Crf2 receptor agonists and their use in therapy

Abstract

This application provides compounds that are peptides comprising the amino acid sequence of formula (I) disclosed herein, or pharmaceutically acceptable salts thereof. These compounds function as agonists of corticotropin-releasing factor receptor 2 (CRF2) and can be used to treat, in particular, cardiovascular disease, obesity, and diabetes.

Description

Technical Field

[0001] This application relates to compounds that are corticotropin-releasing factor receptor 2 (CRF2) agonists and their use in treatment, particularly in the treatment or prevention of cardiovascular disease, obesity, and diabetes. Background Technology

[0002] Urocortin (UCN) is an endogenous peptide that acts through the corticotropin-releasing factor (CRF) receptor, a type 2 G protein-coupled receptor (GPCR). The CRF receptor family includes the CRF1 receptor encoded by the CRHR1 gene and the CRF2 receptor encoded by the CRHR2 gene.

[0003] Three known endogenous urocortins have been identified in mammals: UCN1, UCN2, and UCN3. Despite high sequence homology, these peptides bind differently to CRF1 and CRF2. CRF1 and CRF2 are nonselectively activated by CRH and UCN1, while UCN2 and UCN3 are selective agonists of CRF2. In particular, UCN2 is a 38-amino acid peptide that selectively activates CRF2 receptors, including known isotypes of CRF2-alpha (α), beta (β), and gamma (γ).

[0004] Urocortin and its receptors are involved in neurohumoral responses to various stresses and pathological conditions. In particular, urocortin induces positive hemodynamic effects in preclinical models and in patients with heart failure or hypertension. Urocortin and its CRF receptors are expressed in the heart and blood vessels, with CRF2 being strongly expressed and CRF1 minimally expressed if present (see Waser et al., Peptides, 2006, 27, 3029-3038). In experimental models, urocortin, acting via CRF2 activation, has been shown to improve cardiovascular function by reducing vascular resistance, as well as by exerting myocardial contractility and relaxation effects. In clinical studies, UCN2 and UCN3 have been shown to have direct vasodilatory effects in healthy volunteers and in patients with heart failure (see Stirrat et al., Br. J. Clin. Pharmacol., 2016, 82, 974-982), while UCN2 has been shown to increase cardiac output and reduce vascular resistance in patients with heart failure (see Davis et al., Eur. Heart J., 2007, 28, 2589-2597; and Chan et al., JACC: Heart Failure, 2013, 1, 433-441). Recombinant acetate of UCN3 has been shown to improve cardiac output and reduce vascular resistance in multicenter studies in patients with chronic stable heart failure (see Gheorghiade et al., Eur. J. Heart Fail., 2013, 15, 679-89).

[0005] Recent studies have demonstrated that UCN2 and / or UCN3 gene transfer in mice not only improves cardiac function but also glucose handling (see Giamouridis et al., JACC: Basic to Translational Science, 2018, 3, 2). Furthermore, subcutaneous delivery of PEGylated UCN2 has been shown to improve glucose tolerance and increase glucose uptake in skeletal muscle, while simultaneously reducing body weight through food restriction (see Borg et al., Diabetes, 2019, 1403-1414). These findings suggest that urinary corticosteroids may be used not only to treat cardiovascular diseases but also conditions such as diabetes and obesity.

[0006] However, the extremely short half-life of urocorticin remains a major limitation to its therapeutic use (see Davies et al., JACC, 2007, 49, 461-471). To date, treatment with urocorticin has been unsustainable without long-term intravenous infusion. However, the management of patients with chronic diabetes or heart failure requires treatment suitable for long-term, home-based self-administration.

[0007] To overcome these limitations, various urocorticin analogues have been proposed. For example, WO2018013803 (Alsina-Fernandez; Eli Lilly and Company) discloses an analogue of UCN2, which is taught for use in the treatment of diseases such as chronic kidney disease and type II diabetes.

[0008] However, there remains a need for improved CRF2 receptor agonists for use as therapeutic agents, particularly in the treatment and prevention of cardiovascular disease, obesity, and diabetes. Specifically, there is a need for CRF2 agonists with desirable efficacy, pharmacokinetic properties (e.g., improved half-life), and / or physicochemical properties (e.g., improved stability and / or solubility). Invention Overview

[0010] In a first aspect, this application provides a compound that is a peptide comprising the amino acid sequence (SEQ ID NO: 186) of formula (I):

[0011] X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X 21-X22-X23-X24-X25-X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38(I)

[0012] in

[0013] X1 is either isoleucine (I) or phenylalanine (F);

[0014] X2 is either valine (V) or threonine (T);

[0015] X3 is leucine (L);

[0016] X4 is serine (S);

[0017] X5 is leucine (L);

[0018] X6 is aspartic acid (D);

[0019] X7 is either valine (V) or D-valine (V);

[0020] X8 is proline (P);

[0021] X9 is either isoleucine (I) or threonine (T);

[0022] X10 is lysine (K), glutamic acid (E), histidine (H), or glycine (G);

[0023] X11 is either isoleucine (I) or leucine (L);

[0024] X12 is lysine (K), in which the ε-amino group of the lysine side chain is covalently bound to the albumin binding portion;

[0025] X13 is either glutamine (Q) or lysine (K);

[0026] X14 is isoleucine (I), lysine (K), or 2-aminoisobutyric acid (Aib);

[0027] X15 is leucine (L);

[0028] X16 is either leucine (L) or phenylalanine (F);

[0029] X17 is either glutamic acid (E) or lysine (K);

[0030] X18 is glutamine (Q);

[0031] X19 is alanine (A), glutamic acid (E), or glutamine (Q);

[0032] X20 is either lysine (K) or arginine (R);

[0033] X21 is either glutamine (Q) or lysine (K);

[0034] X22 is lysine (K), arginine (R), or glutamic acid (E);

[0035] X23 is either lysine (K) or 2-aminoisobutyric acid (Aib);

[0036] X24 is glutamine (Q), 2-aminoisobutyric acid (Aib), leucine (L), or glutamic acid (E);

[0037] X25 is arginine (R), lysine (K), or 2-aminoisobutyric acid (Aib);

[0038] X26 can be alanine (A), glutamic acid (E), 2-aminoisobutyric acid (Aib), or glutamine (Q);

[0039] X27 is glutamine (Q), 2-aminoisobutyric acid (Aib), or lysine (K);

[0040] X28 is alanine (A);

[0041] X29 is either glutamic acid (E) or lysine (K);

[0042] X30 is either lysine (K) or threonine (T);

[0043] X31 is either asparagine (N) or alanine (A);

[0044] X32 is lysine (K), alanine (A), valine (V), threonine (T), glutamic acid (E), or 2-aminoisobutyric acid (Aib);

[0045] X33 is arginine (R), lysine (K), or glutamine (Q);

[0046] X34 is either isoleucine (I) or leucine (L);

[0047] X35 is leucine (L);

[0048] X36 is either alanine (A) or glutamic acid (E);

[0049] X37 is either glutamine (Q) or arginine (R); and

[0050] X38 is either isoleucine (I) or valine (V);

[0051] Or its pharmaceutically acceptable salt.

[0052] In a second aspect of this application, a pharmaceutical composition is provided comprising the compound of this application and a pharmaceutically acceptable excipient, diluent, or carrier.

[0053] The compounds and pharmaceutical compositions disclosed herein are useful in treatment and can be used to treat or prevent various diseases by activating the CRF2 receptor. Therefore, in other respects, this application relates to the use of the compounds and pharmaceutical compositions in treatment, particularly in the treatment or prevention of cardiovascular diseases, obesity, diabetes, sarcopenia, muscular dystrophy, kidney disease, pulmonary hypertension, peripheral artery disease, inflammation, allergic reactions, and tissue ischemia; especially in the treatment or prevention of cardiovascular diseases, obesity, and diabetes, particularly including heart failure.

[0054] Brief description of the attached figures

[0055] Figure 1 This is a graph depicting food intake in C57BL / 6N mice (DIO) fed a high-fat diet throughout the administration period, with subcutaneous treatment every other day using the compound of SEQ ID NO:35 (black circle), the reference compound (gray circle), or the mediator (white circle). The x-axis represents the study day, and the y-axis represents food intake (in grams). Values ​​are expressed as mean ± standard error of the mean (SEM).

[0056] Figure 2This is a graph depicting the relative body weight change of C57BL / 6N mice (DIO) fed a high-fat diet throughout the administration period, with the mice subcutaneously treated with the compound of SEQ ID NO:35 (black circle), the reference compound (gray circle), or the mediator (white circle). The x-axis represents the study day, and the y-axis represents the relative body weight change (in %). Values ​​are expressed as mean ± SEM.

[0057] Figure 3 : A representative sequence of a peptide having an optimized stability profile according to the present invention, wherein K[sema] represents K[gGlu-C(O)(CH2). 14 CH3].

[0058] Detailed description

[0059] This application relates to compounds that are UCN2 derivatives and can be used as CRF2 receptor agonists. These compounds exhibit desirable activity and selectivity at the CRF2 receptor, particularly relative to the CRF1 receptor, and demonstrate improved pharmacokinetic properties and beneficial in vivo effects in relevant animal models. Furthermore, these compounds exhibit desirable physicochemical properties, such as ideal solubility and stability, making them excellent candidates for subcutaneous solution formulations. These compounds are useful in treatment, particularly in the treatment or prevention of cardiovascular disease, obesity, diabetes, sarcopenia, muscular dystrophy, kidney disease, pulmonary hypertension, peripheral artery disease, inflammation, allergic reactions, and tissue ischemia; especially in the treatment or prevention of cardiovascular disease, obesity, and diabetes, including heart failure.

[0060] compound

[0061] The compounds of this application are peptides comprising the amino acid sequence of formula (I) above or pharmaceutically acceptable salts of said peptides.

[0062] In this application, amino acids are referred to by their names, their commonly known three-letter symbols, or single-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Committee. Other generally accepted three-letter codes for amino acids may also be used, such as Aib for 2-aminoisobutyric acid. Unless otherwise stated, all amino acids used in the compounds of this application are L-amino acids. Thus, for example, L-valine is referred to as "valine," "V," or "Val," while D-valine is specifically identified as such.

[0063] In one embodiment, X1 is isoleucine (I).

[0064] In one implementation, X2 is valine (V).

[0065] In one implementation, X9 is isoleucine (I).

[0066] In one embodiment, X10 is lysine (K) or glycine (G).

[0067] In one embodiment, X11 is leucine (L).

[0068] In one embodiment, X14 is isoleucine (I).

[0069] In one implementation, X16 is leucine (L).

[0070] In one embodiment, X19 is alanine (A) or glutamic acid (E).

[0071] In one implementation, X21 is glutamine (Q).

[0072] In one implementation, X22 is lysine (K).

[0073] In one embodiment, X24 is glutamine (Q) or 2-aminoisobutyric acid (Aib).

[0074] In one implementation, X25 is arginine (R).

[0075] In one embodiment, X26 is alanine (A), glutamic acid (E), or glutamine (Q).

[0076] In one implementation, X27 is glutamine (Q).

[0077] In one implementation, X29 is glutamic acid (E).

[0078] In one embodiment, X31 is asparagine (N).

[0079] In one implementation, X32 is lysine (K).

[0080] In one implementation, X33 is arginine (R) or glutamine (Q).

[0081] In one embodiment, X34 is isoleucine (I).

[0082] In one implementation, X35 is leucine (L).

[0083] In one implementation, X38 is valine (V).

[0084] In one embodiment, the amino acid residue at X38 is amidated.

[0085] In one implementation, the amino acid residue at X1 is acetylated.

[0086] In one implementation scheme:

[0087] X1 is isoleucine (I);

[0088] X2 is valine (V);

[0089] X9 is isoleucine (I);

[0090] X10 is either lysine (K) or glycine (G);

[0091] X11 is leucine (L);

[0092] X14 is isoleucine (I);

[0093] X16 is leucine (L);

[0094] X19 is either alanine (A) or glutamic acid (E);

[0095] X21 is glutamine (Q);

[0096] X22 is lysine (K);

[0097] X24 is either glutamine (Q) or 2-aminoisobutyric acid (Aib);

[0098] X25 is arginine (R);

[0099] X26 is alanine (A), glutamic acid (E), or glutamine (Q); X27 is glutamine (Q);

[0100] X29 is glutamic acid (E);

[0101] X31 is asparagine (N);

[0102] X32 is lysine (K);

[0103] X33 is either arginine (R) or glutamine (Q);

[0104] X34 is isoleucine (I);

[0105] X35 is leucine (L); and

[0106] X38 is valine (V).

[0107] In one implementation scheme:

[0108] X10 is lysine (K);

[0109] X19 is glutamic acid (E);

[0110] X24 is glutamine (Q); and

[0111] X26 is glutamic acid (E).

[0112] In one implementation scheme:

[0113] X33 is glutamine (Q); and

[0114] X37 is glutamine (Q).

[0115] In one implementation scheme:

[0116] X1 is isoleucine (I);

[0117] X2 is valine (V);

[0118] X9 is isoleucine (I);

[0119] X10 is lysine (K);

[0120] X11 is leucine (L);

[0121] X14 is isoleucine (I);

[0122] X16 is leucine (L);

[0123] X19 is glutamic acid (E);

[0124] X21 is glutamine (Q);

[0125] X22 is lysine (K);

[0126] X24 is glutamine (Q);

[0127] X25 is arginine (R);

[0128] X26 is glutamic acid (E);

[0129] X27 is glutamine (Q);

[0130] X29 is glutamic acid (E);

[0131] X31 is asparagine (N);

[0132] X32 is lysine (K);

[0133] X33 is glutamine (Q);

[0134] X34 is isoleucine (I);

[0135] X35 is leucine (L);

[0136] X37 is glutamine (Q); and

[0137] X38 is valine (V).

[0138] As described above, the compounds of the present invention contain a modified lysine (K) residue at position X12 in formula (I), wherein the albumin-binding portion is covalently bound to the ε-amino group of the lysine side chain.

[0139] As used herein, the term "albumin-binding moiety" refers to a portion capable of binding to albumin via covalent or nonvalent binding. In embodiments, the albumin-binding moiety is capable of binding to albumin via nonvalent binding. The albumin-binding moiety may comprise or consist of a subset selected from the group consisting of fatty acids, phthalocyanines, coumarins, flavonoids, tetracyclines, naphthalene, aryl carboxylic acids, heteroaryl carboxylic acids, lipids, alkylamines, cyclic or linear tetrapyrroles and their organometallic compounds, halogen-substituted aromatic acid derivatives, organic dyes, and derivatives of tryptophan and thyroxine.

[0140] In a particular embodiment, the albumin-binding moiety comprises a C14-C24 fatty acid group, which is conjugated to the ε-amino group of the lysine side chain via a direct bond or linker. As used herein, the term "C14-C24 fatty acid" refers to a carboxylic acid having 14 to 24 carbon atoms. The C14-C24 fatty acid may be a saturated monocarboxylic acid or a saturated diacid. "Saturated" means that the fatty acid does not contain carbon-carbon double bonds or carbon-carbon triple bonds.

