiety.

[1420] 35. In Alternative Embodiment 34, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is C 12 -C 20 A GLP-1- / GIP- / amylin-receptor triple agonist comprising a discrete extender P.

[1421] 36. In Alternative Embodiment 35, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is a linker L selected from the group presented in Table 6. P A GLP-1- / GIP- / amylin-receptor triple agonist including

[1422] 37. In any one of alternative embodiments 34 to 36, peptide Z1 comprises or is composed of an amino acid sequence according to formula XI (SEQ ID NO. 163):

[1423] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLLAGGPSSG (XI),

[1424] During the meal

[1425] X2 represents Aib,

[1426] X 12is a GLP-1- / GIP- / amylin-receptor triple agonist representing Ile(I) or Lys(K).

[1427] 38. In any one of alternative embodiments 34 to 37, peptide Z2 comprises or is composed of an amino acid sequence according to formula X (SEQ ID NO. 166):

[1428] ASX 59 LSTAQTQRLSAELHKLATLPRTETGSGSP(X),

[1429] During the meal

[1430] X 59 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Glu(E) or His(H).

[1431] 39. As a GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to the following chemical formula I:

[1432] Z1―L1―Z2 (I),

[1433] The above peptide includes one lysine (Lys, K) residue, wherein:

[1434] · Z1 is a peptide having up to 4 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[1435] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[1436] In the formula, the amino acid at position X2 represents Aib, and

[1437] Z1 comprises or consists of an amino acid sequence according to chemical formula VII (SEQ ID NO. 162):

[1438] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GGPSSX 34 (VII),

[1439] During the meal

[1440] X2 represents Aib,

[1441] X 22 represents Ile(I) or Lys(K), and

[1442] X 20 represents Arg(R) or Gln(Q), and

[1443] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[1444] X 27 represents Leu(L) or Ile(I),

[1445] X 28 represents Ala(A) or Gln(Q), and

[1446] X 34 represents Gly(G) or Glu(E);

[1447] · L1 is a peptide linker comprising or consisting of 1 to 14, 1 to 10, 4 to 10, or 9 to 10 amino acid residues;

[1448] · Z2 includes a C-terminal amide, and

[1449] It is a peptide having up to 10 amino acid substitutions compared to chemical formula V (sequence number 2):

[1450] ASELSTAALGRLSAELHELATLPRTETGSGSP (V),

[1451] Z2 comprises or consists of an amino acid sequence according to chemical formula VI (SEQ ID NO. 165):

[1452] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[1453] During the meal

[1454] X 52 represents Gly(G) or Ser(S),

[1455] X 53 represents Gln(Q), Glu(E), or His(H), and

[1456] X 58 represents Ala(A) or Gln(Q), and

[1457] X 59 represents Leu(L) or Thr(T),

[1458] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1459] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[1460] X 72 represents Leu(L) or Glu(E);

[1461] Here, the peptide is a peptide derivative comprising an extension moiety, wherein the extension moiety is C 16 -C 20 A linker L including a discrete extender P and selected from the group presented in Table 6 P A GLP-1- / GIP- / amylin-receptor triple agonist additionally comprising

[1462] 40. In any one of the prior alternative embodiments, the compound is a GLP-1- / GIP- / amylin-receptor triple agonist selected from compounds No. 120–197 and 211–221 of Example 2 of the present invention.

[1463] 41. In any one of the prior alternative embodiments, the peptide is a GLP-1- / GIP- / amylin-receptor triple agonist having a C-terminal amide modification.

[1464] 42. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human GIP receptors in any one of the prior alternative embodiments.

[1465] 43. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating the human GIP receptor in a assay in which the entire cell expresses the human GIP receptor, in any one of the prior alternative embodiments.

[1466] 44. In any one of the prior alternative embodiments, when measured in the absence of HSA in the test as described in Example 4, preferably less than 125 pM EC 50 , more preferably EC of less than 100 pM 50 , most preferably EC of less than 50 pM 50 A GLP-1 / GIP- / amylin-receptor triple agonist that in vivo activates human GIP receptors.

[1467] 45. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human GLP-1 receptors in any one of the prior alternative embodiments.

[1468] 46. ​​A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating the human GLP-1 receptor in a assay in which the entire cell expresses the human GLP-1 receptor, in any one of the prior alternative embodiments.

[1469] 47. In any one of the prior alternative embodiments, when measured in the absence of HSA in the test as described in Example 4, preferably less than 125 pM EC 50 , more preferably EC of less than 100 pM 50 , most preferably EC of less than 50 pM 50 A GLP-1- / GIP- / amylin-receptor triple agonist that in vivo activates human GLP-1 receptors.

[1470] 48. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human amylin receptors in any one of the prior alternative embodiments.

[1471] 49. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating the human amylin receptor in a assay in which the entire cell expresses the human amylin receptor, in any one of the prior alternative embodiments.

[1472] 50. In any one of the prior alternative embodiments, when measured in the absence of HSA in the test as described in Example 4, preferably less than 125 pM EC 50 , more preferably EC of less than 100 pM 50 , most preferably EC of less than 50 pM 50 A GLP-1- / GIP- / amylin-receptor triple agonist that in vivo activates human amylin receptors.

[1473] 51. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human GIP, GLP-1, and amylin receptors in any one of the prior alternative embodiments.

[1474] 52. A GLP-1- / GIP- / amylin-receptor triple agonist capable of activating human GIP, GLP-1, and amylin receptors in a assay in which the entire cell expresses human GIP, GLP-1, and amylin receptors in any one of the prior alternative embodiments.

[1475] 53. In any one of the prior alternative embodiments, when measured in the absence of HSA in the test as described in Example 4, preferably less than 125 pM EC 50 , more preferably EC of less than 100 pM 50 , most preferably EC of less than 50 pM 50 A GLP-1- / GIP- / amylin-receptor triple agonist that in vivo activates human GIP, GLP-1, and amylin receptors.

[1476] 54. A GLP-1- / GIP- / amylin-receptor triple agonist having an efficacy ratio of less than 50, which, in any one of the prior alternative embodiments, activates human GIP, GLP-1, and amylin receptors in vitro when measured in the absence of HSA in the assay as described in Example 4.

[1477] 55. A GLP-1- / GIP- / amylin-receptor triple agonist in alternative embodiment 54, wherein the efficacy ratio is less than 20.

[1478] 56. A GLP-1- / GIP- / amylin-receptor triple agonist in alternative embodiment 54 or 55, wherein the efficacy ratio is less than 15, most preferably less than 11.

[1479] 57. A GLP-1- / GIP- / amylin-receptor triple agonist having improved pharmacokinetic properties in any one of alternative embodiments 21 to 41.

[1480] 58. A GLP-1- / GIP- / amylin-receptor triple agonist having an increased half-life in any one of alternative embodiments 21 to 41.

[1481] 59. A GLP-1- / GIP- / amylin-receptor triple agonist having an increased half-life of 40 to 145 hours, preferably 90 to 140 hours, more preferably 85 to 125 hours, as determined in a minipig in alternative embodiment 58.

[1482] 60. A GLP-1- / GIP- / amylin-receptor triple agonist having improved chemical stability in any one of alternative embodiments 21 to 59.

[1483] 61. A GLP-1- / GIP- / amylin-receptor triple agonist having improved chemical stability and a purity loss of 6.0% or less per week as determined in Example 7 described herein, preferably a purity loss of less than 3.0% per week as determined in Example 7 described herein.

[1484] 62. A GLP-1- / GIP- / amylin-receptor triple agonist having an in vivo effect of reducing food intake in normal-weight rats, as determined in the experimental protocol for an efficacy test on appetite such as Example 5 described herein, in any one of alternative embodiments 21 to 61.

[1485] 63. A pharmaceutically acceptable salt of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of the prior alternative embodiments.

[1486] 64. A pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of the prior alternative embodiments, and at least one pharmaceutically acceptable excipient.

[1487] 65. A pharmaceutical composition for oral or subcutaneous administration in Alternative Embodiment 64.

[1488] 66. A pharmaceutical composition, which is a solid pharmaceutical composition, in alternative embodiment 64 or 65.

[1489] 67. A solid pharmaceutical composition, which is a tablet, in Alternative Embodiment 66.

[1490] 68. In alternative embodiment 66 or 67, N -[8-(2-hydroxybenzoyl)amino]caprylate salt, preferably sodium N A solid pharmaceutical composition comprising -(8-(2-hydroxybenzoyl)amino)caprylate, and magnesium stearate.

[1491] 69. In any one of alternative embodiments 66 to 68, 75 to 600 mg of sodium N A solid pharmaceutical composition comprising -(8-(2-hydroxybenzoyl)amino)caprylate and 7 to 8.5 mg of magnesium stearate.

[1492] 70. A pharmaceutical composition for administering, in any one of alternative embodiments 64 to 69, approximately once a day, e.g., once every 12 to 36 hours, e.g., once every 18 to 30 hours, e.g., once every approximately 24 hours, or once a week, e.g., once every 6 to 8 days.

[1493] 71. An injection device comprising a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63, or a pharmaceutical composition according to any one of alternative embodiments 64 to 70.

[1494] 72. A GLP-1- / GIP- / amylin-receptor triple agonist peptide according to any one of alternative embodiments 1 to 19 for use as an intermediate in the preparation of a GLP-1- / GIP- / amylin-receptor triple agonist peptide derivative according to any one of alternative embodiments 22 to 64.

[1495] 73. A GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 or a pharmaceutical composition according to any one of alternative embodiments 64 to 70 for use as a medicine.

[1496] 74. A GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 or a pharmaceutical composition according to any one of alternative embodiments 64 to 70 for use in the treatment of type 2 diabetes, obesity, metabolic dysfunction-associated fatty liver hepatitis (MASH) and / or cardiovascular disease.

[1497] 75. A GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 or a pharmaceutical composition according to any one of alternative embodiments 64 to 70 for use in treating subjects with an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher.

[1498] 76. A GLP-1- / GIP- / amylin-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 treating a subject having an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher in the presence of at least one weight-related comorbidity.

[1499] 77. A GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 or a pharmaceutical composition according to any one of alternative embodiments 64 to 70 for use as an adjunct to a low-calorie diet and increased physical activity for chronic weight management in an adult subject suffering from obesity, i.e., an adult subject with 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., an adult subject with an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher.

[1500] 78. A GLP-1- / GIP- / amylin-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 an adult subject suffering from obesity, i.e., an adult subject with 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., an adult subject with 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.

[1501] 79. In alternative embodiment 76 or alternative embodiment 78, at least one weight-related comorbidity is selected from the group consisting of hypertension, dysglycemia (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease and obstructive sleep apnea.

[1502] 80. Use of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 in manufacturing a medicine for the treatment of type 2 diabetes, obesity, metabolic dysfunction-associated fatty liver hepatitis (MASH), and / or cardiovascular disease.

[1503] 81. Use of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 in manufacturing a medicine for treating a subject whose initial body mass index (BMI) is 25 or higher, 27 or higher, or 28 or higher, or 30 or higher; optionally in the presence of at least one weight-related comorbidity.

[1504] 82. Use of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 in manufacturing a medicine for treating an adult subject who is obese, i.e., an adult subject whose initial body mass index (BMI) is 25 or higher, or 27 or higher, or 28 or higher, or 30 or higher; or an adult subject who is overweight, i.e., an adult subject whose initial body mass index (BMI) is 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher, optionally in the presence of at least one weight-related comorbidity.

[1505] 83. Use of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 in manufacturing a medicine for chronic weight management in an adult subject who is obese, i.e., an adult subject with 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 who is overweight, i.e., an adult subject with an initial body mass index (BMI) of 23 or higher, or 24 or higher, or 25 or higher, or 27 or higher, optionally in the presence of at least one weight-related comorbidity.

[1506] 84. In alternative embodiment 82, the medicine is used as an adjuvant for a low-calorie diet and increased physical activity for chronic weight management in adult subjects suffering from obesity or overweight.

[1507] 85. A method for treating type 2 diabetes, obesity, metabolic dysfunction-associated fatty liver hepatitis (MASH), and / or cardiovascular disease, comprising the step of administering a pharmaceutically relevant amount of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 to a subject in need thereof.

[1508] 86. A method for treating a human subject having an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher, comprising the step of administering a pharmaceutically relevant amount of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 to the human subject.

[1509] 87. A method for reducing excess weight in a human subject in combination with a reduced calorie diet and increased physical activity, comprising the step of administering a pharmaceutically relevant amount of a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63 to said human subject.

[1510] 88. A method according to alternative embodiment 86 or alternative embodiment 87, wherein the human subject is an adult subject who is 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.

[1511] 89. A method according to alternative embodiment 86 or alternative embodiment 87, wherein the human subject is an adult subject who suffers 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.

[1512] 90. A method in any one of alternative embodiments 86 to 89, wherein the human subject has at least one weight-related comorbidity selected from the group consisting of hypertension, dysglycemia (prediabetes or type 2 diabetes), dyslipidemia, hypercholesterolemia, cardiovascular disease and obstructive sleep apnea.

[1513] 91. A method for preparing a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of alternative embodiments 1 to 63.

[1514] 92. A method according to alternative embodiment 91, comprising a solid-phase peptide synthesis step.

[1516] Specific second alternative implementation example

[1517] 1. A GLP-1- / GIP- / amylin-receptor triple agonist comprising a peptide according to the following chemical formula I, or a pharmaceutically acceptable salt thereof:

[1518] Z1―L1―Z2 (I),

[1519] The above peptide includes one lysine (Lys, K) residue, wherein:

[1520] · Z1 is a peptide comprising or composed of an amino acid sequence according to Chemical Formula III (SEQ No. 168):

[1521] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[1522] During the meal

[1523] X2 represents Aib,

[1524] X 12 represents Ile(I) or Lys(K), and

[1525] X 20 represents Arg(R) or Gln(Q), and

[1526] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[1527] X 27 represents Leu(L) or Ile(I),

[1528] X 28 represents Ala(A) or Gln(Q), and

[1529] X 30 represents Gly(G) or Ala(A), and

[1530] X 31represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[1531] X 33 represents Glu(E) or Ser(S),

[1532] X 34 represents Gly(G) or Glu(E);

[1533] · L1 is a peptide linker and;

[1534] · Z2 is a peptide comprising an amino acid sequence according to chemical formula VI (SEQ ID NO. 165) or a C-terminal amide formed therefrom, and:

[1535] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[1536] During the meal

[1537] X 52 represents Gly(G) or Ser(S),

[1538] X 53 represents Gln(Q), Glu(E), or His(H), and

[1539] X 58 represents Ala(A) or Gln(Q), and

[1540] X 59 represents Leu(L) or Thr(T),

[1541] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1542] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[1543] X 72 is representing Leu(L) or Glu(E),

[1544] GLP-1- / GIP- / amylin-receptor triple agonists or pharmaceutically acceptable salts thereof.