[0141] Examples of saturated C14-C24 fatty acids include myristic acid (tetradecanoic acid; C14 monocarboxylic acid), tetradecanoic acid (C14 diacid), pentadecanoic acid (pentadecanoic acid; C15 monocarboxylic acid), pentadecanoic acid (C15 diacid), palmitic acid (hexadecanoic acid; C16 monocarboxylic acid), hexadecanoic acid (C16 diacid), heptadecanoic acid (heptadecanoic acid; C17 monocarboxylic acid), heptadecanoic acid (C17 diacid), stearic acid (octadecanoic acid; C18 monocarboxylic acid), octadecanoic acid (C18 diacid), nonadecanoic acid (nonadecanoic acid; C19 monocarboxylic acid), nonadecanoic acid (C19 diacid), arachadic acid (eicosanoic acid; C20 monocarboxylic acid), eicosanoic acid (C20 diacid), and heneicosylic acid. acid) (eicosanoic acid; C21 monobasic acid), behenic acid (C21 dibasic acid), behenic acid (behenic acid; C22 monobasic acid), behenic acid (C22 dibasic acid), lignoceric acid (tetracosanoic acid; C24 monobasic acid), tricosanoic acid (C23 monobasic acid), tricosanoic acid (C23 dibasic acid) and tetracosanedioic acid (C24 dibasic acid).

[0142] In one embodiment, the C14-C24 fatty acid group is selected from palmitic acid (hexadecanoic acid; C16 monocarboxylic acid), hexadecanoic acid (C16 diacid), stearic acid (octadecanoic acid; C18 monocarboxylic acid), octadecanoic acid (C18 diacid), arachidic acid (eicosanoic acid; C20 monocarboxylic acid) and eicosanoic acid (C20 diacid).

[0143] The C14-C24 fatty acid can be directly bound to the ε-amino group of the lysine side chain. Alternatively, the C14-C24 fatty acid can be bound to the ε-amino group of the lysine side chain via a linker. The linker may comprise one or more groups selected from the following: [2-(2-aminoethoxy)ethoxy]acetyl (hereinafter referred to as "AEEA"), glycine (Gly), N-methylglycine (N-MeGly), 3-[2-[2-[2-[2-(2-aminoethoxy)-ethoxy]-ethoxy]-ethoxy]-propionic acid (CAS No. 663921-15-1, also known as amino-PEG4-acid or (PEO)4-aminopropionic acid), amino-PEG6-acid (CAS No. 905954-28-1), amino-PEG8-acid (CAS No. 756526-04-2), and γ-glutamic acid (gGlu); particularly selected from AEEA, Gly, N-MeGly, and gGlu; more particularly selected from AEEA and gGlu.

[0144] In one embodiment, the albumin-binding moiety is a group of formula (II):

[0145] -Z 1 -YZ 2 -C(O)R 1 (II)

[0146] in

[0147] Y is AEEA, {AEEA}2, {AEEA}3, Gly, {Gly}2, {Gly}3, N-MeGly, {N-MeGly}2, {N-MeGly}3 or does not exist;

[0148] Z 1 and Z 2 Each is independently selected from gGlu, {gGlu}2, {gGlu}3, {gGlu}4, or does not exist; and

[0149] R 1 -(CH2) x COOH or -(CH2) x CH3; specifically -(CH2) x COOH, where x is an integer from 12 to 22.

[0150] In one implementation scheme, Z 1 It does not exist, Y is {AEEA}2 and Z 2 It is gGlu or {gGlu}2.

[0151] In one implementation scheme, Z 1 Y is gGlu or {gGlu}2, and Z is {AEEA}2. 2 It is gGlu or {gGlu}2.

[0152] In one implementation scheme, Z 1 It does not exist, Y does not exist and Z does not exist. 2 It is gGlu or {gGlu}2.

[0153] In one implementation, Y and Z 1 and Z 2 None of them exist.

[0154] Surprisingly, and as is evident from the examples below, albumin-binding moieties containing free carboxylic acid exhibit improved CRF2 selectivity. Therefore, in certain embodiments, R 1 -(CH2) x COOH, where x is 14, 16, or 18; particularly 16 or 18; even more particularly 14 or 16; and even more particularly 14.

[0155] In one implementation, R 1 -(CH2) x CH3, where x is 14, 16 or 18; in particular 14 and 16.

[0156] In one embodiment, the albumin-binding moiety is selected from the following groups:

[0157] -(gGlu) n＝1-4 -C(O)(CH2) 14 CH3

[0158] -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH

[0159] -(gGlu) n＝1-4 -C(O)(CH2) 16 CH3

[0160] -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH

[0161] -(gGlu) n＝1-4 -C(O)(CH2) 18CH3

[0162] -(gGlu) n＝1-4 -C(O)(CH2) 18 COOH

[0163] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 14 CH3

[0164] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH

[0165] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 16 CH3

[0166] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH

[0167] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 18 CH3

[0168] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 18 COOH

[0169] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4- C(O)(CH2) 14 CH3

[0170] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH

[0171] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 16 CH3

[0172] -(gGlu)n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH

[0173] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 18 CH3

[0174] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 18 COOH

[0175] In one embodiment, the albumin-binding moiety is selected from the following groups:

[0176] -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH

[0177] -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH

[0178] -(gGlu) n＝1-4 -C(O)(CH2) 18 COOH

[0179] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH

[0180] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH

[0181] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 18 COOH

[0182] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH

[0183] -(gGlu)n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH

[0184] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 18 COOH

[0185] In one embodiment, the albumin-binding moiety is selected from the following groups:

[0186] -{AEEA}2-gGlu-C(O)(CH2) 16 COOH;

[0187] -{AEEA}2-gGlu-C(O)(CH2) 18 COOH;

[0188] -{AEEA}2-{gGlu}2-C(O)(CH2) 16 COOH;

[0189] -{AEEA}2-{gGlu}2-C(O)(CH2) 18 COOH;

[0190] -C(O)(CH2) 16 COOH;

[0191] -gGlu-C(O)(CH2) 16 COOH;

[0192] -gGlu-C(O)(CH2) 14 CH3;

[0193] -gGlu-C(O)(CH2) 14 COOH;

[0194] -{AEEA}2-gGlu-C(O)(CH2) 14 COOH;

[0195] -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH;

[0196] -{AEEA}2-gGlu-C(O)(CH2) 14 CH3; and

[0197] -{AEEA}2-{gGlu}2-C(O)(CH2) 14 CH3.

[0198] In one embodiment, the albumin-binding moiety is selected from the following groups:

[0199] -{AEEA}2-gGlu-C(O)(CH2) 16 COOH;

[0200] -{AEEA}2-gGlu-C(O)(CH2) 18 COOH;

[0201] -{AEEA}2-{gGlu}2-C(O)(CH2) 16 COOH;

[0202] -{AEEA}2-{gGlu}2-C(O)(CH2) 18 COOH;

[0203] -C(O)(CH2) 16 COOH;

[0204] -gGlu-C(O)(CH2) 16 COOH;

[0205] -gGlu-C(O)(CH2) 14 COOH;

[0206] -{AEEA}2-gGlu-C(O)(CH2) 14 COOH; and

[0207] -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH.

[0208] In one embodiment, the albumin-binding moiety is selected from the following groups:

[0209] -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH;

[0210] -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH;

[0211] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH;

[0212] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH;

[0213] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH; and

[0214] -(gGlu) n＝1-4 -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 16 COOH.

[0215] In one embodiment, the albumin-binding moiety is selected from the following groups:

[0216] -{AEEA}2-gGlu-C(O)(CH2) 16 COOH;

[0217] -{AEEA}2-gGlu-C(O)(CH2) 14 COOH;

[0218] -{AEEA}2-{gGlu}2-C(O)(CH2) 16 COOH;

[0219] -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH;

[0220] -C(O)(CH2) 16 COOH;

[0221] -C(O)(CH2) 14 COOH;

[0222] -gGlu-C(O)(CH2) 16 COOH; and

[0223] -gGlu-C(O)(CH2) 14 COOH.

[0224] In one embodiment, the albumin-binding moiety is selected from the following groups:

[0225] -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH;

[0226] -(AEEA) n＝1,2 -(gGlu) n＝1-4 -C(O)(CH2) 14 COOH; and

[0227] -(gGlu) n＝1-4 -(AEEA) n＝1,2 --(gGlu) n＝1-4 -C(O)(CH2) 14 COOH.

[0228] In one embodiment, the albumin-binding moiety is selected from the following groups:

[0229] -{AEEA}2-gGlu-C(O)(CH2) 14 COOH;

[0230] -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH;

[0231] -C(O)(CH2) 14 COOH; and

[0232] -gGlu-C(O)(CH2) 14 COOH.

[0233] In one embodiment, the albumin-binding moiety is -{AEEA}2-gGlu-C(O)(CH2). 14 COOH; or -{AEEA}2-gGlu-C(O)(CH2) 16 COOH.

[0234] Table 1 below shows the chemical structures and IUPAC names of these groups, where R indicates the ε-amino group of each group at the lysine residue at X12:

[0235]

[0236]

[0237]

[0238]

[0239]

[0240] In a specific embodiment, the albumin-binding moiety is -{AEEA}2-gGlu-C(O)(CH2). 16 COOH, -{AEEA}2-gGlu-C(O)(CH2)14 COOH or -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH. In a more specific embodiment, the albumin-binding moiety is -{AEEA}2-gGlu-C(O)(CH2). 16 COOH.

[0241] In one embodiment, the compound is a peptide comprising any of the amino acid sequences of SEQ ID NO 1 to 227 or a pharmaceutically acceptable salt thereof.

[0242] In one embodiment, the compound is a peptide comprising any amino acid sequence of SEQ ID No. 3, 7, 35, 83, 130, 135, 136, 137, 138, 139, 140, 141, 142, 147, 149, 151, 152, 171, 172, 173, and 174, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is a peptide comprising any amino acid sequence of SEQ ID No. 35, 130, 135, 137, 140, 142, 149, 151, and 152. In one embodiment, the compound is a peptide comprising any amino acid sequence of SEQ ID No. 35, 130, 83, 135, 136, 137, 138, 139, 147, 151, and 174. In a further embodiment, the compound is a peptide or a pharmaceutically acceptable salt thereof comprising any of the amino acid sequences of SEQ ID No 35, 130, 135, 137, 138, 139, 140, 141, 142, 149, 151 and 152.

[0243] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I), optionally wherein the amino acid residue at X1 is acetylated and optionally wherein the amino acid residue at X38 is amidated; or a pharmaceutically acceptable salt thereof.

[0244] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof; wherein:

[0245] X1 is isoleucine (I);

[0246] X2 is valine (V);

[0247] X7 represents either valine (V) or D-valine (V).

[0248] X9 is either isoleucine (I) or threonine (T); specifically, isoleucine (I);

[0249] X10 is either lysine (K) or glycine (G);

[0250] X11 is leucine (L);

[0251] X13 is either lysine (K) or glutamine (Q);

[0252] X14 is either lysine (K) or isoleucine (I); specifically, isoleucine (I).

[0253] X16 is leucine (L);

[0254] X19 is either alanine (A) or glutamic acid (E);

[0255] X21 is glutamine (Q);

[0256] X22 is glutamic acid (E), arginine (R), or lysine (K); particularly arginine (R) or lysine (K); even more particularly lysine (K);

[0257] X23 is lysine (K) or 2-aminoisobutyric acid (Aib); specifically lysine (K);

[0258] X24 is glutamic acid (E), glutamine (Q), or 2-aminoisobutyric acid (Aib); particularly glutamine (Q) or 2-aminoisobutyric acid (Aib);

[0259] X25 is either lysine (K) or arginine (R); specifically, arginine (R).

[0260] X26 is alanine (A), glutamic acid (E), or glutamine (Q); particularly glutamic acid (E) or glutamine (Q);

[0261] X27 is lysine (K) or glutamine (Q); particularly lysine (K) or glutamine (Q); even more particularly glutamine (Q);

[0262] X29 is glutamic acid (E);

[0263] X30 is either lysine (K) or threonine (T); specifically, lysine (K).

[0264] X31 is asparagine (N);

[0265] X32 is either lysine (K) or alanine (A); specifically, lysine (K).

[0266] X33 is either arginine (R) or glutamine (Q);

[0267] X34 is isoleucine (I);

[0268] X35 is leucine (L);

[0269] X36 is either alanine (A) or glutamic acid (E); specifically, glutamic acid (E);

[0270] X37 is arginine (R) or glutamine (Q); particularly glutamine (Q); and

[0271] X38 is valine (V);

[0272] Optionally, the amino acid residue at X1 is acetylated, and optionally, the amino acid residue at X38 is amidated.

[0273] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof; wherein:

[0274] X1 is isoleucine (I);

[0275] X2 is valine (V);

[0276] X7 is D-valine (v);

[0277] X9 is isoleucine (I);

[0278] X10 is either lysine (K) or glycine (G);

[0279] X11 is leucine (L);

[0280] X13 is glutamine (Q);

[0281] X14 is isoleucine (I);

[0282] X16 is leucine (L);

[0283] X19 is either alanine (A) or glutamic acid (E);

[0284] X21 is glutamine (Q);

[0285] X22 is lysine (K);

[0286] X23 is either lysine (K) or 2-aminoisobutyric acid (Aib);

[0287] X24 is either glutamine (Q) or 2-aminoisobutyric acid (Aib);

[0288] X25 is arginine (R);

[0289] X26 is either glutamic acid (E), glutamine (Q), or alanine (A);

[0290] X27 is either lysine (K) or glutamine (Q); specifically, glutamine (Q).

[0291] X29 is glutamic acid (E);

[0292] X30 is either lysine (K) or threonine (T);

[0293] X31 is asparagine (N);

[0294] X32 is lysine (K);

[0295] X33 is either arginine (R) or glutamine (Q);

[0296] X34 is isoleucine (I);

[0297] X35 is leucine (L);

[0298] X36 is either glutamic acid (E) or alanine (A);

[0299] X37 is either glutamine (Q) or arginine (R);

[0300] X38 is valine (V);

[0301] Optionally, the amino acid residue at X1 is acetylated, and optionally, the amino acid residue at X38 is amidated.

[0302] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof; wherein:

[0303] X1 is isoleucine (I);

[0304] X2 is valine (V);

[0305] X9 is isoleucine (I);

[0306] X10 is lysine (K);

[0307] X11 is leucine (L);

[0308] X14 is isoleucine (I);

[0309] X16 is leucine (L);

[0310] X19 is glutamic acid (E);

[0311] X21 is glutamine (Q);

[0312] X22 is lysine (K);

[0313] X24 is glutamine (Q);

[0314] X25 is arginine (R);

[0315] X26 is glutamic acid (E);

[0316] X27 is glutamine (Q);

[0317] X29 is glutamic acid (E);

[0318] X31 is asparagine (N);

[0319] X32 is lysine (K);

[0320] X33 is glutamine (Q);

[0321] X34 is isoleucine (I);

[0322] X35 is leucine (L);

[0323] X37 is glutamine (Q); and

[0324] X38 is valine (V);

[0325] Optionally, the amino acid residue at X1 is acetylated, and optionally, the amino acid residue at X38 is amidated.

[0326] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof; wherein:

[0327] X7 is D-valine (V);

[0328] X10 is lysine;

[0329] X19 is glutamic acid (E);

[0330] X24 is glutamine (Q);

[0331] X25 is arginine (R);

[0332] X26 is glutamic acid (E);

[0333] X27 is glutamine (Q).

[0334] X30 is lysine (K);

[0335] X33 is glutamine (Q);

[0336] X36 is alanine (A);

[0337] X37 is glutamine (Q);

[0338] Optionally, the amino acid residue at X1 is acetylated, and optionally, the amino acid residue at X38 is amidated.

[0339] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof; wherein the amino acid residue at X38 is amidated to a primary amide.