[1545] 2. In a specific second alternative embodiment 1,

[1546] · Z1 is a peptide having up to 5 amino acid substitutions compared to Chemical Formula II (Sequence No. 1), and:

[1547] YX2EGTFTSDYSILLEEQAAREFIEWLLAGGPSKG(II),

[1548] In the formula, the amino acid at position X2 represents Aib, and

[1549] Z1 comprises or consists of an amino acid sequence according to Chemical Formula III (Sequence No. 168):

[1550] YX2EGTFTSDYSX 12 LLEEIAAX 20 EFIX 24 WLX 27 X 28 GX 30 X 31 SX 33 X 34 (III),

[1551] During the meal

[1552] X2 represents Aib,

[1553] X 12 represents Ile(I) or Lys(K), and

[1554] X 20 represents Arg(R) or Gln(Q), and

[1555] X 24 represents Ala(A), Glu(E), or Gln(Q), and

[1556] X 27 represents Leu(L) or I(Ile),

[1557] X 28 represents Ala(A) or Gln(Q), and

[1558] X 30represents Gly(G) or Ala(A), and

[1559] X 31 represents Gly(G), Gln(Q), Ala(A), or Pro(P), and

[1560] X 33 represents Glu(E) or Ser(S),

[1561] X 34 represents Gly(G) or Glu(E);

[1562] · L1 is a peptide linker and;

[1563] · Z2 is a peptide containing a C-terminal amide, and Z2 comprises or consists of an amino acid sequence according to Formula VI (SEQ ID NO. 165):

[1564] AX 52 X 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATX 72 PRTETGSGSP (VI),

[1565] During the meal

[1566] X 52 represents Gly(G) or Ser(S),

[1567] X 53 represents Gln(Q), Glu(E), or His(H), and

[1568] X 58 represents Ala(A) or Gln(Q), and

[1569] X 59 represents Leu(L) or Thr(T),

[1570] X 60 represents Ala(A), Gly(G), or Gln(Q), and

[1571] X 68 represents Gln(Q), Glu(E), or Lys(K), and

[1572] X 72 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Leu(L) or Glu(E).

[1573] 3. In any one of the prior specific second alternative embodiments, Z1 comprises or consists of an amino acid sequence according to Formula IV (SEQ ID NO. 169):

[1574] YX2EGTFTSDYSX 12 LLEEIAAREFIEWLX 27 AGX 30 X 31 SSG (IV),

[1575] During the meal

[1576] X2 represents Aib,

[1577] X 12 represents Ile(I) or Lys(K), and

[1578] X 27 represents Leu(L) or I(Ile),

[1579] X 30 represents Gly(G) or Ala(A), and

[1580] X 31 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Gly(G), Ala(A), or Pro(P).

[1581] 4. In any one of the prior specific second alternative embodiments, Z2 comprises or consists of an amino acid sequence according to Formula IX (SEQ ID NO. 61):

[1582] ASX 53 LSTAX 58 X 59 X 60 RLSAELHX 68 LATLPRTETGSGSP (IX),

[1583] During the meal

[1584] X 53 represents Glu(E) or His(H),

[1585] X 58 represents Ala(A) or Gln(Q), and

[1586] X 59 represents Leu(L) or Thr(T),

[1587] X 60 represents Gly(G) or Gln(Q), and

[1588] X 68 is a GLP-1- / GIP- / amylin-receptor triple agonist representing Gln(Q), Glu(E), or Lys(K).

[1589] 5. In any one of the prior specific second alternative embodiments, the peptide linker L1 comprises or consists of an amino acid sequence according to Formula VIII:

[1590] X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 X 50 (VIII),

[1591] During the meal

[1592] X 41 represents Ala(A), Gly(G), or Glu(E),

[1593] X 42 represents or is absent from Glu(E) and Gly(G),

[1594] X 43 ... represents or is absent from Glu(E), Gly(G), and Gln(Q),

[1595] X 44 represents or is absent from Ala(A), Glu(E), and Gly(G),

[1596] X 45 represents or is absent of Glu(E), Gly(G), and Pro(P),

[1597] X 46 ... represents or is absent from Glu(E) and Gly(G),

[1598] X 47 is Gln(Q) or Glu(E) and is absent,

[1599] X 48 ... represents or is absent from Ala(A) and Glu(E),

[1600] X 49 is indicative of or absent Glu(E) and Pro(P),

[1601] X 50 is a GLP-1- / GIP- / amylin-receptor triple agonist having or lacking Ala(A), Glu(E), Gly(G), Leu(L), Pro(P), Ser(S), or Val(V).

[1602] 6. A GLP-1- / GIP- / amylin-receptor triple agonist, wherein in any one of the prior specific second alternative embodiments, peptide Z1-L1-Z2 comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs 170 to 252.

[1603] 7. In any one of the prior specific second alternative embodiments, peptide Z1 - L1 - Z2 is:

[1604] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAQLGRLSAELHQLATLPRETTSGSP (SEQ ID NO: 230),

[1605] YX2EGTFTSDYSILLEEIAAREFIEWLLAGGASSGAGEAPGEAPGASHLSTAQTQRLSAELHKLATLPRTETGSGSP (SEQ ID NO: 243),

[1606] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 244),

[1607] YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHQLATLPRTETGSGSP (SEQ ID NO: 246),

[1608] YX2EGTFTSDYSKLLEEIAAREFIEWLIAGAPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (SEQ ID NO: 250),

[1609] YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGGSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (Sequence No. 251), and

[1610] A sequence of amino acids selected from the group consisting of YX2EGTFTSDYSKLLEEIAAREFIEWLLAGGPSSGAGASELSTAALGRLSAELHELATLPRTETGSGSP (SEQ No. 252), comprising or composed of such a sequence, wherein X2 is an Aib, a GLP-1- / GIP- / amylin-receptor triple agonist.

[1611] 8. In any one of the prior specific second alternative embodiments, the peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, a GLP-1- / GIP- / amylin-receptor triple agonist.

[1612] 9. In any one of the prior specific second alternative embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, and said extension moiety is C 12 -C 20 A GLP-1- / GIP- / amylin-receptor triple agonist comprising a discrete extender P.

[1613] 10. In any one of the prior specific second alternative embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is a linker L P A GLP-1- / GIP- / amylin-receptor triple agonist additionally comprising

[1614] 11. In any one of the prior specific second alternative embodiments, peptide Z1 - L1 - Z2 is a peptide derivative comprising an extension moiety, wherein the extension moiety is a GLP-1- / GIP- / amylin-receptor triple agonist selected from the group consisting of:

[1615]

[1616] 12. A GLP-1- / GIP- / amylin-receptor triple agonist that is compound 104; compound 105; compound 107; compound 111; compound 112; compound 113; or compound 183.

[1617] 13. A pharmaceutical composition comprising a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of specific second alternative embodiments 1 to 12, and at least one pharmaceutically acceptable excipient.

[1618] 14. A GLP-1- / GIP- / amylin-receptor triple agonist according to any one of specific second alternative embodiments 1 to 12 or a pharmaceutical composition according to specific second alternative embodiment 13 for use as a medicine.

[1619] 15. A GLP-1- / GIP- / amylin-receptor triple agonist according to any one of specific second alternative embodiments 1 to 12 or a pharmaceutical composition according to specific second alternative embodiment 13 for use in the treatment of a subject having an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher, and optionally having at least one weight-related comorbidity.