[0340] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof; wherein:

[0341] X1 is isoleucine (I);

[0342] X2 is valine (V);

[0343] X9 is isoleucine (I);

[0344] X10 is either lysine (K) or glycine (G);

[0345] X11 is leucine (L);

[0346] X14 is isoleucine (I);

[0347] X16 is leucine (L);

[0348] X19 is either alanine (A) or glutamic acid (E);

[0349] X21 is glutamine (Q);

[0350] X22 is lysine (K);

[0351] X24 is either glutamine (Q) or 2-aminoisobutyric acid (Aib);

[0352] X25 is arginine (R);

[0353] X26 is alanine (A), glutamic acid (E), or glutamine (Q);

[0354] X27 is glutamine (Q);

[0355] X29 is glutamic acid (E);

[0356] X31 is asparagine (N);

[0357] X32 is lysine (K);

[0358] X33 is either arginine (R) or glutamine (Q);

[0359] X34 is isoleucine (I);

[0360] X35 is leucine (L); and

[0361] X38 is valine (V);

[0362] Furthermore, the amino acid residue at X38 is amidated to a primary amide.

[0363] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof; wherein:

[0364] X1 is isoleucine (I);

[0365] X2 is valine (V);

[0366] X9 is isoleucine (I);

[0367] X10 is lysine (K), glutamic acid (E), or glycine (G);

[0368] X11 is leucine (L);

[0369] X14 is isoleucine (I);

[0370] X15 is leucine (L).

[0371] X16 is leucine (L);

[0372] X19 is either alanine (A) or glutamic acid (E); specifically, glutamic acid (E).

[0373] X21 is glutamine (Q);

[0374] X22 is either lysine (K) or glutamic acid (E);

[0375] X23 is 2-aminoisobutyric acid (Aib);

[0376] X24 is glutamine (Q);

[0377] X25 is arginine (R);

[0378] X26 is glutamic acid (E);

[0379] X27 is glutamine (Q);

[0380] X29 is glutamic acid (E);

[0381] X31 is asparagine (N);

[0382] X32 is either lysine (K) or glutamic acid (E); specifically, glutamic acid (E).

[0383] X33 is glutamine (Q);

[0384] X34 is isoleucine (I);

[0385] X35 is leucine (L); and

[0386] X38 is valine (V);

[0387] Furthermore, the amino acid residue at X1 is acetylated, and the amino acid residue at X38 is amidated to a primary amide.

[0388] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof; wherein:

[0389] X1 is isoleucine (I);

[0390] X2 is valine (V);

[0391] X9 is isoleucine (I);

[0392] X10 is lysine (K);

[0393] X11 is leucine (L);

[0394] X14 is isoleucine (I);

[0395] X16 is leucine (L);

[0396] X19 is glutamic acid (E);

[0397] X21 is glutamine (Q);

[0398] X22 is lysine (K);

[0399] X24 is glutamine (Q);

[0400] X25 is arginine (R);

[0401] X26 is glutamic acid (E);

[0402] X27 is glutamine (Q);

[0403] X29 is glutamic acid (E);

[0404] X31 is asparagine (N);

[0405] X32 is lysine (K);

[0406] X33 is glutamine (Q);

[0407] X34 is isoleucine (I);

[0408] X35 is leucine (L);

[0409] X37 is glutamine (Q); and

[0410] X38 is valine (V);

[0411] Furthermore, the amino acid residue at X38 is amidated to a primary amide.

[0412] In one embodiment, the compound is a peptide of any one of SEQ ID NO 1 to 227 or a pharmaceutically acceptable salt thereof. These peptides are listed in Table 2 below, where K* represents a lysine residue modified at X12, and R... a This indicates the albumin-binding region, where Ac- indicates N-terminal acetylation and -NH2 indicates that the C-terminal amino acid residue is amidated to a primary amide.

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:7):

[0426] IVLSLDvPTKLK*QKLLKQERQRKEREQAEKNARILARV-NH2

[0427] in

[0428] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain interacts with -gGlu-C(O)(CH2). 14 COOH covalently bonded; and

[0429] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0430] Or its pharmaceutically acceptable salt.

[0431] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:32):

[0432] IVLSLDvPTKLK*QKLLKQERQRKEREQAEKNVRILERV-NH2

[0433] in

[0434] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain interacts with -gGlu-C(O)(CH2). 14 COOH covalently bonded; and

[0435] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0436] Or its pharmaceutically acceptable salt.

[0437] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:35):

[0438] IVLSLDVPIKLK*KILLEQEKQKKQREQAETNKQILAQV-NH2

[0439] in

[0440] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain interacts with -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0441] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0442] Or its pharmaceutically acceptable salt.

[0443] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:83):

[0444] IVLSLDvPIGLK*QILLKQERQKKAibREQAETNKRILERV-NH2

[0445] in

[0446] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is selected from -gGlu-C(O)(CH2). 14 COOH and -gGlu-C(O)(CH2) 14 CH3 is covalently bound to the albumin-binding portion; and

[0447] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0448] Or its pharmaceutically acceptable salt.

[0449] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:130):

[0450] IVLSLDvPIKLK*QILLKQERQKAibQREQAEKNKQILAQV-NH2

[0451] in

[0452] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is covalently bound to an albumin-binding moiety selected from: -{AEEA}2-gGlu-C(O)(CH2). 16 COOH, -gGlu-C(O)(CH2) 14 COOH, -{AEEA}2-gGlu-C(O)(CH2) 14 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 14 CH3、-{AEEA}2-gGlu-C(O)(CH2) 14 CH3 and -{AEEA}2-{gGlu}2-C(O)(CH2) 14 CH3, particularly with -{AEEA}2-gGlu-C(O)(CH2) 16 COOH covalently bonded; and

[0453] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0454] Or its pharmaceutically acceptable salt.

[0455] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:135):

[0456] IVLSLDvPIKLK*QILLKQERQKAibQRQQAEKNKQILAQV-NH2

[0457] in

[0458] The K residue at position 12 (denoted as K*) is chemically modified such that the ε-amino group of its side chain is selected from -{AEEA}2-gGlu-C(O)(CH2). 16COOH and -gGlu-C(O)(CH2) 14 The albumin-binding portion of COOH is covalently bound, particularly to -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0459] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0460] Or its pharmaceutically acceptable salt.

[0461] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO: 136):

[0462] IVLSLDvPIKLK*QILLKQERQKKAibRQKAEKNKQILAQV-NH2

[0463] in

[0464] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is covalently bound to an albumin-binding moiety selected from: -gGlu-C(O)(CH2). 14 COOH, -{AEEA}2-gGlu-C(O)(CH2) 14 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 14 CH3、-{AEEA}2-gGlu-C(O)(CH2) 14 CH3 and -{AEEA}2-{gGlu}2-C(O)(CH2) 14 CH3; and

[0465] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0466] Or its pharmaceutically acceptable salt.

[0467] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:137):

[0468] IVLSLDvPIKLK*QILLKQERQKKQREQAEKNKQILEQV-NH2

[0469] in

[0470] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is selected from -gGlu-C(O)(CH2). 14COOH, -gGlu-C(O)(CH2) 14 CH3 and -{AEEA}2-gGlu-C(O)(CH2) 16 The albumin-binding portion of COOH is covalently bound, particularly to -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0471] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0472] Or its pharmaceutically acceptable salt.

[0473] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:138):

[0474] IVLSLDvPIKLK*QILLKQERQKKQREQAEKNKQILEQV-NH2

[0475] in

[0476] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is selected from -gGlu-C(O)(CH2). 14 COOH and -gGlu-C(O)(CH2) 14 CH3 is covalently bound to the albumin-binding portion; and

[0477] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0478] Or its pharmaceutically acceptable salt.

[0479] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:139):

[0480] IVLSLDvPIKLK*QILLKQERQKKQRQQAEKNKQILAQV-NH2

[0481] in

[0482] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is selected from -gGlu-C(O)(CH2). 14 COOH and -gGlu-C(O)(CH2) 14 CH3 is covalently bound to the albumin-binding portion; and

[0483] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0484] Or its pharmaceutically acceptable salt.

[0485] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:140):

[0486] IVLSLDvPIKLK*QILLEQARQKAibQRAQAEKNKRILERV-NH2

[0487] in

[0488] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain interacts with -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0489] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0490] Or its pharmaceutically acceptable salt.

[0491] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:141):

[0492] IVLSLDvPIKLK*QILLKQARQKAibQRAQAEKNKRILERV-NH2

[0493] in

[0494] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain interacts with -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0495] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0496] Or its pharmaceutically acceptable salt.

[0497] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:142):

[0498] IVLSLDvPIKLK*QILLEQARQKAibQREQAEKNKRILERV-NH2

[0499] in

[0500] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain interacts with -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0501] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0502] Or its pharmaceutically acceptable salt.

[0503] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:147):

[0504] IVLSLDvPIGLK*QILLKQERQKKAibREQAETNKQILAQV-NH2

[0505] in

[0506] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is covalently bound to an albumin-binding moiety selected from: -gGlu-C(O)(CH2). 14 COOH, -{AEEA}2-gGlu-C(O)(CH2) 14 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 14 CH3、-{AEEA}2-gGlu-C(O)(CH2) 14 CH3 and -{AEEA}2-{gGlu}2-C(O)(CH2) 14 CH3; and

[0507] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0508] Or its pharmaceutically acceptable salt.

[0509] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:149):

[0510] IVLSLDvPIKLK*QILLKQERQKKAibREQAETNKRILERV-NH2

[0511] in

[0512] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain interacts with -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0513] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0514] Or its pharmaceutically acceptable salt.

[0515] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:150):

[0516] IVLSLDvPIGLK*QILLKQERQKKAibRQQAETNKRILERV-NH2

[0517] in

[0518] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is selected from -gGlu-C(O)(CH2). 14 COOH and -gGlu-C(O)(CH2) 14 CH3 is covalently bound to the albumin-binding portion; and

[0519] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0520] Or its pharmaceutically acceptable salt.

[0521] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:151):

[0522] IVLSLDvPIGLK*QILLKQERQKKAibREQAEKNKRILERV-NH2

[0523] in

[0524] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is selected from gGlu-C(O)(CH2). 14 COOH, -gGlu-C(O)(CH2) 14 CH3 and -{AEEA}2-gGlu-C(O)(CH2) 16 The albumin-binding portion of COOH is covalently bound, particularly to -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0525] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0526] Or its pharmaceutically acceptable salt.

[0527] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:152):

[0528] IVLSLDVPIKLK*QILLKQERQKKAibREQAETNKRILERV-NH2

[0529] in

[0530] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain interacts with -{AEEA}2-gGlu-C(O)(CH2). 16 COOH covalently bonded; and

[0531] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0532] Or its pharmaceutically acceptable salt.

[0533] In one embodiment, the compound is a peptide with the following amino acid sequence (SEQ ID NO:174):

[0534] IVLSLDvPIKLK*QILLKQARQKAibQRAQAEKNKRILERV-NH2

[0535] in

[0536] The K residue at position 12 (denoted as K*) is chemically modified so that the ε-amino group of its side chain is selected from -gGlu-C(O)(CH2). 14 COOH and -gGlu-C(O)(CH2) 14 CH3 is covalently bound to the albumin-binding portion; and

[0537] -NH2 indicates that the C-terminal amino acid residue has been amidated to a primary amide;

[0538] Or its pharmaceutically acceptable salt.

[0539] The compounds of this application can be prepared and used in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts and methods for their preparation are well known in the art (see, for example, Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection and Use”, 2nd revised edition, Wiley-VCH, 2011; and Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 1977, 66, 1). Examples of pharmaceutically acceptable salts include trifluoroacetates, acetates, and hydrochlorides.

[0540] Compound Synthesis

[0541] The compounds of this application can be prepared using various methods. The compounds can be prepared by synthesis in solution or on a solid support, followed by isolation and purification. Alternatively, the peptides can be prepared by gene expression in host cells with a DNA sequence encoding the peptide already introduced. Gene expression can also be achieved without using a cellular system. Combinations of methods can also be used.

[0542] In particular, the compound can be prepared by solid-phase synthesis on a suitable resin. Solid-phase peptide synthesis is a well-established method (see, for example, Stewart and Young, “Solid Phase Peptide Synthesis”, Pierce Chemical Co., Rockford, Ill., 1984; and Atherton and Sheppard, “Solid Phase Peptide Synthesis: A Practical Approach”, Oxford-IRL Press, New York, 1989).

[0543] Standard manual or automated solid-phase synthesis procedures can be used to prepare compounds. Automated peptide synthesizers are commercially available from companies such as Applied Biosystems (Foster City, CA) and Protein Technologies Inc. (Tucson, AZ). Reagents used in solid-phase synthesis are readily available from commercial sources. According to the manufacturer's instructions, solid-phase synthesizers can be used to block interfering groups, protect amino acids during the reaction, couple, deprotect, and cap unreacted amino acids.

[0544] Solid-phase synthesis can be initiated by linking an N-terminally protected amino acid with a carboxyl terminus to an inert solid support with a cleavable linker. This solid support can be any polymer that allows for initial amino acid coupling, such as triphenylmethyl resin, chlorotriphenylmethyl resin, Wang resin, or Rink resin, where the linking of the carboxyl group (or the formamide group of the Rink resin) to the resin is acid-sensitive (when using the Fmoc strategy). The support must be stable under conditions used for α-amino deprotection during peptide synthesis.

[0545] After coupling the first N-terminal protected amino acid to a solid support, the α-amino protecting group of that amino acid is removed using a reagent such as trifluoroacetic acid (TFA) or piperidine. The remaining protected amino acids are then coupled one after another, in the order shown in the peptide sequence, or added as pre-formed dipeptides, tripeptides, or tetrapeptides, using a suitable amide coupling agent. Examples of coupling agents include benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazole tetramethylurea hexafluorophosphate (HBTU), azabenzotriazole tetramethylurea hexafluorophosphate (HATU), diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBt), and 1-hydroxy-7-azabenzotriazole, and combinations thereof. Typically, coupling is carried out at room temperature in an inert solvent such as dimethylformamide (DMF), N-methylpyrrolidone (NMP), or dichloromethane (DCM).

[0546] Typically, the reactive side chain groups of amino acids are protected with suitable blocking groups. These protecting groups are removed after the desired peptide assembly, and they can be removed under the same conditions as the desired product is cleaved from the resin. Protecting groups and their introduction procedures are well known in the art (see, for example, Greene and Wuts, “Protective Groups in Organic Synthesis”, 3rd ed., 1999, Wiley & Sons). Examples of protecting groups include tert-butyloxycarbonyl (tBoc) and fluorenemethyloxycarbonyl (Fmoc).

[0547] The albumin-binding moiety can be introduced by selectively functionalizing a lysine (K) residue at the position shown in X12. Therefore, the lysine residue can contain a selectively removable side-chain protecting group, while other side-chain protecting groups remain intact, allowing the deprotected lysine residue to be selectively functionalized by the albumin-binding moiety. The conjugation of the albumin-binding moiety to the ε-amino group of the lysine side chain can be achieved by acylation or other suitable reactions known in the art.

[0548] As an illustration, the lysine residue can be protected with a 1-(4,4-dimethyl-2,6-dioxocyclohexyl-1-ylidene)-3-methylbutyl (“ivDde”) protecting group, which is unstable to highly nucleophilic bases such as 4% hydrazine in DMF solution (see Chhabra et al., Tetrahedron Lett. 1998, 39, 1603). Therefore, if the N-terminal amino group and all side chain functional groups are protected with acid-unstable protecting groups, the ivDde group can be selectively removed using highly nucleophilic bases. The resulting free amino group can then be partially conjugated to albumin, for example, by acylation. Alternatively, the lysine residue can be protected with a (4-methoxyphenyl)diphenylmethyl (“Mmt”) protecting group, which is unstable to very mild acids such as acetic acid and trifluoroethanol in dichloromethane solution (see Dubowchik et al., Tetrahedron Lett. 1997, 38(30), 5257). Therefore, if the N-terminal amino group and all side-chain functional groups are protected with protecting groups that are unstable only to strong acids, the Mmt group can be selectively removed using, for example, a mixture of acetic acid and trifluoroethanol in dichloromethane (e.g., in a 1:2:7 ratio). The resulting free amino group can then be conjugated to the albumin-bound portion, for example, by acylation.