[1620] Examples

[1621] Materials and Methods

[1622] List of abbreviations

[1623] The following abbreviations are used in alphabetical order:

[1624] Ado: 8-amino-3,6-dioxaoctanic acid

[1625] Aib: 2-aminoisobutyric acid

[1626] amu: atomic mass unit

[1627] BHK Baby Hamster Height

[1628] Boc: t- Butyloxycarbonyl

[1629] CAD: Charged Aerosol Detector

[1630] cAMP: Cyclic adenosine monophosphate

[1631] CRE: cAMP response elements

[1632] DCM: Dichloromethane

[1633] DIC: N,N' - Diisopropylcarbodiimide

[1634] DIO: Diet-induced obesity

[1635] DMB: 2,4-Dimethoxybenzyl

[1636] DMEM: Dulbecco's Modified Eagle Medium

[1637] (Dulbecco's Modified Eagle's Medium)

[1638] DMF: N,N -Dimethylformamide

[1639] DTT: 1,4-Dithiothreitol

[1640] EC 50 : Half-maximum effective concentration

[1641] EDTA: Ethylenediaminetetraacetic acid

[1642] ES: Electrospray

[1643] FBS: Fetal Bovine Serum

[1644] Fmoc: 9-Fluorenylmethyloxycarbonyl

[1645] FWHM: Full FWHM

[1646] GIP: Glucose-dependent insulin-releasing polypeptide

[1647] GLP-1: Glucagon-like peptide-1

[1648] hAMYR3: Human amylin receptor 3

[1649] hGIPR: Human glucose-dependent insulin-releasing polypeptide receptor

[1650] hGLP-1R: Human glucagon-like peptide 1 receptor

[1651] HEPES: N -(2-hydroxyethyl)piperazine- N -(2-ethanesulfonic acid)

[1652] HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol

[1653] or hexafluoroisopropanol

[1654] HPLC: High-performance liquid chromatography

[1655] HSA: Human serum albumin

[1656] iv: intravenous

[1657] LCMS or LC-MS: Liquid Chromatography Mass Spectrometry

[1658] LLoQ: Lower bound on quantification

[1659] Luc: Luciferase

[1660] MeCN: Acetonitrile

[1661] MRI: Magnetic Resonance Imaging

[1662] MS: Mass Spectrometry

[1663] Mtt: 4-methyltrityl

[1664] NCA: Non-compartment pharmacokinetic method

[1665] nd: Undetermined

[1666] OtBu: Tertiary-butoxy

[1667] Oxyma Pure®: Cyano-hydroxyimino-ethyl acetate

[1668] Pbf: 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl

[1669] PBS: Phosphate-buffered saline

[1670] PK: Pharmacokinetics

[1671] QD: Quark die (once a day)

[1672] QTof: Quadrupole Flight Time

[1673] RAMP3: Receptor Modifier Protein 3

[1674] RT: Room temperature

[1675] sc: subcutaneous

[1676] SD: Sprag Dawley

[1677] SEM: Standard error of the mean

[1678] SPPS: Solid-phase peptide synthesis

[1679] tBu: tert-butyl

[1680] TFA: Trifluoroacetic acid

[1681] TIS: Triisopropylsilane

[1682] TQ: Triple quadrupole

[1683] Trt: Triphenylmethyl or trityl

[1684] UPLC: Ultra-high Performance Liquid Chromatography

[1685] UV: Ultraviolet rays

[1687] Fatty acids and specific amino acid building blocks

[1688] Octadecandioic acid mono-tert-butyl ester (C 18 For the synthesis of diacid mono-tert-butyl esters, refer to patent application WO 2010 / 102886 (pages 27 to 28). Accordingly, C 12 -C 20 Discrete, especially C 16 Discrete and C20 The corresponding mono-tert-butyl ester of this acid can be prepared.

[1689] Fmoc-Leu-Ser(ø Me , Me pro)-OH, Fmoc-Tyr(tBu)-Ser(ø Me , Me pro)-OH, and Fmoc-Gly-(DMB)Gly-OH were commercially available from TechnoComm Ltd.

[1691] General method for peptide synthesis

[1692] The preparation of peptides (for the reference compound and the compound of the present invention) was carried out with SPPS using Fmoc-based chemistry based on Protein Technologies’ Symphony X, Protein Technologies’ PurePep Chorus, CEM’s MultiPep 2, Vapourtec’s Vapourtec RS-500, or CSBio’s CS136XT. The Fmoc-protected amino acids used in this method were the following standard recommended substances: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, provided by, for example, Gyros Protein Technologies, Bachem, Iris Biotech, or NovabioChem. 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. Building block Fmoc-Leu-Ser(ø Me,Me pro)-OH, Fmoc-Tyr( t Bu)-Ser(ø Me,Me pro)-OH and Fmoc-Gly-(DMB)Gly-OH were introduced where applicable, for example, commercially available from TechnoComm Ltd.

[1693] Fmoc-PAL AM resin or Rink-Amide AM resin was used, which was commercially available from NovabioChem. Subsequent amino acids were introduced stepwise using a Symphony X peptide synthesizer according to the SPPS principle.

[1694] Fmoc-deprotection was achieved for 2 x 10 minutes with 20% piperidine in DMF in 0.1 M Oxyma Pure. Substituents at the alpha-position of the N-terminal amino acid (i.e., "extender P") and selective "linker L P The introduction of an extension moiety (including ") was achieved using standard Fmoc-protected amino acids. Peptide coupling was performed with DIC and colidin. An amino acid / Oxyma Pure solution (0.3 M / 0.3 M in DMF at a 5 to 10 molar excess) was first added to the resin. Then, an equal molar equivalent of DIC (1.5 M in DMF) was followed by the addition of colidin (1.5 M in DMF). In the most conventional manner, this was mixed for 1 hour. In some cases, the coupling time was increased, additional DIC was added, or the coupling step was repeated. Subsequently, a capping step was performed with 1 M acetic anhydride in DMF and colidin. The introduction of an extension moiety to the epsilon-nitrogen of lysine (Lys, K) within the sequence was achieved using Fmoc-Lys(Mtt)-OH. After synthesizing the peptide backbone sequence, the Mtt group The extension moiety was removed by treatment with HFIP / DCM / TIPS (75:23:2) (5 min) and subsequently washed with DCM. Then, the resin was resuspended in HFIP / DCM / TIPS (75:23:2) (2 x 25 min) and subsequently washed with DCM and DMF. The extension moiety was removed using a linker L such as a standard Fmoc-protected amino acid, such as Fmoc-Fmoc-8-amino-3,6-dioxoctanic acid or Fmoc-Glu-OtBu. PUsing a suitably protected building block for, it was introduced in the stepwise procedure as described above. The introduction of the fatty acid group, which is the extension group, was achieved using a suitable building block, such as octadecandioic acid mono-tert-butyl ester or eicosandioic acid mono-tert-butyl ester, but is not limited thereto.

[1696] General cutting method

[1697] The peptide was cleaved in a resin with TFA / TIPS / H2O / DTT (90:4:3:3) for 2 to 3 hours. Afterward, the peptide was drained with cold diethyl ether and centrifuged. The ether was decanted, and the peptide precipitate was washed twice with ether.

[1699] General method for the purification and quantification of derivatives

[1700] The unpurified peptide was dissolved in acetic acid / MeCN / Milli-Q water (45:10:45 or 40:20:40) and orthogonally purified by reverse-phase preparative HPLC (Waters Delta Prep 4000) on a column containing a C18-silica gel. The first elution was performed with an increasing gradient of 20 to 50% of MeCN in Milli-Q water containing 1% ammonium bicarbonate. The relevant fraction was analyzed by UPLC. The fraction containing the target peptide was collected and diluted with Milli-Q water (1:1) prior to the second reverse-phase preparative HPLC. The second elution was performed with an increasing gradient of 20 to 50% of MeCN in Milli-Q water containing 0.1% TFA. The relevant fraction was analyzed by UPLC. The fraction containing the pure target peptide was collected. The generated solution was analyzed (UPLC, LCMS), and the peptide derivative was quantified using a CAD-specific HPLC detector (Thermo-Fischer Vanquish HPLC-CAD). The product was dispensed into a glass vial. The vial was capped with a Millipore glass fiber pre-filter. The trifluoroacetate salt of the derivative was obtained as a white solid by freeze-drying.

[1701] The synthesized compound presented below was prepared using the method described above.

[1702] Example 1: Reference Compound

[1703] Reference Compound 1

[1704] (WO 2023 / 288313, Example 1, Peptide / Compound No. 16; GLP-1- / GIP- / Amylin-Receptor Triple Actor disclosed in SEQ ID No. 11)

[1705]

[1706] Reference Compound 2

[1707] (Triple agent based on the conjugation of tyrzepatide and cagrilintide, SEQ ID NO. 12)

[1708]

[1709] Reference Compound 3

[1710] (Example 21 of WO 2016 / 034604. A triple agent based on the conjugation of tyrzepatide and an amylin receptor agonist disclosed in SEQ ID NO. 13)

[1711]

[1712] Reference Compound 4

[1713] (WO 2019 / 211451, Example 1, Compound 31, GIP receptor agonist disclosed in SEQ ID NO. 14)

[1714]

[1719] Reference Compound 5

[1720] (GLP-1 / GIP co-agonist tyrzepatide, SEQ ID NO. 15)

[1721]

[1722] Reference Compound 6

[1723] (Amylin receptor agonist cagrilintide, WO 2012 / 168432, Example 53, SEQ ID NO. 16)

[1724]

[1725] Reference Compound 7

[1726] (GLP-1 receptor agonist semaglutide, WO 2006 / 097537, Example 4, SEQ ID No. 17)

[1727]

[1728] Example 2: GLP-1- / GIP- / amylin-receptor triple agonist according to the present invention

[1729]

[1730]

[1731]

[1732]

[1733]

[1734]

[1735]

[1736]

[1737]

[1738]

[1739]

[1740]

[1741]

[1742]

[1743]

[1744]

[1745]

[1746]

[1747]

[1748]

[1749]

[1750]

[1751]

[1752]

[1753]

[1754]

[1755]

[1756]

[1757]

[1758]

[1759]

[1760]

[1761]

[1762]

[1763]

[1764]

[1765]

[1766]

[1767]

[1768]

[1769]

[1770]

[1771]

[1772]

[1773]

[1774]

[1775]

[1776]

[1777]

[1778]

[1779]

[1780]

[1781]

[1782]

[1783]

[1784]

[1785]

[1787] Example 3: LCMS Characterization of the Synthesized Compound

[1788] LCMS Characterization Method

[1789] LCMS analysis was performed in an environment consisting of a Waters Acquity UPLC H class system and a Waters Xevo G2-XS QTof. Eluent: A: Milli-Q water; B: MeCN; C: 2% formic acid + 0.1% TFA in Milli-Q water.

[1790] An appropriate volume of sample was injected onto a column at room temperature (column temperature 60°C). The sample was eluted with a linear gradient of 5 to 95% B and a constant 5% C in A.

[1791] 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 x 50 mm. Gradient: Linear 5% to 95% B and constant 5% C for 4.0 min at 0.4 ml / min. Total run time: 7.0 min. Detect: MS sensitivity mode, ionization method: ES. Scan: 50–5000 amu.

[1792] The single-isotope masses of the synthesized compounds were recorded, and their measured and calculated values Table 10 It is presented in.

[1793]

[1794]

[1795]

[1796]

[1797]

[1799] Example 4: In vitro efficacy assay of human GLP-1, GIP, and amylin receptors (high-throughput assay)

[1800] GLP-1 receptor assay

[1801] To determine the ability of a compound to activate or act on GLP-1 receptors, an in vitro efficacy assay was performed in baby hamster kidney (BHK) cells expressing human GLP-1 (hGLP-1) receptors as described below. To evaluate how receptor activation is potentially affected by the presence of human serum albumin (HSA), the in vitro assay was performed in the absence of HSA and in the presence of 1% (w / v) HSA. Unless otherwise noted, throughout the specification, references to "GLP-1 receptor assay as described in Example 4" refer to the assay procedure (hGLP-1R assay) described herein in the absence of HSA.

[1803] Testing principles

[1804] Activation of the human GLP-1 receptor increases the intracellular concentration of cyclic AMP (cAMP) and, consequently, increases transcriptional activation from promoters containing multiple copies of cAMP-responsive factor (CRE). Therefore, it is possible to measure GLP-1 receptor activity using a CRE-luciferase reporter gene introduced into baby hamster kidney (BHK) cells co-expressing the human GLP-1 receptor.

[1806] Cells and assay reagents

[1807] A cell mother liquor was prepared by culturing a cell line containing a CRE-reactive luciferase (CRE-Luc) reporter gene (BHK 467-12A KZ-10, prepared according to a method known to those skilled in the art) that stably expresses the human GLP-1 receptor in a growth medium consisting of DMEM (Gibco, 61965-026) supplemented with 10% FBS (Gibco, 10100-147), 1% penicillin / streptomycin (Gibco, 15140-122), 1 mM sodium pyruvate (Gibco, 11360-039), 0.5 mg / mL G418 (Gibco, 10131-027), and 240 nM methotrexate (Pfizer, 15936). Cells that had reached approximately 80–90% confluence were washed once in PBS (Gibco 14190-094) and separated from the cell flask using Versene (Gibco, 15040-033). After centrifugation, the cell pellet was resuspended in Recovery frozen cell culture medium (Gibco, 12648-010) at approximately 1.5 x 10 6 The cells were diluted to cells / mL. Cells were aliquoted and stored at -180℃ until use.

[1808] 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), with or without HSA (Sigma, A9511).

[1810] Procedure (hGLP-1R test)

[1811] To perform the assay, serial dilutions of the reference compound and the GLP-1- / GIP- / amylin-receptor triagonist (7-fold dilutions, 7 concentrations per compound, and one well containing only assay buffer) were prepared in a 96-well plate with assay buffer. The serial dilutions were transferred to a 384-well assay plate (Revvity, 6007688) and mixed with an equal volume (10 μL) of assay buffer, with or without 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 x 10⁶ cells in assay buffer (without HSA). 5 The solution was diluted to (1.5E+5) cells / mL, and (10 μL) was added to each well of a 384-well assay plate. After a brief centrifugation, the assay plate was incubated at 37°C under 5% CO2 for 3 hours, equilibrated at room temperature for 10 minutes, and then 30 μL of steadylite plus™ (Revvity, 6066759) was added per well. The plate was sealed and incubated at room temperature in the dark with gentle shaking for 30 minutes. 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).

[1813] GIP receptor assay

[1814] To determine the ability of a compound to activate or act on the GIP receptor, an in vitro efficacy assay was performed in baby hamster kidney (BHK) cells expressing the human GIP receptor (hGIPR) as described below. To evaluate how receptor activation is potentially affected by the presence of human serum albumin (HSA), the in vitro assay was performed in the absence of HSA and in the presence of 1% (w / v) HSA. Unless otherwise noted, throughout the specification, references to "GIP receptor assay as described in Example 4" refer to the assay procedure (hGIPR assay) described herein in the absence of HSA.

[1816] Testing principles

[1817] Activation of the human GIP receptor increases the intracellular concentration of cyclic AMP (cAMP) and, consequently, increases transcriptional activation from promoters containing multiple copies of cAMP-responsive factor (CRE). Therefore, it is possible to measure GIP receptor activity using a CRE-luciferase reporter gene introduced into baby hamster kidney (BHK) cells co-expressing the human GIP receptor.

[1819] Cells and assay reagents

[1820] A cell mother liquor was prepared by culturing a cell line stably expressing the human GIP receptor and CRE-reactive luciferase (CRE-Luc) reporter gene (hGIPR BHK Cre-Luc2p clone#5, prepared according to methods known to those skilled in the art) in a growth medium consisting of DMEM (Gibco, 61965-026) supplemented with 10% fetal calf 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 that had reached approximately 80 to 90% confluence were washed once with PBS (Gibco 14190-094) and separated from the cell flask using Versene (Gibco, 15040-066). After centrifugation, the cells were counted, resuspended, and stored in recovered frozen cell culture medium (Gibco, 12648-010) at a level of approximately 1.5 to 3.0 x 10⁶ 6 It was diluted to (1.5E+6 to 3.0E+6) cells / mL and stored in appropriate aliquots at -180℃ until use.