[0549] Alternatively, the albumin-binding moiety can be introduced during peptide synthesis using a prefunctionalized structural unit as a coupling chaperone along with a lysine residue. Examples of such prefunctionalized structural units include Fmoc-L-Lys(Palm-L-Glu-OtBu)-OH and Fmoc-L-Lys[{AEEA}2-gGlu(OtBu)-C(O)(CH2). 16 -C(O)OtBu]-OH.

[0550] If desired, the N-terminus of the peptide chain can be modified, for example, by acetylation. For the synthesis of C-terminal amide peptides, resins incorporating Rink amide 4-methyldiphenylamine (MBHA) or Rink amide AM linkers are typically used in conjunction with Fmoc synthesis, while MBHA resins are typically used in conjunction with tBoc synthesis.

[0551] After synthesis, the peptide is cleaved from the solid support using standard processing methods, while simultaneously deprotecting the side chains. This can be achieved using King's cocktail (King et al., Int. J. Peptide Protein Res., 1990, 36, 255-266) or similar cleavage mixtures known in the art.

[0552] If necessary, the raw materials can be purified by chromatography (e.g., by preparative RP-HPLC). Crude peptides are typically purified using RP-HPLC on a C8 or C18 column using a water-acetonitrile gradient of 0.05 to 0.1% trifluoroacetic acid (TFA). The purity of the peptides can be verified by analytical RP-HPLC. Peptide identity can be verified by mass spectrometry. Compounds can be separated in solid form (e.g., as a dry powder) using techniques such as lyophilization.

[0553] This application also relates to intermediate compounds for the synthesis of the compounds of the present invention. Specifically, a compound is provided that is a peptide comprising the amino acid sequence of formula (I) disclosed herein, wherein residues X1 to X11 and X13 to X38 have meanings associated with formula (I), and X12 is lysine (K); or a salt thereof. This compound can be used as an intermediate for the preparation of the compounds of this application, which can be obtained by conjugating an albumin-binding moiety to the ε-amino group of the lysine side chain at X12. The addition of the albumin-binding moiety can be performed while the peptide is still attached to a solid phase. After the albumin-binding moiety is added, the peptide can be released from the resin and purified.

[0554] Specific methods for preparing the compounds of this application are described in the following examples. The specific synthetic steps of each route can be combined in different ways to prepare the compounds. The reagents and starting materials are readily available or can be prepared by methods known in the art.

[0555] Pharmaceutical Composition

[0556] This document also discloses pharmaceutical compositions comprising the compounds of this application and pharmaceutically acceptable carriers or excipients.

[0557] The pharmaceutical composition may comprise from about 0.1% to about 99.9% by weight of the compound of this application and from about 99.9% to about 0.1% by weight of one or more pharmaceutically acceptable carriers, excipients, or diluents. In one example, the pharmaceutical composition comprises from about 5% to about 75% by weight of the compound of this application, with the remainder being a suitable pharmaceutical carrier, diluent, or excipient. Methods for preparing the pharmaceutical composition are known or will be obvious to those skilled in the art, for example, according to literature such as Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press.

[0558] In one embodiment, the pharmaceutical composition further comprises one or more additional therapeutic agents.

[0559] The pharmaceutical composition is suitable for administration via a parenteral route, such as oral, subcutaneous, intravenous, intraperitoneal, intramuscular, pulmonary, or transdermal administration. In particular, the pharmaceutical composition is suitable for subcutaneous administration. In one embodiment, the pharmaceutical composition is a ready-to-use composition suitable for administration via a pen device or an autoinjector device.

[0560] The compound exhibits desirable solubility, chemical stability, and / or physical stability, particularly in solvents at physiological pH and in solvents containing antimicrobial preservatives such as phenol or m-cresol. Therefore, the compound may be particularly suitable for use in pharmaceutical compositions in solution form.

[0561] In a particular embodiment, the pharmaceutical composition is a solution comprising a solvent and dissolved therein the compounds of this application and an antimicrobial preservative selected from phenol and m-cresol; wherein the compounds of this application are present in an amount of at least 1 mg / ml, at least 5 mg / ml, at least 10 mg / ml, or at least 20 mg / ml; and wherein the solution has a pH of 6 to 8 (e.g., pH 7.0 or pH 7.4) as measured at 25°C.

[0562] Therapeutic uses

[0563] The compounds of this application are useful in treatment and can be used to treat or prevent a variety of diseases. Therefore, in other respects, this application relates to the use of said compounds in treatment and to methods of administering an effective amount of the compounds of this application to a patient. This application also relates to the use of said compounds in the preparation of medicaments for treatment. The compounds are particularly useful for treating or preventing diseases that can be treated or prevented by agonistic action of the CRF2 receptor.

[0564] As used in this article, the term "therapy" refers to the treatment or prevention of a patient's illness.

[0565] As used herein, the term "treat" or "treating" includes preventing, inhibiting, slowing, stopping, or reversing the progression or severity of a patient's existing disease. Treatment can eliminate disease; inhibit or slow a patient's disease; inhibit or slow the development of new disease in a patient; reduce the frequency or severity of symptoms and / or relapses in patients who currently have or previously had a disease; and / or prolong, i.e., increase a patient's lifespan. In particular, treatment of disease can result in the cure, shortening of duration, improvement, slowing of progression, or inhibition of the disease or its symptoms.

[0566] As used in this article, the term “prevent” or “preventing” refers to suppressing or delaying the onset or progression of a patient’s disease.

[0567] As used in this article, the term "disease" refers to any symptom or disorder that impairs or interferes with the normal function of cells, tissues, or organs.

[0568] As used herein, the term "patient" refers to a mammal, such as a human, mouse, guinea pig, pig, rat, dog, or cat. In a particular embodiment, the patient is a human patient.

[0569] As used herein, the term "effective amount" refers to the amount or dose of the compound of this application that provides the desired effect in a patient after administration of a single or multiple doses. The effective amount can be readily determined by the attending physician using known techniques and observing results obtained in similar circumstances. In determining the effective amount for a patient, the attending physician will consider numerous factors, including but not limited to: the species of the mammal; its size, age, and general health condition; the specific disease or illness involved; the extent or severity of the disease or illness; the individual patient's response; the specific compound administered; the route of administration; the bioavailability characteristics of the administration formulation; the selected dosage regimen; the use of concomitant medications; and other relevant circumstances.

[0570] The compounds of this application are effective over a wide dose range. For example, the daily dose can fall within the range of about 0.01 to about 50 mg / kg body weight.

[0571] The compounds of this application have been observed to exhibit excellent stability in various testing environments. Therefore, the compounds of this application are particularly suitable for the following embodiments, wherein the compounds are administered once daily, once weekly, twice monthly, or once monthly. This is especially true for the compounds of this application having D-valine at position 7 and lysine derived from fatty acids as provided herein for extending half-life, exhibiting excellent potency against CRF2 and fairly good selectivity against CRF1.

[0572] The compound may be administered in combination with one or more other therapeutic agents. As used herein, the term "in combination with" means to administer the compound of this application with one or more other therapeutic agents simultaneously, sequentially, or in a single combination formulation.

[0573] The compounds of this application can be administered via parenteral routes, such as by inhalation, subcutaneous, intravenous, intraperitoneal, intramuscular, pulmonary, or transdermal administration.

[0574] In certain embodiments, the compound is administered subcutaneously. The compound can be administered by a physician or self-administered using an injection device. It should be understood that the size and injection volume are determined by a skilled practitioner. In one embodiment, the injection volume is less than or equal to 2 ml, for example, less than or equal to 1 ml. In another embodiment, a needle spacing greater than or equal to 27, for example, greater than or equal to 29, is used. Administration can be accomplished using an autoinjector or a multi-dose delivery device.

[0575] The compounds of this application can be used to treat or prevent diseases that can be treated or prevented by agonistic effects of the CRF2 receptor.

[0576] The compound is particularly useful for treating or preventing sarcopenia, pulmonary hypertension, muscular dystrophy, nephropathy, peripheral artery disease (PAD), cardiovascular diseases, especially heart failure, obesity, and diabetes. Therefore, embodiments of this application relate to the use of the compound in treating or preventing sarcopenia, pulmonary hypertension, muscular dystrophy, nephropathy, peripheral artery disease (PAD), cardiovascular diseases, especially heart failure, obesity, or diabetes in patients. This application also relates to methods for treating or preventing sarcopenia, pulmonary hypertension, muscular dystrophy, nephropathy, peripheral artery disease (PAD), cardiovascular diseases, especially heart failure, obesity, or diabetes in patients, comprising administering an effective amount of the compound of this application to a patient. Furthermore, this application relates to the use of the compound in the preparation of a medicament for treating or preventing cardiovascular diseases, especially heart failure, obesity, or diabetes in patients.

[0577] Examples of cardiovascular diseases that can be treated or prevented using the compounds of the present invention include heart failure, hypertension, dyslipidemia, atherosclerosis, arteriosclerosis, coronary artery disease, and stroke. The effects of the compounds in these conditions may be a result of or related to their effects on body weight, or may not be related to them. In certain embodiments, the compounds are used to treat or prevent heart failure. The compounds may be administered in combination with one or more other therapeutic agents used to treat heart failure, such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), diuretics, sodium-glucose cotransporter inhibitors (SGLTi), beta-blockers, mineralocorticoid antagonists, or neprilysin inhibitors.

[0578] The compounds can also be used to treat or prevent obesity and other diseases caused by or characterized by overweight, such as obesity-related inflammation, obesity-related gallbladder disease, and obesity-induced sleep apnea. For adult patients, obesity can be defined as a body mass index (BMI) greater than or equal to 30 kg / m². 2BMI is a simple weight-to-height index, commonly used to classify overweight and obesity in adults. It is defined as a person's weight (in kilograms) divided by the square of his / her height (in meters), and is expressed in kg / m². 2 The unit is expressed as [unit name missing]. This compound can be administered in combination with one or more other therapeutic agents used to treat obesity. Alternatively or additionally, the treatment can be combined with diet and exercise.

[0579] The compound can also be used to treat or prevent diabetes, particularly type 2 diabetes. The compound can be administered alone or in combination with one or more other therapeutic agents for the treatment of diabetes, such as one or more agents selected from metformin, thiazolidinediones (TZDs), sulfonylureas (SUs), dipeptidyl peptidase-IV (DPP-IV) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose cotransporter (SGLT) agents. Alternatively or additionally, treatment can be combined with diet and exercise. The compound can also be used to treat or prevent hyperglycemia, type 1 diabetes, and impaired glucose tolerance.

[0580] The compounds may also be used to treat or prevent other diseases, such as sarcopenia, pulmonary hypertension, nephropathy, peripheral artery disease (PAD), metabolic syndrome, chronic kidney disease, degenerative diseases (such as neurodegenerative diseases), or diseases accompanied by nausea or vomiting.

[0581] The present invention is further illustrated by the following embodiments, which are provided for illustrative purposes only. These embodiments should not be construed as limiting the scope or content of this application in any way. Example

[0582] Abbreviations

[0583] Certain abbreviations are used in the embodiments and elsewhere in this document:

[0584] “AA” refers to amino acids;

[0585] “AEEA” refers to [2-(2-aminoethoxy)ethoxy]acetyl;

[0586] “Aib” refers to 2-amino-isobutyric acid;

[0587] "AUC" refers to the area under the curve;

[0588] “cAMP” refers to cyclic adenosine monophosphate;

[0589] “Boc” refers to tert-butyloxycarbonyl;

[0590] “BOP” refers to (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate;

[0591] “BSA” refers to bovine serum albumin;

[0592] “tBu” refers to tert-butyl.

[0593] "DCM" refers to dichloromethane;

[0594] “Dde” refers to 1-(4,4-dimethyl-2,6-dioxocyclohexyl)-ethyl;

[0595] “IvDde” refers to 1-(4,4-dimethyl-2,6-dioxocyclohexyl)-3-methyl-butyl;

[0596] “DIC” refers to N,N'-diisopropylcarbodiimide;

[0597] "DIPEA" refers to N,N-diisopropylethylamine;

[0598] “DMEM” refers to Duchenne modified Eagle medium;

[0599] "DMF" refers to dimethylformamide;

[0600] "DMSO" refers to dimethyl sulfoxide;

[0601] "EDT" refers to ethylene dithiol;

[0602] "FA" stands for nail acid;

[0603] "FBS" refers to fetal bovine serum;

[0604] “Fmoc” refers to fluorene methoxycarbonyl group;

[0605] “gGlu” refers to γ-glutamic acid (γE);

[0606] “HATU” refers to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylureonium hexafluorophosphate;

[0607] "HBSS" refers to Hanks' equilibrium salt solution;

[0608] “HBTU” refers to 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate;

[0609] “HEPES” refers to 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;

[0610] “HOAt” refers to 1-hydroxy-7-azabenzotriazole;

[0611] “HOBt” refers to 1-hydroxybenzotriazole;

[0612] “HOSu” refers to N-hydroxysuccinimide;

[0613] "HPLC" refers to High Performance Liquid Chromatography;

[0614] “hr” indicates hours;

[0615] "HTRF" refers to homogeneous time-resolved fluorescence;

[0616] "IBMX" refers to 3-isobutyl-1-methylxanthine;

[0617] “iv” refers to the vein;

[0618] “kDa” refers to kilodaltons;

[0619] "LC / MS" refers to liquid chromatography / mass spectrometry.

[0620] “Mmt” refers to monomethoxy-triphenylmethyl;

[0621] "MS" refers to mass spectrometry.

[0622] “OtBu” refers to O-tert-butyl;

[0623] "Palm" refers to palmitoyl;

[0624] “Pbf” refers to 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl;

[0625] "PBS" refers to phosphate-buffered saline solution;

[0626] "PK" refers to pharmacokinetics;

[0627] "RP-HPLC" refers to reversed-phase high-performance liquid chromatography.

[0628] “sc” refers to subcutaneous tissue;

[0629] “SEM” refers to the standard error of the mean;

[0630] “Stea” refers to stearoyl;

[0631] "TIPS" refers to triisopropylsilane;

[0632] "TFA" refers to trifluoroacetic acid;

[0633] “Trt” refers to triphenylmethyl; and

[0634] "UV" refers to ultraviolet rays.

[0635] Materials and methods

[0636] The following starting materials and methods are used in the synthesis procedures described in the examples.

[0637] Rink amide resins (e.g., 4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-leucine methyl resin, Merck Biosciences; 4-[(2,4-dimethoxyphenyl)(Fmoc-amino)methyl]phenoxyacetamidomethyl resin, Agilent Technologies) were used for the synthesis of peptide amides with a loading range of 0.2–0.7 mmol / g. Alternatively, pre-loaded Wang resins (e.g., ((S)-(9H-fluorene-9-yl)methyl(1-(tert-butoxy)-3-oxopropane-2-yl)carbamate resin, Fmoc-Ser(tBu)-Wang resin, Bachem) were used for the synthesis of peptide acids with a loading range of 0.2–0.7 mmol / g.

[0638] Natural amino acids protected by Fmoc were purchased from Protein Technologies Inc., Senn Chemicals, Merck Biosciences, Novabiochem, Iris Biotech, Bachem, Chem-Lmpex International, or MATRIX Innovation. The following standard amino acids were used in the synthesis: Fmoc-L-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc-L-Cys(Trt)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Ala-OH, Fmoc-L ... c-L-Ile-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Met-OH, Fmoc-L-Phe-OH, Fmoc-L-Pro-OH, Fm oc-L-Ser(tBu)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Val-OH. In addition, the following amino acids were purchased from the same supplier as above: Fmoc-L-Lys(ivDde)-OH, Fmoc-L-Lys(Dde)-OH, Fmoc-L-Lys(Mmt)-OH, Fmoc-Aib-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-D-Ala-OH, and Boc-L-Tyr(tBu)-OH.

[0639] The following side-chain structural units were obtained from commercial sources or synthesized by stepwise or solid-phase synthesis as described in, for example, the examples in CN104356224 (Liu; Hangzhou Adlai Nortye Pharmaceutical Technology Co., Ltd.): Fmoc-L-Lys(Palm-L-Glu-OtBu)-OH; Fmoc-L-Lys[{AEEA}2-gGlu(OtBu)-C(O)(CH2) 16 C(O)OtBu]-OH; Fmoc-AEEA-OH; Fmoc-AEEA-AEEA-OH; Fmoc-L-Ile-Aib-OH; and Boc-L-Tyr-Aib-OH.

[0640] The following side-chain structural unit was obtained from commercial sources (e.g., Chengdu Pukang) or synthesized by stepwise or solid-phase synthesis as described in WO2009022006 (Madsen; Novo Nordisk A / S), WO2009115469 (Madsen; Novo Nordisk A / S), or WO2015028966 (Barlos; Chemical & Biopharmaceutical Laboratories of Patras SA): HO-{AEEA}2-gGlu(OtBu)-C(O)(CH2) 16 C(O)OtBu;HO-{AEEA}2-gGlu(OtBu)-C(O)-(CH2) 18 C(O)OtBu;HO-{AEEA}2-{gGlu(OtBu)}2C(O)(CH2) 16 C(O)OtBu;HO-{AEEA}2-{gGlu(OtBu)}2-C(O)(CH2) 18 -C(O)OtBu ;HO-C(O)(CH2) 18 C(O)OtBu;HO-C(O)(CH2) 16 C(O)OtBu; and HO-gGlu(OtBu)-C(O)(CH2) 18 C(O)OtBu.

[0641] crude peptides in Purification was performed on a purifier system, a Jasco semi-preparative HPLC system, an Agilent 1100 HPLC system, or a similar HPLC system. Depending on the amount of crude peptide to be purified, preparative RP-C18-HPLC columns of different sizes and flow rates were used. Specifically, the following columns were used: Waters XSelect CSH C18 OBD Prep 5μm 30x250mm, Waters SunFire C18 OBD Prep 5μm 30x250mm, Waters SunFire C18 OBD Prep 5μm 50x150mm, and Phenomenex Luna Prep C18 5μm 21.2x250mm. Acetonitrile (B) and water + 0.1% TFA (A) or water + 0.1% FA (A) were used as eluents. Fractions containing the product were collected and lyophilized to obtain the purified product, typically a TFA salt.

[0642] Alternatively, the compound can be isolated as an acetate using the following procedure: the compound is dissolved in water, and the solution is adjusted to pH 7.05 with NaHCO3. The dissolved compound is then subjected to a chromatography column (RP Kinetex 21.2 x 250 mm, column volume CV 88 ml, 5 μm, C18, 100A). (Avant 25) Purification. Equilibrate the column with solvent A (3xCV), inject the compound, and wash with a mixture of solvent A (95%) and solvent B (5%) at 3CV. Then, run a gradient of solvent A:B (95:5) to A:B (20:80) at 15CV. Collect the purified peptide and lyophilize. Column: Kinetex AXIA 5μm C18 21.2x250mm; Solvent: A (H2O + 0.5% acetic acid): B (ACN + H2O + 0.5% acetic acid) (flow rate 7ml / min); Gradient: 95:5 (0min) to 95:5 (37min) to 20:80 (180min) to 0:100 (6min).

[0643] HPLC / UHPLC analysis was performed according to one of the following methods:

[0644] Method A:

[0645] Detection at 214nm

[0646] Column: Waters ACQUITY CSH TM C18 1.7μm (150x2.1mm), 50℃

[0647] Solvent: H₂O + 0.05% TFA; ACN + 0.045% TFA (flow rate 0.5 ml / min)

[0648] Gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 5:95 (23.5 min) to 5:95 (26.5 min) to 80:20 (27 min) to 80:20 (33 min)

[0649] Optional use of the mass analyzer: LCT Premier, electrospray positive ion mode

[0650] Method B:

[0651] Detection at 214nm

[0652] Column: Waters ACQUITY CSH TM C18 1.7μm (150x2.1mm), 50℃

[0653] Solvent: H₂O + 0.05% TFA; ACN + 0.035% TFA (flow rate 0.5 ml / min)

[0654] Gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 2:98 (23.5 min) to 2:98 (30.5 min) to 80:20 (31 min) to 80:20 (37 min)

[0655] Mass analyzer: Agilent 6230 Precision Mass TOF or Agilent 6550iFunnel Q-TOF; both equipped with Agilent dual-jet ESI ion source.

[0656] Method C:

[0657] Detection at 214nm

[0658] Column: Waters ACQUITY CSH TM C18 1.7μm (150x2.1mm), 70℃

[0659] Solvent: H₂O + 0.05% TFA; ACN + 0.035% TFA (flow rate 0.5 ml / min)

[0660] Gradient: 63:37 (0 min) to 63:37 (3 min) to 45:55 (23 min) to 2:98 (23.5 min) to 2:98 (30.5 min) to 63:37 (31 min) to 63:37 (38 min)

[0661] Mass analyzers: Agilent 6230 Precision Mass Time-of-Flight (TOF), Agilent Jet Flow ESI

[0662] Example 1: Synthesis of compounds via automated solid-phase peptide programming

[0663] Compounds were prepared via solid-phase synthesis using a Prelude peptide synthesizer (Mesa Laboratories / Gyros Protein Technologies) or a CSBio automated synthesizer, employing standard Fmoc chemistry and HBTU / DIPEA or HATU / DIPEA activation. DMF was used as the solvent.

[0664] Use the following conditions:

[0665] Deprotection: 20% piperidine / DMF for 2 x 2.5 minutes.

[0666] Washing: 7xDMF.

[0667] Coupling: 2:5:10 200mM AA / 500mM HBTU / 2M DIPEA in DMF 2x for 20 minutes.

[0668] Washing: 5xDMF.

[0669] HBTU / DIPEA activation is used for all standard couplings. HATU / DIPEA activation is used for the following couplings: Ile-Aib, Aib-Lys[{AEEA}2-gGlu(OtBu)-C(O)(CH2)] 16 C(O)OtBu], Lys[{AEEA}2-gGlu(OtBu)-C(O)(CH2) 16 C(O)OtBu]-Asp, Gln-Aib, and Leu-Leu. HATU coupling reactions are performed, usually twice for 40 minutes, sometimes twice for 1 hour, and up to 12 hours.

[0670] For the modified lysine side chain, Fmoc-L-Lys(Mmt)-OH was used at the position represented as X12 in formula (I). After the synthesis was completed, the Mmt group was removed by repeated treatment with AcOH / TFE / DCM (1 / 2 / 7) for 15 minutes at room temperature, followed by repeated washing of the resin with DCM, a DCM solution of 5% DIPEA, and a DCM / DMF solution of 5% DIPEA.

[0671] After removing the Mmt group, the resin was treated with a solution of the protected albumin-binding moiety. As an illustration, HO-{AEEA}2-gGlu(OtBu)-C(O)(CH2) was pre-activated with HATU (3 equivalents), HOAt (3 equivalents), and DIPEA (4 equivalents). 16 The preparation of resin containing -{AEEA}2-gGlu-C(O)(CH2) by solution treatment of C(O)OtBu (1 equivalent) in DMF. 16 The COOH portion of the peptide is then removed. The resin is then washed as described above. The OtBu protecting group is cleaved from the final peptide cleavage from the resin.

[0672] Peptide cleavage is performed from the resin using either the King cleavage mixture consisting of 82.5% TFA, 5% phenol, 5% water, 5% anisole, and 2.5% EDT, or a modified cleavage mixture consisting of 82.5% TFA, 5% phenol, 5% water, 5% anisole, and 2.5% DODT. The resin used in the synthesis allows the C-terminus to be cleaved from the resin as a primary amide.

[0673] The crude peptide was then precipitated in diethyl ether or diisopropyl ether, centrifuged, and lyophilized. The peptide was analyzed by HPLC and verified by ESI mass spectrometry. The crude peptide was purified using a standard preparative RP-HPLC purification procedure.

[0674] Example 2: Synthesis of compounds via manual solid-state synthesis procedure

[0675] In addition, compounds are prepared by manual synthesis procedures. Exemplary procedures are described below.

[0676] Dry Rink amide MBHA resin (0.3 g; 0.5–0.8 mmol / g) was placed in a polyethylene container equipped with a polypropylene filter. The resin was swollen in DCM (15 ml) for 1 hour and in DMF (15 ml) for 1 hour. The Fmoc groups on the resin were deprotected by treatment twice with a 20% (v / v) piperidine / DMF solution for 5 min and 15 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Kaiser test (quantitative method; see Kaiser et al., Anal. Biochem., 1970, 34, 595–598) was used to confirm the removal of Fmoc from the solid support. C-terminal Fmoc-amino acids (5 equivalents excess relative to the resin load) in anhydrous DMF were added to the deprotected resin, and coupling of the next Fmoc-amino acid was initiated using DIC and HOBT in 5 equivalents excess in DMF. The concentration of each reactant in the reaction mixture was approximately 0.4 M. The mixture was rotated on a rotor at room temperature for 2 hours. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). A Kaiser test on the peptide resin aliquots was negative (i.e., no color on the resin) upon completion of coupling. After the first amino acid linkage, unreacted amino groups (if any) in the resin were capped for 20 minutes with acetic anhydride / pyridine / DCM (1 / 8 / 8) to avoid any sequence deletion. After capping, the resin was washed with DCM / DMF / DCM / DMF (6 / 6 / 6 / 6 times each). The Fmoc groups on the C-terminal amino acids of the linked peptide resin were deprotected by treatment twice with 20% (v / v) piperidine / DMF solution for 5 minutes and 15 minutes respectively. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). A Kaiser test on the peptide resin aliquots was positive upon completion of Fmoc deprotection.

[0677] Using the Fmoc AA / DIC / HOBt method, the remaining amino acids in the target sequence on Rink amide MBHA resin were sequentially coupled using an excess of 5 equivalents of resin loading in DMF. The concentration of each reactant in the reaction mixture was approximately 0.4 M. The mixture was rotated on a rotor at room temperature for 2 hours. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). A Kaiser test was performed after each coupling step and the Fmoc deprotection step to confirm the completion of the reaction.

[0678] After linear sequencing was completed, the ε-amino group of lysine (protected with Dde) was deprotected using a 2.5% hydrazine hydrate DMF solution for 15 min x 2, followed by washing with DMF / DCM / DMF (6 / 6 / 6 times each). The γ-carboxyl terminus of glutamic acid was then linked to the ε-amino group of Lysine using Fmoc-Glu(OH)-OtBu in DMF via the DIC / HOBt method (5 equivalents excess relative to resin loading). The mixture was rotated on a rotor at room temperature for 2 hours. The resin was filtered and washed with DMF / DCM / DMF (30 ml each, 6 / 6 / 6 times each). The Fmoc group on glutamic acid was deprotected by treatment twice with a 20% (v / v) piperidine / DMF solution for 5 min and 15 min (25 ml each time). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser tests on aliquots of the peptide resin were positive upon completion of Fmoc deprotection.

[0679] For peptides with an additional γ-glutamic acid in the side chain branch, a second Fmoc-Glu(OH)-OtBu was attached to the free amino group of γ-glutamic acid in DMF using the DIC / HOBt method (with a 5-equivalent excess relative to the resin load). The mixture was rotated on a rotor at room temperature for 2 hours. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each, 30 ml each time). The Fmoc group on the γ-glutamic acid was deprotected by treatment twice with 20% (v / v) piperidine / DMF solution for 5 minutes and 15 minutes (25 ml). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). A Kaiser test on the peptide resin aliquots was positive when Fmoc deprotection was complete.

[0680] The albumin-binding moiety was ligated as described in Example 1. The tert-butyl ester protecting group was cleaved from the final peptide cleavage of the resin.

[0681] Alternatively, a prefunctionalized structural unit is used to introduce the albumin-binding moiety, which has already been linked to a lysine residue as a coupling chaperone in peptide synthesis. This procedure avoids the need for selective deprotection steps and the selective attachment of side-chain structural units to a very advanced synthetic intermediate. As an illustration, the following procedure is used to prepare Fmoc-L-Lys[{AEEA}2-gGlu(OtBu)-C(O)(CH2). 16 [C(O)OtBu]-OH was introduced into the peptide. 0.67 mmol of peptide resin containing amino groups was washed with 20 ml of dimethylformamide. 2.93 g of Fmoc-L-Lys[{AEEA}2-gGlu(OtBu)-C(O)(CH2) was then added. 16 -C(O)OtBu]-OH was dissolved in 20 ml of dimethylformamide along with 310 mg of hydroxybenzotriazole hydrate and 0.32 ml of diisopropylcarbodiimide. After stirring for 5 minutes, the solution was added to the resin. The resin was stirred for 20 hours, and then washed three times with 20 ml of dimethylformamide each time. A small amount of resin sample was taken and subjected to Kaiser and Chloranil tests (see Vojkovsky, Peptide Research 1995, 8, 236-237).

[0682] After coupling the albumin-bound fraction, the peptide-based resin was washed with DCM (6 x 10 ml), MeOH (6 x 10 ml), and diethyl ether (6 x 10 ml) and dried overnight in a vacuum desiccator. Peptide cleavage from the solid support was achieved by treating the peptide-resin with a reagent mixture (92% TFA, 2% anisole, 2% phenol, 2% water, and 2% TIPS) for 3 to 4 hours at room temperature. The cleavage mixture was collected by filtration and the resin was washed with TFA (2 ml) and DCM (2 x 5 ml). Excess TFA and DCM were concentrated to a small volume under nitrogen, and a small amount of DCM (5-10 ml) was added to the residue and evaporated under nitrogen. This process was repeated 3-4 times to remove most volatile impurities. The residue was cooled to 0°C and anhydrous diethyl ether was added to precipitate the peptide. The precipitated peptide was centrifuged, the supernatant diethyl ether was removed, fresh diethyl ether was added to the peptide, and centrifugation was repeated. The crude sample was purified by preparative HPLC and lyophilized. Peptide identity was confirmed by LCMS.

[0683] Example 3: SEQ ID Synthesis of peptide NO:35

[0684] The compound of SEQ ID NO:35 was prepared according to the procedure described in Example 1. Novabiochem Rink amide resin (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucyl-aminomethyl resin), 100-200 mesh, was used with a loading of 0.36 mmol / g. An automated Fmoc synthesis strategy with HBTU / DIPEA activation or HATU / DIPEA activation was applied according to the amino acid sequence. At position 12, Fmoc-Lys(Mmt)-OH was used in the solid-phase synthesis scheme. The Mmt group was cleaved from the peptide as described in Example 1. Subsequently, using DIPEA as a base and HATU / HOAt as a coupling agent, HO-{AEEA}2-gGlu(OtBu)-C(O)(CH2) was used. 16 C(O)OtBu was coupled with the released amino group. The peptide was cleaved from the resin using a King's mixture. The crude product was purified by preparative HPLC on a Waters column (Waters SunFire C18 OBD Prep 5 μm 50 x 150 mm) using an acetonitrile / water gradient (water with 0.1% TFA). The purified peptide was analyzed by LCMS (Method B). Deconvolution of the mass signal found at a retention time of 11.19 min showed a peptide mass of 5154.09, consistent with the expected value of 5154.06.