[1821] 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), with or without HSA (Sigma, A9511).

[1823] Procedure (hGIPR test)

[1824] To perform the analysis, serial dilutions of the reference compound and the GLP-1- / GIP- / amylin-receptor triagonist (7-fold dilutions, 7 concentrations per compound, and one well containing only assay buffer) were prepared in the assay buffer of 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 with or without 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 x 10⁶ cells in assay buffer (without HSA). 5 The solution was diluted to (1.5E+5) cells / mL, and (10 μL) was added to each well of a 384-well assay plate. After a brief centrifugation, the assay plate was incubated at 37°C under 5% CO2 for 3 hours, equilibrated at room temperature for 10 minutes, and then 30 μL of steadylite plus™ (Revvity, 6066759) was added per well. The plate was sealed and incubated at room temperature in the dark with gentle shaking for 30 minutes. 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).

[1826] Amylin receptor test

[1827] To determine the ability of a compound to activate or act on the amylin receptor, an in vitro efficacy assay was performed in baby hamster kidney (BHK) cells expressing the human amylin receptor (hAMYR3) as described below. To evaluate how receptor activation is potentially affected by the presence of human serum albumin (HSA), the in vitro assay was performed in the absence of HSA and in the presence of 1% (w / v) HSA. Unless otherwise noted, throughout the specification, references to "amylin receptor assay as described in Example 4" refer to the assay procedure (hAMYR3 assay) described herein in the absence of HSA.

[1829] Testing principles

[1830] Activation of the human amylin 3 receptor increases the intracellular concentration of cAMP and, consequently, increases transcriptional activation from promoters containing multiple copies of cAMP-responsive factor (CRE). Therefore, it is possible to measure hAMYR3 activity using a CRE-luciferase reporter gene introduced into baby hamster kidney (BHK) cells co-expressing hAMYR3.

[1832] Cells and assay reagents

[1833] According to methods known to those skilled in the art, human calcitonin receptor (a) BHK cell lines (Hollex-1 cell line, purchased from Zymogentics as described in U.S. Patent No. 5,622,839) were engineered to stably express and contain the CRE-reactive luciferase (CRE-Luc) reporter gene. Cell lines were further transfected with human receptor modified protein 3 (hRAMP3) using standard methods. The binding of hRAMP3 to the human calcitonin receptor forms the human amylin-3-(a) receptor (hAMYR3).

[1834] A cell mother liquor was prepared by culturing the hAMYR3 BHK CRE-Luc cell line in a growth medium composed of 10% FBS (Gibco, 10100-147), 1% penicillin / streptomycin (Gibco, 15140-122), 0.5 mg / mL geneticin (Gibco, 10131-027), 0.4 mg / mL hygromycin (ThermoFisher, 10687010), and DMEM (Gibco, 31966-021) supplemented with 250 nM methotrexate (Sigma, A6770). Cells that have reached approximately 80 to 90% confluence are washed once with PBS (Gibco 14190-094), and Versene (Gibco, 15040-033) or TrypLE TM It was separated from the cell flask using (Gibco, 12605-010). After centrifugation, the cell pellet was resuspended in Recovery frozen cell culture medium (Gibco, 12648-010) and approximately 2.5 to 4.0 x 10⁶ 6 It was diluted to (2.5E+6 to 4.0E+6) cells / mL. Cells were aliquoted and stored at -180℃ until use.

[1835] The assay buffer consisted of DMEM supplemented with 1X GlutaMAX (Gibco, 35050-038) without phenol red (Gibco, 11880-028), 10 mM HEPES (Gibco, 15630-056), and 1% (w / v) ovalbumin (Sigma, A5503), with or without 0.1% (v / v) Pluronic F-68 (Gibco, 24040-032) and with or without HSA (Sigma, A9511).

[1837] Procedure (hAMYR3)

[1838] To perform the assay, hAMYR3 BHK CRE-Luc cells were thawed the day before the experiment, washed once in PBS (Gibco 14190-094), and 4.0 x 10⁶ cells were placed in 40 μL of growth medium in a white 384-well culture plate (Revvity, 6007688). 3 Cells were seeded at a cell density of (4.0E+3) cells / well. Plates were incubated overnight at 37°C under 5% CO2. On the day of the assay, serial dilutions of the reference compound and the GLP-1- / GIP- / amylin-receptor triagonist (7-fold dilutions, 7 concentrations per compound, and one well containing only assay buffer) were prepared in assay buffer within a 96-well plate. Then, the serial dilutions were mixed in a new 96-well plate containing equal volumes (1:1:1 ratio) of assay buffer and either assay buffer with or without 3% HSA (Sigma, A9511). 20 μL of the solution mixture was transferred to cells that had been previously washed once with PBS (Gibco 14190-094). After a brief centrifugation, the calibration plates were incubated at 37°C under 5% CO2 for 3 hours and equilibrated at room temperature for 10 minutes, after which 30 μL of steadylite plus™ (Revvity, 6066759) was added per well. The plates were sealed and incubated at room temperature in the dark with gentle shaking for 30 minutes. 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 = 1.5, floor response shared within each plate) with GraphPad Prism (GraphPad Software, Boston, MA, USA) or by TIBCO Enterprise Runtime for R (TIBCO Software, Palo Alto, CA, USA).

[1840] result:

[1841]

[1842] Table 11 The results indicate that reference compounds 4 to 7 are agonists or co-agonists for one or two of the GLP-1 receptor, GIP receptor, and amylin receptor (hAMYR3).

[1843] Table 11 According to the data, the activity data for reference compound 2 indicates that linking the C-terminus of a potent GLP-1 / GIP co-agonist (tyrzepatide) to the N-terminus of a potent amylin receptor agonist (cagrilintide) via a peptide linker does not produce a compound that is equally potent for these three receptors and can inevitably act as a GLP-1 / GIP- / amylin-receptor triple agonist (i.e., a compound according to the present invention). This is exemplified by a comparison of reference compound 2 with reference compound 5 (tyrzepatide) and reference compound 6 (cagrilintide). Reference compound 2 exhibits a significant loss of efficacy for the GLP-1 receptor and, when compared to the original compounds, reference compounds 5 (tyrzepatide) and 6 (cagrilintide), shows an additional partial loss of efficacy for the amylin receptor.

[1844] Reference compounds 1 to 3 exhibit functional activation of all three receptors, but all of them impair efficacy for one or more of the GLP-1, GIP-, and amylin receptors when compared to the GLP-1 / GIP- / amylin receptor triple agonist of the present invention. Therefore, reference compounds 1 to 3 are not potent for all three receptors and are not balanced.

[1845]

[1846]

[1847]

[1848] Table 12The results indicate that the compound of the present invention potently and functionally activates all three receptors: the human GLP-1 receptor, the human GIP receptor, and the human amylin receptor (hAMYR3).

[1849] Most of the GLP-1- / GIP- / amylin-receptor triple agonists of the present invention are ECs similar to the GIP, GLP-1, and amylin receptor agonists and GLP-1 / GIP co-agonists disclosed herein as reference compounds 4 to 7. 50 It acts on different receptors with different values. Also, Table 12 As shown in [figure], the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention is shown to functionally activate all three receptors potently and in a balanced manner, and is a balanced GLP-1- / GIP- / amylin-receptor triple agonist in contrast to reference compounds 1, 2, and 3.

[1850]

[1851]

[1852]

[1853]

[1854] Absolute EC created under the existence of 1% HSA 50 Values ​​can vary significantly depending on the batch of HSA used. Therefore, absolute data cannot be used on its own and needs to be compared with a reference compound running on the same batch of HSA.