[0685] Example 4: SEQ ID Synthesis of peptide NO:141

[0686] The compound of SEQ ID NO:141 was prepared according to the procedure described in Example 1. Novabiochem Rink amide resin (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucyl-aminomethyl resin), 100-200 mesh, was used, with a loading of 0.34 mmol / g. Based on the amino acid sequence, an automated Fmoc synthesis strategy was applied with HBTU / DIPEA activation or HATU / DIPEA activation. At position 12, Fmoc-L-Lys[{AEEA}2-gGlu(OtBu)-C(O)(CH2) was added. 16[-C(O)OtBu] was used in the solid-phase synthesis scheme. The peptide was cleaved from the resin using King's mixture. The crude product was first purified by preparative HPLC on a Waters column (Waters SunFire C18 OBD Prep 5μm 50x150mm) using an acetonitrile / water gradient (water with 0.1% TFA), and then by preparative HPLC on a Waters column (Waters Xselect CSH Prep C18 5μm 30x250mm) using an acetonitrile / water gradient (water with 0.1% formic acid). The purified peptide was collected and lyophilized. The purified peptide was analyzed by LCMS (Method B). The deconvolution of the mass signal found at the peak at retention time of 9.97 min showed a peptide mass of 5163.18, consistent with the expected value of 5163.17.

[0687] Example 5: SEQ ID Synthesis of peptide NO:171

[0688] The compound of SEQ ID NO:171 was prepared according to the procedure described in Example 1. Novabiochem Rink amide resin (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucyl-aminomethyl resin), 100-200 mesh, was used with a loading of 0.35 mmol / g. An automated Fmoc synthesis strategy with HBTU / DIPEA activation or HATU / DIPEA activation was applied according to the amino acid sequence. At position 12, Fmoc-Lys(Mmt)-OH was used in the solid-phase synthesis scheme. The Mmt group was cleaved from the peptide as described in Example 1. Subsequently, HO-{AEEA}2-{gGlu(OtBu)}2-C(O)(CH2) was coupled using DIPEA as a base and HATU / HOAt as a coupling agent. 16 C(O)OtBu is coupled with the released amino group. The peptide is cleaved from the resin using a King's mixture. The crude product is purified by preparative HPLC on a Waters column (Waters SunFire C18 OBD Prep 5 μm 50 x 150 mm) using an acetonitrile / water gradient (water with 0.1% TFA). The purified peptide is analyzed by LCMS (Method B). Deconvolution of the mass signal found at a retention time of 9.94 min indicates a peptide mass of 5294.21, consistent with the expected value of 5294.13.

[0689] Example 6: Synthesis of other peptides

[0690] The following peptides were synthesized according to the procedures described in Examples 1-5. The calculated and determined masses and retention times of these peptides, as well as the compounds from Examples 3-5, are shown in Table 3 below:

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698] Table 3

[0699] Example 7: Activity assessment of human CRF2α receptor

[0700] The agonistic effect of the compound on human adrenocorticotropic hormone-releasing factor 2α (CRF2α receptor) was determined by a functional assay measuring the cAMP response of the TeloHEAC cell line stably expressing the human CRF2α receptor.

[0701] Cells were grown to near confluence in DMEM / 10% FBS in T175 culture flasks at 37°C and collected in 2ml vials containing 10% DMSO at a concentration of 10-50 million cells / ml. Each vial contained 1.8ml of cells. These vials were slowly frozen in isopropanol to -80°C and then transferred to liquid nitrogen for storage. Before use, frozen cells were rapidly thawed at 37°C and washed with 20ml of cell buffer (1x HBSS; 20mM HEPES; 0% or 0.1% HSA) (at 900rpm for 5 minutes). Cells were resuspended in test buffer (cell buffer plus 2mM IBMX) and adjusted to a cell density of 1 million cells / ml. For measurement, 5μl of cells (finally 2000 cells / well) and 5μl of test compound were added to 384-well plates and incubated at room temperature for 30 minutes.

[0702] cAMP levels in cells were determined using a kit from Cisbio Corp. (catalog number 62AM4PEC) based on HTRF (homogeneous time-resolved fluorescence). Plates were incubated for 1 hour after adding HTRF reagent (kit component) diluted in lysis buffer, followed by measurement of the fluorescence ratio at 665 / 620 nm. The percentage of activity (E%) was calculated by setting 1000 nM urocortin 2 (UCN2) to 100%. The in vitro potency of the compound was quantified by determining the concentration that elicited the maximum response at 50% activation (EC50).

[0703] Representative EC50 values ​​are provided in Table 4 below:

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710] Table 4

[0711] Example 8: Evaluation of the activity of rat CRF2α receptor

[0712] The activity of the compounds against the rat CRF2Rα receptor was evaluated using the procedure described in Example 7. The A7R5 rat aortic smooth muscle cell line was used in this study.

[0713] Representative EC50 values ​​are provided in Table 5 below:

[0714]

[0715]

[0716]

[0717] Table 5

[0718] Example 9: Activity assessment against the target CFR1R receptor

[0719] The activity of the compounds against the target CRF1R receptor was evaluated using the procedure described in Example 7. This study used CHO cell lines overexpressing CRF1R.

[0720] Table 6 below provides representative EC50 and Emax values:

[0721]

[0722]

[0723]

[0724] Table 6

[0725] Example 10: Activity assessment in cells expressing endogenous human CRF2

[0726] The agonist effect of the compound was evaluated in NCI-H82 cells expressing endogenous human CRF2.

[0727] NCI-H82 cells in suspension were seeded at a density of 30,000 cells / well in 5 μl of test medium (RPMI + 1 mM IBMX) in low-volume 384-well plates. The plates were briefly centrifuged at 800 rpm to allow the cell suspension to reach the bottom of the wells, and then incubated at 37°C and 5% CO2 for 2 hours. Then, 5 μl of medium was added to the plate at an appropriate concentration (10... -11 Up to 3x10 -7 The test compound diluted in the test medium was transferred to a 384-well plate. After activation for 5 minutes, the reaction was stopped by adding HTRF display reagents using a multi-drop dispenser. The two reagents were 5 μl / well of anti-cAMP-D2 diluted 20-fold in conjugate and lysis buffer and 5 μl / well of cAMP-D2 diluted 20-fold in conjugate and lysis buffer. After incubation in the dark at room temperature for one hour, the plates were read on a Clariostar instrument. HTRF signals were read at 620 nm and 665 nm and calculated as follows: HTRF ratio = [(665 nm signal) / (620 nm signal)] x 10⁴. The EC50 value was determined from the cAMP measurements using standard cAMP curves (0.17 nM to 712 nM) plotted on each plate.

[0728] Representative EC50 values ​​are provided in Table 7 below:

[0729] 35 23 59 6.8 81 110 101 4.1 130 4.3 135 110 137 120 138 8.4 139 18 141 12 143 93 147 13 151 7.4

[0730] Table 7

[0731] Example 11: Binding study in HEK cells expressing recombinant CRF2

[0732] The receptor binding of the compound was evaluated using the CRF2α(h) (agonist radioligand) assay.

[0733] HEK cells expressing recombinant human CRF2 were used as the receptor source for membrane preparation. [125l]frog skin antihypertensive peptide was used as a competitive ligand for the CRF2 receptor. The test compound was competitively incubated with [125l]frog skin antihypertensive peptide (0.1 nM) at several concentrations for one hour to determine residual binding. Compound binding was calculated as the percentage inhibition of CRF2-specific binding by [125l]frog skin antihypertensive peptide.

[0734] The IC50 value (the concentration at which half-maximal inhibition of control-specific binding occurs) and the Hill coefficient (nH) were determined using nonlinear regression analysis of the competition curves generated by average replicates, fitted with the Hill equation. The inhibition constant (Ki) was calculated using the Cheng Prusoff equation [Ki = IC50 ≈ (1 + L / KD), where L is the concentration of the radioligand in the experiment and KD is the affinity of the radioligand for the receptor]. KD was determined using Scatchard plotting.

[0735] Representative Ki and nH values ​​are provided in Table 8 below:

[0736] 17 4.4 1.5 35 7.9 1.7 51 4.3 0.8 59 7.2 0.6 68 5.4 0.8

[0737] Table 8

[0738] Example 12: Chemical Stability Assessment

[0739] The chemical stability of compounds was assessed by storing them under various conditions and then determining the purity loss by UPLC-UV.

[0740] Before measuring the chemical stability of a batch of test compounds, the purity of the compounds was determined by UPLC / MS. For the stability test, the target concentration was 300 μM of pure compound. Therefore, based on the previously determined purity %, solutions with a compound concentration of 300 μM were prepared from the solid sample in a pH 4.5, 20 mM acetate buffer system.

[0741] The solution of the test compound was filtered through a filter (0.22 μM pore size) and aseptically loaded into aliquots. At the start, UPLC-UV was performed by injecting 2 μl of undiluted sample. The aliquots were then stored at 5 °C and 40 °C for 28 days. After this period, the samples were centrifuged at 2500 RCF for 15 min. The 2 μl undiluted supernatant was then analyzed by UPLC-UV. Chemical stability was calculated using the following equation: [(purity after 28 days at 5 °C) - (purity after 28 days at 40 °C)] / (purity after 28 days at 5 °C)] x 100%. Purity was calculated as: [(compound peak area) / (total peak area)] x 100%.

[0742] Representative stability data are provided in Table 9 below:

[0743]

[0744]

[0745] Table 9

[0746] Example 13: Solubility Assessment

[0747] The solubility of the compounds was evaluated in the following buffer systems: 100 mM acetate buffer, pH 4.5 (buffer A); 100 mM acetate buffer, pH 4.5, 2.7 mg / ml m-cresol (buffer B); and 100 mM phosphate buffer, pH 7.4 (buffer C).

[0748] Prior to solubility measurements, the purity of the compound was determined by UPLC / MS. For the solubility test, the target concentration was 10 mg pure compound / mL. Therefore, based on the previously determined purity %, a solution with a compound concentration of 10 mg / mL was prepared from the solid sample in a buffer system.

[0749] The supernatant obtained after centrifugation at 2500 RCF (relative centrifugal acceleration) for 15 minutes was gently stirred for 1 hour before UPLC-UV analysis. Solubility was determined by comparing the UV peak area of ​​a 2 μL injection of a 1:10 diluted buffer sample with a standard curve of a reference compound at a known concentration. Different UV extinction coefficients for the sample and reference compound were calculated based on different amino acid sequences, and these coefficients were considered in concentration calculations.

[0750] Representative solubility data are provided in Table 10 below:

[0751]

[0752]

[0753] Table 10

[0754] Example 14: Evaluation of physical stability using the thioflavin T test

[0755] The physical stability of the compound was assessed using the thioflavin T (ThT) test.

[0756] The low physical stability of peptide solutions can lead to the formation of amyloid fibrils, which are observed as ordered linear macromolecular structures in samples and can eventually lead to gel formation. ThT is widely used to visualize and quantify the presence of misfolded protein aggregates (see Biancalana et al., Biochim. Biophys. Acta, 2010, 1804(7), 1405). When it binds to fibrils, such as those in amyloid aggregates, the dye exhibits a distinct fluorescent characteristic (see Naiki et al., Anal. Biochem., 1989, 177, 244; and LeVine et al., Methods. Enzymol., 1999, 309, 274). The time course of fibril formation typically follows the characteristic shape of an S-curve and can be divided into three regions: a lag phase, a rapid growth phase, and a plateau phase. The typical fibril formation process begins in the lag phase, during which the amount of partially folded peptides converted into fibrils is insufficient to be detected. The lag time corresponds to the time when the critical mass of the nucleus forms. This is followed by a rapid elongation period and a rapid increase in fibrillation concentration. Therefore, the fibrillation tendency of the peptide can be determined by measuring the increase in fluorescence intensity attributed to ThT and the increased hysteresis time, thus providing a measure of the peptide's physical stability.

[0757] In this study, the test compound was diluted in buffer to a final concentration of 3 mg / mL. Subsequently, 20 μL of an aqueous solution of 10.1 mM ThT was added to 2 mL of the peptide solution to obtain a final concentration of 100 μM ThT. The following two buffers were used for the experiments: 100 mM acetate buffer, pH 4.5 (Buffer A); and 100 mM acetate buffer, pH 4.5 and 2.7 mg / mL m-cresol (Buffer B).

[0758] The fibrillation tendency of peptides under stress was determined using a Fluoroskan Ascent FL or Fluoroskan Ascent fluorometer. 200 μL of sample was placed in a 96-well microtiter plate (PS), flat-bottomed, Greiner Fluotrac No. 655076. The plate was sealed with Scotch tape (Quiagen). The sample was stressed by continuous cycling of shaking at 960 rpm for 10 seconds and resting at 37°C for 50 seconds. Fibrillation development was monitored by measuring fluorescence intensity every 20 minutes. The test was repeated eight times for each sample.

[0759] Table 11 below provides representative stability data obtained in buffer A, where "Fl" refers to fluorescence intensity:

[0760] 4 yes 18 6 no >45 35 no >45 60 no >45 75 no >45 141 no >45 146 no >45

[0761] Table 11

[0762] Representative stability data obtained in buffer B are provided in Table 12 below:

[0763]

[0764]

[0765] Table 12

[0766] Example 15: Evaluating physical stability using dynamic light scattering experiments

[0767] In addition, dynamic light scattering experiments were used to assess the physical stability of the compounds.

[0768] Dynamic light scattering (DLS) measures light scattered by particles (1 nm ≤ radius ≤ 1 μm) undergoing Brownian motion. This motion is caused by collisions between particles and solvent molecules, which themselves move due to their thermal energy. The diffusion motion of the particles results in time fluctuations in the scattered light (Pecora, "Dynamic Light Scattering: Applications of Photon Correlation Spectroscopy", Plenum Press, 1985). The fluctuations in the intensity of the scattered light are recorded and converted into an autocorrelation function. By fitting the autocorrelation curve to an exponential function, the diffusion coefficient D of the particles in the solution can be derived. Then, assuming spherical particles, the hydrodynamic radius R is calculated using the diffusion coefficient through the Stokes-Einstein equation. h(or apparent Stokes radius). This calculation is defined in the following international standards: International Standard ISO 13321, Methods for Determination of Particle Size Distribution Part 8: Photon Correlation Spectroscopy, International Organization for Standardization (ISO) 1996; and International Standard ISO 22412 Particle Size Analysis – Dynamic Light Scattering, International Organization for Standardization (ISO) 2008.

[0769] DLS interaction parameter (k) D k is a measure of interparticle interactions, where the particles are folded proteins or peptides (Yadav et al., J. Pharm. Sc. 2010, 99(3), 1152; and Connolly et al., Biophys. J. 2012, 103, 69). High values ​​indicate strong net repulsive interactions, while low values ​​indicate net attractive interactions. Therefore, k D It can be used for relative, qualitative comparison purposes.

[0770] In this study, the apparent hydrodynamic radius (R) was measured after synthesis (0 weeks) and after storage at 40°C for 4 weeks. h The physical stability of the test compounds was assessed by scattering intensity (I) and mass contribution (M).

[0771] The stability of the compound was evaluated in five different buffer systems: 100 mM acetate buffer, pH 4.5 (Buffer A); 100 mM acetate buffer, pH 4.5, 2.7 mg / mL m-cresol (Buffer B); 20 mM phosphate buffer, pH 6.2 (Buffer C); 20 mM phosphate buffer, pH 7.4 (Buffer D); and 20 mM acetate buffer, pH 4.5 (Buffer E).