[1856] Example 5: Experimental protocol for testing efficacy on appetite using a free-feeding rat model

[1857] For the acute feeding experiment, male Sprag Daulley (SD) rats from Taconic, Denmark were used in compliance with laboratory animal care principles.

[1858] At the start of the experiment, the rats weighed 250–350 g and were not fed an obese diet. To allow the rats to acclimate to the experimental environment, they were arranged to arrive at least 7 days prior to the start of the experiment. Upon arrival, the rats were switched to a backlight cycle (darkness from 11:00 AM to 11:00 PM) and transferred to an automated food intake measurement system (HM2 system, MBRose; Faaborg, Denmark), where three rats were housed per cage. The rats had free access to a 10% fat diet (study diet D12450B) and water, and were housed at room temperature (approx. 22°C). To enable the recording of individual food intake, ID chips were implanted in the rats during the acclimation period. Since rats are generally active and consume the majority of their daily calories during the dark period, food was administered to the rats in the morning, just before the lights were turned off. This setup resulted in the lowest data variability and the highest test sensitivity. Each dose of the triple-acting agent was tested in groups of 5 to 8 rats. A vehicle group of 5 to 8 rats was included in each test set. Each cage housed three different treatment groups (to eliminate potential influence of the cage on the primary reading, food intake, e.g., cage malfunction). The rats were administered a single subcutaneous (sc) dose of the compound of interest in the vehicle or the vehicle itself using NovoPen® (Novo Nordisk, Bagsvaerd, Denmark), depending on body weight (10, 30, or 100 nmol / kg). The infusion volume was 0.5 mL / kg.

[1859] The compound of the present invention was formulated into the following vehicle: 8 mM phosphate; 250 mM glycerol; 0.007% polysorbate 20, pH 7.4.

[1860] After administration, the rats were returned to their original cages, where a 10% fat diet and water remained freely available. Food intake was continuously recorded using the HM2 system from 24 hours prior to the administration of the test substance (baseline) to 0–72 hours after the administration of the test compound. Data recorded and obtained by the HM2 system were stored in the HMBase SQL database (Firebird® relational database management system) and processed by HM2Lab software (MBRose; Faaborg, Denmark) installed on the onboard 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 records the number of feeding events defined as a decrease of 0.001 g of food within 5 seconds (detailed information on the system can be found in the literature of Rathod, YD and Di Fulvio, M. [(2021). The feeding microstructure of male and female mice. PLoS One 16, e0246569]). After the experimental session ended, the animals were euthanized.

[1861] Table 15 Figure [] represents the acute food intake in normal-weight (lean) rats based on the aforementioned protocol for efficacy testing on appetite. The results allowed for the evaluation of the in vivo effects on food intake and the determination of the duration of action of the compound. Data are expressed as the mean inhibition rate relative to the mean food intake within the vehicle group on each study day (Day 1 [0 to 24 hours], Day 2 [24 to 48 hours], and Day 3 [48 to 72 hours]), and food intake was administered to rats for up to 72 hours. The food intake on each study day (e.g., Day 1) refers to the cumulative food intake during that day (i.e., the 24-hour period).

[1862]

[1863] After administering the GLP-1 / GIP- / amylin-receptor triple agonists of the present invention to rats, it was observed that many of them induced significant inhibition of food intake compared to vehicle treatment, as can be inferred from the data presented in Table 15. Generally, Table 15 The compound was shown to have a similar or improved reduction in food intake compared to reference compound 1 as disclosed in WO 2023 / 288313 at a dosage level much lower than the disclosed dosage level of 50 nmol / kg of reference compound 1.

[1865] Example 6: Pharmacokinetic study in minipigs and rats

[1866] The purpose of this study is to investigate the in vivo half-life (t) of the GLP-1- / GIP- / amylin-receptor triple agonist of the present invention after intravenous (iv) administration to minipigs or rats. 1 / 2 ), that is, determining the residence time in the body and the resulting duration of action. This was performed in pharmacokinetic (PK) studies, where the final half-life (t) of the corresponding compound or derivative is determined. 1 / 2 ) was determined. The final half-life refers to the time it takes to reduce a specific plasma concentration by half during the final elimination phase and reflects the duration of the drug's action in the body.

[1868] Minipig Research

[1869] The female Göttingen minipigs obtained from Ellegaard Göttingen (Dalmose, Denmark) used in this study were approximately 8–12 months old and weighed approximately 20–30 kg. The minipigs (pigs fitted with permanent catheters) were housed individually in fences with straw bedding and fed Altromin 9023 minipig feed (Altromin Spezialfutter GmbH & Co. KG) once a day in a limited manner.

[1870] After 3 weeks of adaptation, two permanent central venous catheters were implanted behind the vena cava in each animal. After allowing the animals to recover for 10 days post-surgery, they were subsequently used in a repeated pharmacokinetic study with appropriate flushing periods between consecutive administrations.

[1871] The compound of the present invention was formulated into the following vehicle (40 nmol / ml): 8 mM phosphate; 250 mM glycerol; 0.007% polysorbate 20, pH 7.4.

[1872] Intravenous infusion of the derivative (0.05 ml / kg and 2 nmol / kg / volume corresponding to the dosage of the derivative) was performed through one catheter, and blood was sampled (preferably through another catheter) at a set time up to day 14 after administration.

[1873] Collect a blood sample (e.g., 1.3 ml) in an EDTA-coated tube (obtain 1.6 mg K3EDTA / ml blood using a 1.3 ml tube containing K3EDTA), then at 4°C and 2000 x g It was centrifuged for 10 minutes.

[1875] Sampling and Analysis

[1876] Plasma within 30 minutes of centrifugation was pipetted into a micronic tube and stored on dry ice. It was maintained at -20°C until the plasma concentration of the compound was analyzed using LCMS.

[1877] The plasma concentrations of the peptides of the present invention were determined by plasma protein precipitation and analyzed by LC-MS. Calibrators were prepared by spiking donor plasma from minipigs with test compounds in the conventional range of 0.05 to 200 nM. LLoQ was typically in the range of 0.2 to 2 nM. Four volumes of ethanol containing 20 nM of an internal standard (a structurally similar analog with different mass) were added to one volume of sample, and then centrifuged at 6200 rpm at 4°C for 10 minutes to prepare calibrators, plasma blanks, or study samples for LC-MS by protein precipitation. The supernatant was diluted with one volume of Milli-Q water containing 1% formic acid and injected into the LC-MS system. Individual plasma concentration-time profiles were analyzed using Phoenix v. Analysis was performed by non-compartment pharmacokinetics (NCA) in Section 6.4 (Pharsight Inc., Mountain View, CA, USA), and the generated terminal half-life (harmonic mean) was determined. LC-MS analysis was performed using a TurboFlow HPLC system from Thermo Fisher Scientific (Bremen, Germany) coupled to a Q Exactive Orbitrap or Altis Triple Quadrupole (TQ) mass spectrometer. The LC mobile phases 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. After using a TurboFlow Cyclone 0.5 x 100 mm column from Thermo Fischer Scientific (Bremen, Germany) for extraction, XBridge peptide BEH C18 was eluted on a 300 Å, 3.5 μm, 2.1 x 50 mm column, and both analyses were performed at 60°C.Typically, 40–45% B and 75–80% B were loaded onto a TurboFlow column and used for elution, respectively, followed by linear gradient elution of approximately 45% B to 85% B over 2.33 minutes on an analytical column. The Orbitrap mass spectrometer [recorded] 5 in the most abundant charge state of the compound with a resolution of 35K on the Orbitrap MS. m / z It was operated in positive ionization mode with a spray voltage of 4.0 kV using a parallel reaction monitoring scan mode with an isolation window. The TQ mass spectrometer was operated in positive ionization mode with a spray voltage of 4.0 kV using a single reaction monitoring scan mode with Q1 and Q3 resolutions of 1.2 (FWHM).

[1878] For all compounds, individual optimal fragmentation collision energies were discovered and used. Data were processed using the Quan Browser of Xcalibur software from Thermo Fisher Scientific (Bremen, Germany), and linear calibration curves (1 / x 2 Data was used to calculate concentrations in plasma samples by fitting the data to (weighted by ). Quality control samples were included. The deviation between the nominal concentration and the calculated concentration in the calibrator and quality control samples was less than 15%.

[1880] Rat study

[1881] Male Sprag Dowley rats (250–320 g) were obtained from Charles River (Germany) or Janvier Labs (France). Throughout the study, animals were housed two per cage with free access to a rodent diet (Altromin 1324) and water.

[1882] After a 12-day acclimatization period, a triple-acting compound formulated with 8 mM phosphate; 250 mM glycerol, pH 7.4 was administered by IV injection (50 nmol / 0.5 ml / kg), and blood was sampled at various predefined time points up to 72 hours after administration.

[1884] Sampling and Analysis

[1885] Blood samples (approx. 120 μl / sample) were collected in K3EDTA-coated vials and centrifuged at 2000 xg for 5 minutes at 4°C. Plasma samples (50–60 μl / sample) were transferred to micronic tubes, rapidly frozen, and stored at -20°C until the plasma concentration of the compound was analyzed using LC-MS. The plasma concentration of the peptide of the present invention was determined by plasma protein precipitation and analyzed by LC-MS. Calibrators were prepared by spiking donor plasma from rats with test compounds in the typical range of 0.5 to 2000 nM. The LLOQ was typically in the range of 0.5 to 1 nM. Six volumes of methanol containing 20 nM of an internal standard (a structurally similar analog with a different mass) were added to one volume of sample, and then centrifuged at 6400 rpm at 4°C for 10 minutes to prepare a calibrator, plasma blank, or study sample for LC-MS by protein precipitation. The supernatant was diluted with one volume of Milli-Q water containing 1% formic acid and injected into the LC-MS system. LC-MS analysis was performed using a TurboFlow or HPLC system from Thermo Fisher Scientific (Bremen, Germany) coupled to a Q Exactive Plus or Q Exactive HF Orbitrap mass spectrometer. The LC mobile phases 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; for 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. After using a TurboFlow Cyclone 0.5 x 100 mm column from Thermo Fischer Scientific (Bremen, Germany) for extraction, XBridge Peptide BEH C18 300 Å, 3.5 μm, 2.Analytical elution was performed on a 1 x 50 mm column, and both analyses were operated at 60°C. An Accucore 150-C4 analytical column (2.1 x 100 mm, 2.6 µM, Thermo Fischer Scientific) was used in the HPLC system. Generally, 20% B and 75% B were loaded and eluted onto a TurboFlow column, respectively, followed by linear gradient elution on the analytical column over 4 minutes, with a gradient of approximately 49% B to 89% B. The HPLC gradient ranged from 20% to 80% B. The Q Exactive Plus or Q Exactive HF Orbitrap mass spectrometers were operated in positive ionization mode using a spray voltage of 4.0 kV, and a Single Ion Monitoring (SIM) scan mode was used with a 5 m / z isolation window for the most abundant charge state of the corresponding compound; the resolutions of the mass spectrometers were 35 K and 60 K, respectively. Data were processed using the Quan Browser of Xcalibur software from Thermo Fisher Scientific (Bremen, Germany) and used to calculate concentrations in plasma samples by fitting the data to a linear calibration curve (weighted by 1 / x2). Quality control samples were included. The deviation between nominal and calculated concentrations in the calibrator and quality control samples was less than 15%.

[1887] result:

[1888]

[1889]

[1890] As shown in Table 16, the tested GLP-1- / GIP- / amylin-receptor triple agonist of the present invention has a very long half-life (t) of at least 14 hours in rats or at least 95 hours in minipigs. 1 / 2It has ). Based on the half-life measured in rats and minipigs, the half-life in humans is considered sufficient for administration at least once a week via liquid subcutaneous injection or at least once a day via oral tablet.

[1892] Example 7: Evaluation of chemical stability in the formulation

[1893] A test was performed to investigate the degree of in vitro chemical decomposition over time during incubation at 37℃ for a period of 2 weeks.

[1894] A peptide solution with a target concentration of 1 mg / mL was prepared by dissolving the freeze-dried powder in 8 mM phosphate buffer at pH 7.4. The pH of the peptide solution was adjusted to 7.4 using 0.02 M HCl or 0.02 M NaOH. The samples were loaded into Agilent HPLC vials containing fixed inserts. The vials were capped to prevent evaporation. The HPLC vials were incubated at 37°C, samples were extracted at different time points over a period of two weeks, flash-frozen at -80°C, and stored at -20°C until analysis.

[1895] Sample analysis was performed using a UPLC coupled to a UV detector at 215 nm and MS (UPLC-UV-MS). 1 μL of the sample was injected into a Waters Acquity UPLC using a flow-through-needle injection system and onto a Waters Acquity CSH C18 column (1 x 150 mm) with a particle size of 1.7 μm, maintained at 55°C. It was delivered at a flow rate of 100 μL / min using a binary solvent manager pump containing 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 for 0 to 2 minutes, followed by 20 to 50% B for 2 to 20 minutes (total run time 30 minutes). The identity of the peptide was confirmed by MS, the peak purity and area % from the UV signal at 215 nm were plotted against time, and the weekly purity loss was calculated using the slope from linear regression ( Table 17 ).

[1896]

[1897]

[1898]

[1899] All GLP-1- / GIP- / amylin-receptor triagonists tested in this study exhibit acceptable chemical stability with an acceptable degradation rate (less than 5% of purity loss per week) in aqueous buffer (37°C). Most of the tested GLP-1- / GIP- / amylin-receptor triagonists exhibit good chemical stability with a purity loss of less than 2.0% per week or much better chemical stability (less than 1.5% of purity loss per week). Therefore, the GLP-1- / GIP- / amylin-receptor triagonists of the present invention are considered to be chemically stable in solution.

[1901] Although certain features of the present invention have been illustrated and described herein, numerous variations, substitutions, modifications, and equivalents will now occur to those skilled in the art. Accordingly, it should be understood that the appended claims are intended to include all such modifications and modifications that fall within the true spirit of the invention.

Claims

Claim 1 GLP-1- / GIP- / amylin-receptor triple agonists selected from the following group: and Claim 2 A GLP-1- / GIP- / amylin-receptor triple agonist characterized as compound 105 in claim 1: Claim 3 A GLP-1- / GIP- / amylin-receptor triple agonist characterized as compound 107 in claim 1: Claim 4 A GLP-1- / GIP- / amylin-receptor triple agonist characterized as compound 113 in claim 1: Claim 5 A GLP-1- / GIP- / amylin-receptor triple agonist characterized as compound 183 in claim 1: Claim 6 A pharmaceutical composition for use in the treatment of type 2 diabetes, obesity, or metabolic dysfunction-associated steatohepatitis (MASH) in a subject, comprising a GLP-1- / GIP- / amylin-receptor triple agonist according to any one of claims 1 to 5 and one or more pharmaceutically acceptable excipients. Claim 7 A GLP-1- / GIP- / amylin-receptor triple agonist according to any one of claims 1 to 5 for use as a medicine. Claim 8 A pharmaceutical composition according to claim 6, characterized in that the subject has an initial body mass index (BMI) of 25 or higher, 27 or higher, 28 or higher, or 30 or higher. Claim 9 A pharmaceutical composition according to claim 6, characterized in that the subject has at least one weight-related comorbidity, and the weight-related comorbidity is selected from the group consisting of hypertension, dysglycemia, prediabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, and obstructive sleep apnea. Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete

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