[0772] For each solution of the test compound, the hydrodynamic radius R hThe diffusion constant D (correlated with the Stokes-Einstein equation) was determined as the average of three copies. In the same buffer system, at different compound concentrations (e.g., R...),... h1 And D1: 1 mg / ml, and R h5 And D5: 5mg / ml, R h10 and D 10 Two parameters were measured at 10 mg / mL. The difference between these parameters at low and high peptide concentrations is the DLS interaction parameter k. D Alternatives. As peptide concentration increases, the D value increases or R... h The value decreases corresponding to k D >0, therefore corresponding to repulsive interparticle interactions that lead to increased physical (or colloidal) stability. Furthermore, the hydrodynamic radius R... h The corresponding scattering intensity (%) was determined as an average of two copies. The target concentration was 300 μM. Therefore, based on the previously determined purity %, a solution with a compound concentration of 300 μM was prepared from the solid sample in a buffer system.

[0773] DLS measurements were performed on a DynaPro Plate Reader I (Wyatt Technology, Santa Barbara, CA, US) with an 837nm laser source at a 150° scattering angle. Data were collected and processed using Dynamics V7.8.1.3 or 7.8.2.18 software provided by Wyatt Technology.

[0774] The hydrodynamic radius was determined using the nonnegative constrained least squares (NNLS) method with a regularized fit DYNALS algorithm. For comparison purposes, all samples were taken with the refractive index of water n = 1.330 and η = 0.89cP. Samples were tempered at +25°C for more than 1 hour and visually inspected before analysis.

[0775] Mix the sample using the tip of a pipette. Repeat the measurement 5 times. Alternatively, pipette five 15 μL aliquots onto a polystyrene 384 test plate (Greiner Bio-One, Germany) with a transparent bottom and seal it. Centrifuge the plate at 600 rcf for 2 minutes. After removing the seal, measure the sample at +25°C.

[0776] Representative stability data are provided in Table 13 below:

[0777]

[0778]

[0779] Table 13

[0780] Example 16: Pharmacokinetic Characteristics Assessment

[0781] The pharmacokinetic properties of exemplary peptides SEQ ID NO:35 and SEQ ID NO:24 were evaluated in mice and rats.

[0782] Depending on the dose, species, and administration volume, the test compound was administered at a concentration of 0.05, 0.1, 0.5, or 1 mg / ml in a suitable buffer system (PBS buffer solution at pH 7.4, or DPBS solution). Female C57BI / 6 mice and male SD rats were administered intravenously or subcutaneously at doses of 0.1 mg / kg or 0.3 mg / kg. Animals were sacrificed, and blood samples were collected at 0.08, 0.25, 0.5, 1, 2, 4, 8, 24, 32, and 48 hours after intravenous administration and at 0.25, 0.5, 1, 2, 4, 8, 24, 32, and 48 hours after subcutaneous administration. Plasma samples were analyzed by liquid chromatography-mass spectrometry (LC / MS) after protein precipitation. Pharmacokinetic parameters and half-life were calculated using a non-compartmental model and linear trapezoidal interpolation in Phoenix-WinNonlin 8.1.

[0783] The results of these peptide studies are presented in Table 14 below:

[0784]

[0785] Table 14

[0786] Example 17: Evaluation of its effect on blood pressure

[0787] In a telemetry study, the effect of the compound on blood pressure was determined in Sprague Dawley rats at a dose of 0.1 mg / kg SC.

[0788] Rats were pre-implanted with a telemetry device (DSI, Saint-Paul, USA, HD-S10, HD-S11, or HD S21) and allowed a minimum recovery period of 2 weeks before treatment with the medium or different peptides. Blood pressure (BP) was recorded via a catheter inserted into the abdominal aorta. The main body of the device was placed in the abdomen. At the end of the procedure, the animals were placed in separate cages until the end of the study.

[0789] Pressure signals were recorded one hour prior to treatment (basal phase). Subcutaneous administration of the test compound or its mediator was then performed with continuous signal recording over a 48-hour period. Hem 4.3 acquisition software connected to a telemetry device was used. Data collection was conducted at Le Pecq (France). Hemodynamic parameters were recorded every 4 hours during the 2-hour period before treatment and every 4 hours within 48 hours after subcutaneous administration.

[0790] The study parameters (calculated based on BP signals) were heart rate (HR) in terms of heart rate per minute (bpm), diastolic and systolic blood pressure (DBP) in mmHg, and mean blood pressure (MBP) in mmHg.

[0791] Use Microsoft Data from Hem was processed. For each parameter, the baseline value was determined as the average calculated during the 1-hour period prior to sequential treatment, while the post-treatment value was calculated using 4-hour cycles over a 48-hour period following administration ([0-4], [4-8], [8-12], [12-16], [16-20], [20-24], [24-28], [32-36], [36-40], [40-44], and [44-48] hours).

[0792] Representative data are presented in Table 15 below, where “n” represents the number of animals for which individual values ​​were obtained, and “duration” represents the last time point at which a significant effect on BP was still visible: Table 15.

[0793] Table 15

[0794]

[0795]

[0796] Example 18: Evaluation of the effect on body weight and body fat percentage

[0797] The ability of the peptide of SEQ ID NO:35 to reduce body weight and body fat content was evaluated in mice. Its efficacy was compared with that of the reference compound, WO2018013803 (Alsina-Fernandez; Eli Lilly and Company), compound of Example 4 (referred to herein as "Compound A").

[0798] Female C57BL / 6N CR1 mice were housed in groups under animal housing conditions including a 12-hour light / dark cycle and a room temperature of 23 ± 1 °C. For the first 18 weeks prior to drug intervention (administration phase), all animals had free access to water and food (a Ssniff-regulated high-fat diet: TD.97366, Soest, Germany). After the pre-feeding period, mice were housed individually and randomly assigned to n = 8 treatment groups based on body weight to ensure similar mean body weights in each group. At the start of the study, mice were 25–26 weeks old and weighed 42–50 g. Every other day, in the late afternoon before lights out, mice were treated with a subcutaneous injection of 8 nmol / kg of the test compound or its mediator (phosphate-buffered saline (PBS)). Body weight and food intake were measured daily throughout the administration phase, while body fat percentage was measured on day 0 and day 15 prior to the start of treatment. The study ended on day 15.

[0799] For statistical analysis, one-way ANOVA was performed using SigmaStat 3.5. The test was conducted with an α risk of 0.050 and compared with the high-fat diet-media group using the Dunnett test.

[0800] Figure 1 and Figure 2 The results of this study are presented. From Figure 1 As can be seen, the first administration of SEQ ID NO:35 and compound A caused a significant reduction in food intake, which normalized after the second treatment, parallel to mice treated with the vector. Compared with the vector control, mice treated with SEQ ID NO:35 or compound A had a significant decrease in body weight after a 15-day treatment period (P<0.001). Mice treated with the vector had almost constant body weight over 15 days (-1.9±1.6% over two weeks), while mice treated with SEQ ID NO:35 had a decrease in body weight of -10.8±1.4%, and mice treated with compound A had a decrease of -7.1±1.3%, and (see...) Figure 2The reduction in weight corresponded to a significant decrease in body fat percentage: -34.2 ± 2.9% for SEQ ID NO:35 and -27.5 ± 1.9% for compound A. Furthermore, when compared with semaglutide administered subcutaneously at 10 nmol / kg every other day in the same study, SEQ ID NO:35 reduced obesity to a similar degree, but with a lower incidence of food intake (15-day cumulative food intake: 39.3 ± 2.5 g for SEQ ID NO:35 and 29.6 ± 0.9 g for semaglutide, compared to 43.7 ± 1.3 g for the carrier), and better maintenance of lean body mass: -6.3 ± 1.7% for SEQ ID NO:35, -14.8 ± 0.7% for semaglutide, compared to -8.6 ± 1.1% for the carrier.

[0801] Example 19: Fatty acid modification

[0802] The effects of fatty acid modifications on the peptides disclosed in Table 2 have been evaluated. These peptides exhibit selectivity curves for hCRF2 < 0.2 nM at EC 50, hCRF1 / hCRF2 > 500, and lack known metabolic and chemical tendencies. Preferred sequence characteristics include the presence of D-valine at position 7, and preferably a bulky amino acid flanking N31.

[0803] Ten optimized sequences with the aforementioned profiles were selected from the list in Table 2 and are displayed. Figure 3 In addition to the peptides mentioned above, the following additional peptides were synthesized (Table 16). These compounds are derived from... Figure 3 The compounds previously disclosed in the patent applications share the same amino acid sequence but differ in their linker / fatty acid derivatization. Table 16 below also indicates the original Seq ID# of the filed patent application for each newly proposed compound, which shares the same amino acid sequence with that original Seq ID#.

[0804] Peptide Synthesis: Materials and Methods

[0805] The following starting materials and methods were used in the synthetic procedures described in the examples. Rink amide AM resin LL 0.29 mmol / g (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucine aminomethyl resin, Novabiochem), 100-200 mesh, was used for the synthesis of all peptide amides. Fmoc-protected natural amino acids were purchased from Novabiochem, Iris Biotech, Bachem, or Chem-Lmpex International. The following standard amino acids were used in the synthesis: Fmoc-L-Ala-OH, Fmoc-L-Arg(Pbf)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Asp(OMpe)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-L-Gly-OH, Fmoc-L-Ile-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Pro-OH, Fmoc-L-Ser(tBu)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Tyr(tBu)-OH, and Fmoc-L-Val-OH.

[0806] In addition, the following amino acids were purchased from the same supplier as above: Fmoc-L-Lys(Dde)-OH, Fmoc-Aib-OH, and Fmoc-D-Val-OH.

[0807]

[0808]

[0809]

[0810] Table 16

[0811] Peptide Synthesis: Materials and Methods - Continued

[0812] The following side-chain structural units were obtained from Iris Biotech, TCI, and Merck: Fmoc-AEEA-OH, Fmoc-L-Glu-OtBu, and palmitic acid (HO-C(O)(CH2)). 14 CH3), hexadecanoic acid (HO-C(O)(CH2)) 14 COOH).

[0813] The crude peptide was purified using a preparative HPLC Waters system equipped with a C4 column. Specifically, the following column was used: Reprosil Gold C4 Prep (Dr Maisch), 250 x 40 cm. 5 μm. Acetonitrile + 0.1% TFA and water + 0.1% TFA were used as eluents. The fraction containing the product was collected and lyophilized to obtain the purified product, typically a TFA salt.

[0814] Alternatively, the compound can be isolated as an acetate using the following procedure: Using HiTrap. TM Ion exchange was performed using a Q HP column (GE Healthcare). The purified peptide was dissolved in 0.16 M acetic acid at a concentration of 2 mg / ml, slowly loaded onto the column, and eluted with 0.16 M acetic acid. The collected solution was lyophilized.

[0815] Crude and purified peptides were analyzed by ultra-high performance liquid chromatography (UPLC-UV-MS) with ultraviolet light and mass spectrometry detection. The UPLC analysis was performed according to one of the following methods:

[0816] Method A:

[0817] Detection at 214nm

[0818] Column: Acquity Waters BEH130 C4, 1.7μm (2.1x100 mm), 45℃

[0819] Solvent: H₂O + 0.1% TFA; ACN + 0.1% TFA (flow rate 0.4 ml / min)

[0820] Gradient: 70:30 (0 min) to 70:30 (1 min) to 50:50 (5 min) to 10:90 (5.2 min) to 10:90 (5.5 min) to 70:30 (5.7 min) to 70:30 (6 min)

[0821] Mass analyzer: Waters SQ detector with electrospray ionization in positive ion detection mode.

[0822] Method B:

[0823] Detection at 214nm

[0824] Column: Acquity Waters BEH130 C4, 1.7μm (2.1x100 mm), 45℃

[0825] Solvent: H₂O + 0.1% TFA; ACN + 0.1% TFA (flow rate 0.4 ml / min)

[0826] Gradient: 65:35 (0 min) to 65:35 (1 min) to 45:55 (5 min) to 10:90 (5.2 min) to 10:90 (5.5 min) to 65:35 (5.7 min) to 65:35 (6 min)

[0827] Mass analyzer: Waters SQ detector with electrospray ionization in positive ion detection mode.

[0828] Example 19.1: Universal Synthesis Procedure of SEQ ID NO:187-222

[0829] All peptides (SEQ ID NO: 187-222) were synthesized using standard Fmoc stepwise solid-phase synthesis (SPPS) on a Liberty Blue microwave synthesizer (CEM corp.). Assembly was performed using 0.1 mmol of Rink amide AM resin LL 0.29 mmol / g activated with DIC / Oxyma. DMF was used as the solvent. For modified lysine side chains, Fmoc-L-Lys(Dde)-OH was used at position 12.

[0830] Use the following conditions:

[0831] Standard deprotection: 20% piperidine in DMF solution, for 2 x 120 s, at 90°C.

[0832] Washing: 4xDMF.

[0833] Standard single coupling: 5 equivalent AA 0.4M / 5 equivalent DIC 1M / 5 equivalent Oxyma 1M, 120s, 90℃

[0834] Washing: 4xDMF.

[0835] At the end of assembly, the N-terminus of the peptide was protected using tert-butyl butyl carbonate in DMF (10 equivalent excess relative to resin loading, FluoroChem); the mixture was shaken at room temperature for 30 minutes and the reaction was monitored by a Kaiser test.

[0836] The Dde groups on Lys12 were removed by adding 2% hydrazine monohydrate, and the resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0837] After removing the Dde group, the treated resin was derivatized according to the peptide sequence side chain as reported in Examples 2-7.

[0838] The peptide was cleaved from the resin using the following cleavage mixture: 87.5% TFA, 5% phenol, 5% water, and 2.5% TIPS, for 2 to 2.5 hours. The resin used in the synthesis allowed the C-terminus to be cleaved from the resin as a primary amide.

[0839] The cleavage mixture was collected by filtration, the crude peptide was precipitated in methyl tert-butyl ether, centrifuged, the supernatant was removed, fresh ether was added to the peptide and centrifuged twice more; then the crude peptide was lyophilized.

[0840] Peptides were analyzed by UPLC and then subjected to ESI. + Mass spectrometry was used to validate the peptide. The crude peptide was purified using a standard preparative RP-HPLC purification procedure.

[0841] Example 19.2: Synthesis of the peptide of SEQ ID NO:187

[0842] The compound of SEQ ID NO:186 was prepared according to the procedure described in Example 19.1. NovabiochemRink amide AM resin LL 0.29 mmol / g (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucineaminomethyl resin), 100-200 mesh, was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. Fmoc-L-Lys(Dde)-OH at position 12 was used in the solid-phase synthesis scheme.

[0843] At the end of assembly, the N-terminus of the protective peptide was removed as reported in Example 19.1, and the Dde protecting group on Lys12 was removed.

[0844] The γ-carboxyl terminus of glutamic acid was linked to the ε-amino group of Lys using Fmoc-L-Glu-OtBu in DMF via the DIC / HOAt method (4 equivalents excess relative to resin loading). The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on the glutamic acid was removed by treating twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml). The resin was washed with NMP / DCM / NMP (6 / 6 / 6 times each). A Kaiser test for the peptide resin aliquot was positive when Fmoc deprotection was complete.

[0845] In NMP, hexadecanoic acid (HO-C(O)(CH2)) is used with the DIC / HOAt method (5 equivalents excess relative to resin loading). 14The albumin-binding moiety was ligated using COOH. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored using a Kaiser test. The resin was filtered and washed with NMP / DCM / NMP (6 times each).

[0846] Peptide cleavage from resin as described in Example 19.1. Preparation was performed by RP-HPLC on Reprosil Gold C4 Prep (Dr Maisch), 250 x 40 cm⁻¹. The crude product was purified using an acetonitrile / water gradient (with 0.1% TFA) at 5 μm. The purified peptide was analyzed by LC / MS (Method A). A (M / 4+H) peak was observed at a retention time of 3.84 min. + The quality signal showed that the peptide mass was 1213.97, which is consistent with the expected value of 1213.47.

[0847] Example 19.3: Synthesis of the peptide of SEQ ID NO:198

[0848] The compound of SEQ ID NO:197 was prepared according to the procedure described in Example 19.1. NovabiochemRink amide AM resin LL 0.29 mmol / g (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucineaminomethyl resin), 100-200 mesh, was used. An automated Fmoc synthesis strategy was employed with DIC / Oxyma activation. Fmoc-L-Lys(Dde)-OH at position 12 was used in the solid-phase synthesis scheme.

[0849] At the end of assembly, the N-terminus of the protective peptide was removed as reported in Example 19.1, and the Dde protecting group on Lys12 was removed.

[0850] Fmoc-AEEA-OH was attached to the ε-amino group of Lys in DMF using the DIC / HOAt method (4 equivalents excess relative to resin loading). The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on AEEA was removed by treating the resin twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml each time). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Kaiser test of the peptide resin aliquot was positive when Fmoc deprotection was complete.

[0851] In DMF, the second Fmoc-AEEA-OH is attached to the deprotected amino group using the DIC / HOAt method, and then deprotected from Fmoc as reported above.

[0852] The γ-carboxyl terminus of glutamic acid was attached to the deprotected amino group using Fmoc-L-Glu-OtBu in DMF via the DIC / HOAt method (4 equivalents excess relative to resin loading). The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on the glutamic acid was removed by treating twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml). The resin was washed with NMP / DCM / NMP (6 / 6 / 6 times each). A Kaiser test on an aliquot of the peptide resin was positive when Fmoc deprotection was complete.

[0853] In NMP, hexadecanoic acid (HO-C(O)(CH2)) is used with the DIC / HOAt method (5 equivalents excess relative to resin loading). 14 The albumin-binding moiety was ligated using COOH. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored using a Kaiser test. The resin was filtered and washed with NMP / DCM / NMP (6 times each).

[0854] Peptide cleavage from resin as described in Example 19.1. Preparation was performed by RP-HPLC on Reprosil Gold C4 Prep (Dr Maisch), 250 x 40 cm⁻¹. The crude product was purified using an acetonitrile / water gradient (with 0.1% TFA) at 5 μm. The purified peptide was analyzed by LC / MS (Method A). A (M / 4+H) peak was observed at a retention time of 3.66 min. + The quality signal showed that the peptide mass was 1286.7, which is consistent with the expected value of 1286.05.

[0855] Example 19.4: Synthesis of the peptide of SEQ ID NO:199

[0856] The compound of SEQ ID NO:198 was prepared according to the procedure described in Example 19.1. NovabiochemRink amide AM resin LL 0.29 mmol / g (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucineaminomethyl resin), 100-200 mesh, was used. An automated Fmoc synthesis strategy was employed with DIC / Oxyma activation. Fmoc-L-Lys(Dde)-OH at position 12 was used in the solid-phase synthesis scheme.

[0857] At the end of assembly, the N-terminus of the protective peptide was removed as reported in Example 19.1, and the Dde protecting group on Lys12 was removed.

[0858] Fmoc-AEEA-OH was attached to the ε-amino group of Lys in DMF using the DIC / HOAt method (4 equivalents excess relative to resin loading). The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on AEEA was removed by treating the resin twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml each time). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Kaiser test of the peptide resin aliquot was positive when Fmoc deprotection was complete.

[0859] In DMF, the second Fmoc-AEEA-OH is attached to the deprotected amino group using the DIC / HOAt method, and then deprotected from Fmoc as reported above.

[0860] Using the DIC / HOAt method in DMF (with a 4-equivalent excess relative to resin loading), Fmoc-L-Glu-OtBu was used to attach the γ-carboxyl terminus of glutamic acid to the deprotected amino group. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on the glutamic acid was removed by treating twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). A Kaiser test on an aliquot of the peptide resin was positive when Fmoc deprotection was complete.

[0861] The second Fmoc-L-Glu-OtBu was linked to the deprotected amino group in DMF using the DIC / HOAt method, followed by deprotection from Fmoc as reported above. The resin was washed with NMP / DCM / NMP (6 / 6 / 6 times each).

[0862] In NMP, hexadecanoic acid (HO-C(O)(CH2)) is used with the DIC / HOAt method (5 equivalents excess relative to resin loading). 14 The albumin-binding moiety was ligated using COOH. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored using a Kaiser test. The resin was filtered and washed with NMP / DCM / NMP (6 times each).

[0863] Peptide cleavage from resin as described in Example 19.1. Preparation was performed by RP-HPLC on Reprosil Gold C4 Prep (Dr Maisch), 250 x 40 cm⁻¹. The crude product was purified using an acetonitrile / water gradient (with 0.1% TFA) at 5 μm. The purified peptide was analyzed by LC / MS (Method A). A (M / 4+H) peak was observed at a retention time of 3.50 min. + The quality signal showed that the peptide mass was 1318.70, which is consistent with the expected value of 1318.33.

[0864] Example 19.5: Synthesis of the peptide of SEQ ID NO:204

[0865] The compound of SEQ ID NO:203 was prepared according to the procedure described in Example 19.1. NovabiochemRink amide AM resin LL 0.29 mmol / g (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucineaminomethyl resin), 100-200 mesh, was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. Fmoc-L-Lys(Dde)-OH at position 12 was used in the solid-phase synthesis scheme.

[0866] At the end of assembly, the N-terminus of the protective peptide was removed as reported in Example 19.1, and the Dde protecting group on Lys12 was removed.

[0867] The γ-carboxyl terminus of glutamic acid was linked to the ε-amino group of Lys using Fmoc-L-Glu-OtBu in DMF via the DIC / HOAt method (4 equivalents excess relative to resin loading). The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on the glutamic acid was removed by treating twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). A Kaiser test for the peptide resin aliquot was positive when Fmoc deprotection was complete.

[0868] Palmitic acid (HO-C(O)(CH2)) was used in DMF using the DIC / HOAt method (with an excess of 5 equivalents relative to the resin loading). 14 CH3) was used to ligate the albumin-binding moiety. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0869] Peptide cleavage from resin as described in Example 19.1. Preparation was performed by RP-HPLC on Reprosil Gold C4 Prep (Dr Maisch), 250 x 40 cm⁻¹. The crude product was purified using an acetonitrile / water gradient (with 0.1% TFA) at 5 μm. The purified peptide was analyzed by LC / MS (Method B). A (M / 4+H) peak was observed at a retention time of 3.84 min. + The quality signal showed that the peptide mass was 1206.50, which is consistent with the expected value of 1205.98.

[0870] Example 19.6: Synthesis of the peptide of SEQ ID NO:205

[0871] The compound of SEQ ID NO:204 was prepared according to the procedure described in Example 1. Novabiochem Rink amide AM resin LL 0.29 mmol / g (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucineaminomethyl resin), 100-200 mesh, was used. An automated Fmoc synthesis strategy was employed with DIC / Oxyma activation. Fmoc-L-Lys(Dde)-OH at position 12 was used in the solid-phase synthesis scheme.

[0872] At the end of assembly, the N-terminus of the protective peptide was removed as reported in Example 19.1, and the Dde protecting group on Lys12 was removed.

[0873] Fmoc-AEEA-OH was linked to the ε-amino group of Lys using the DIC / HOAt method (4 equivalents excess relative to resin loading) in DMF. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on AEEA was removed by treating the resin twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml each time). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Kaiser test of the peptide resin aliquot was positive when Fmoc deprotection was complete.

[0874] In DMF, the second Fmoc-AEEA-OH is attached to the deprotected amino group using the DIC / HOAt method, and then deprotected from Fmoc as reported above.

[0875] The γ-carboxyl terminus of glutamic acid was linked to the ε-amino group of Lys using Fmoc-L-Glu-OtBu in DMF via the DIC / HOAt method (4 equivalents excess relative to resin loading). The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on the glutamic acid was removed by treating twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). A Kaiser test for the peptide resin aliquot was positive when Fmoc deprotection was complete.

[0876] Palmitic acid (HO-C(O)(CH2)) was used in DMF using the DIC / HOAt method (with an excess of 5 equivalents relative to the resin loading). 14 CH3) was used to ligate the albumin-binding moiety. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0877] Peptide cleavage from resin as described in Example 19.1. Preparation was performed by RP-HPLC on Reprosil Gold C4 Prep (Dr Maisch), 250 x 40 cm⁻¹. The crude product was purified using an acetonitrile / water gradient (with 0.1% TFA) at 5 μm. The purified peptide was analyzed by LC / MS (Method B). A (M / 4+H) peak was observed at a retention time of 3.45 min. + The quality signal showed that the peptide mass was 1279.0, which is consistent with the expected value of 1278.56.

[0878] Example 19.7: Synthesis of the peptide of SEQ ID NO:206

[0879] The compound of SEQ ID NO:205 was prepared according to the procedure described in Example 19.1. NovabiochemRink amide AM resin LL 0.29 mmol / g (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-neoleucineaminomethyl resin), 100-200 mesh, was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. Fmoc-L-Lys(Dde)-OH at position 12 was used in the solid-phase synthesis scheme.

[0880] At the end of assembly, the N-terminus of the protective peptide was removed as reported in Example 19.1, and the Dde protecting group on Lys12 was removed.

[0881] Fmoc-AEEA-OH was linked to the ε-amino group of Lys using the DIC / HOAt method (4 equivalents excess relative to resin loading) in DMF. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on AEEA was removed by treating the resin twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml each time). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Kaiser test of the peptide resin aliquot was positive when Fmoc deprotection was complete.

[0882] In DMF, the second Fmoc-AEEA-OH is attached to the deprotected amino group using the DIC / HOAt method, and then deprotected from Fmoc as reported above.

[0883] The γ-carboxyl terminus of glutamic acid was attached to the deprotected amino group using Fmoc-L-Glu-OtBu in DMF via the DIC / HOAt method (4 equivalents excess relative to resin loading). The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group on the glutamic acid was removed by treating twice with 20% (v / v) piperidine / DMF solution for 5 minutes each time (25 ml). The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). A Kaiser test on an aliquot of the peptide resin was positive when Fmoc deprotection was complete.

[0884] The second Fmoc-L-Glu-OtBu was linked to the deprotected amino group in DMF using the DIC / HOAt method, and then deprotected from Fmoc as reported above.

[0885] Palmitic acid (HO-C(O)(CH2)) was used in DMF using the DIC / HOAt method (with an excess of 5 equivalents relative to the resin loading). 14 CH3) was used to ligate the albumin-binding moiety. The mixture was shaken at room temperature for 1 hour, and the reaction was monitored by a Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0886] Peptide cleavage from resin as described in Example 19.1. Preparation was performed by RP-HPLC on Reprosil Gold C4 Prep (Dr Maisch), 250 x 40 cm⁻¹. The crude product was purified using an acetonitrile / water gradient (with 0.1% TFA) at 5 μm. The purified peptide was analyzed by LC / MS (Method B). A (M / 4+H) peak was observed at a retention time of 3.30 min. + The quality signal showed that the peptide mass was 1311.35, which is consistent with the expected value of 1310.83.

[0887] Example 19.8: Synthesis of other peptides

[0888] The following peptides were synthesized according to the procedures described in Examples 19.1-7. The calculated and determined masses and retention times of these peptides, as well as the compounds of Examples 19.2-7, are shown in Table 3 below:

[0889] Table 17

[0890]

[0891]

[0892] Abbreviations

[0893] Certain abbreviations are used in the embodiments and elsewhere in this document:

[0894] “AA” refers to amino acids;

[0895] “AEEA” refers to [2-(2-aminoethoxy)ethoxy]acetyl;

[0896] “Aib” refers to 2-amino-isobutyric acid;

[0897] “Boc” refers to tert-butyloxycarbonyl;

[0898] “tBu” refers to tert-butyl.

[0899] "DCM" refers to dichloromethane;

[0900] “Dde” refers to 1-(4,4-dimethyl-2,6-dioxocyclohexyl)-ethyl; “DIC” refers to N,N'-diisopropylcarbodiimide.

[0901] "DMF" refers to dimethylformamide;

[0902] “Fmoc” refers to fluorene methoxycarbonyl group;

[0903] “gGlu” refers to γ-glutamic acid (γE);

[0904] “HOAt” refers to 1-hydroxy-7-azabenzotriazole;

[0905] "HPLC" refers to High Performance Liquid Chromatography;

[0906] "LC / MS" refers to liquid chromatography / mass spectrometry.

[0907] "MS" refers to mass spectrometry.

[0908] “NMP” refers to N-methyl-2-pyrrolidone;

[0909] “OtBu” refers to O-tert-butyl;

[0910] “Oxyma” refers to ethyl cyanohydroxyimino.

[0911] “Pbf” refers to 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl;

[0912] "RP-HPLC" refers to reversed-phase high-performance liquid chromatography.

[0913] "TIPS" refers to triisopropylsilane;

[0914] "TFA" refers to trifluoroacetic acid;

[0915] “Trt” refers to triphenylmethyl.

[0916] Example 19.9: Evaluation of the activity of these FA-modified peptides against the human CRF2α receptor

[0917] The agonistic effect of the compound on human adrenocorticotropic hormone-releasing factor 2α (CRF2α receptor) was determined by measuring cAMP regulation in TeloHEAC cells stably expressing the human CRF2α receptor.

[0918] The compound was dissolved in 100% DMSO at 0.5 mM and serially diluted (1:2) 16 times in 100% DMSO. Then, 20 nL of each dilution was transferred to a 384-well plate using an acoustic droplet ejector. 5 μL of compound buffer (1xHBSS; 20 mM HEPES, 2 mM IBMX, 0% or 0.2% HSA) was then added to each well.

[0919] Before use, thaw frozen cells rapidly at 37°C and wash with 20 mL of cell buffer (1x HBSS; 20 mM HEPES) (at 900 rpm for 5 minutes). Resuspend cells in cell buffer and adjust to a cell density of 800,000 cells / mL.

[0920] 5 μL of cells (final cell density: 4000 cells / well) were dispensed into 384-well plates containing the compound and incubated at 37°C for 30 minutes.

[0921] Following the manufacturer's instructions, cAMP levels in treated cells were determined using the Cisbio 62AM4PEC kit. Finally, the plates were incubated at room temperature for 1 hour, and then the fluorescence ratio between 665 and 620 nm was measured.

[0922] The percentage of activity (E%) was calculated by setting 100 nM urocortin 2 (UCN2) to 100%. The in vitro potency of the compound was quantified by determining the concentration that elicited 50% activation relative to the maximum response of urocortin 2 (EC50).

[0923] Representative EC50 values ​​are provided in Table 18 below:

[0924]

[0925]

[0926]

[0927] Table 18

[0928] Example 19.10: Activity assessment of the compound according to the invention against the target CFR1R receptor

[0929] CHO-K1 cell line clone 2, overexpressing CRF1R, was purchased from PerkinElmer.

[0930] Cells were grown to near confluence in 10 cm culture dishes at 37 °C / 5% CO2 in medium (F12 (Hams) / 10% FBS / 400 μg / ml G418). At this stage, cells were harvested and resuspended to 10 million / mL in medium without G418 and with 10% DMSO. Aliquots of 1 mL vials were slowly frozen in isopropanol to -80 °C and then transferred to liquid nitrogen for storage. These vials were used for experiments following the procedures reported in previous paragraphs, except for the compound used to define 100% activation (100 nM frog skin antihypertensive peptide) in the control wells.

[0931] Representative EC50 and Emax values ​​are provided in Table 19 below:

[0932]

[0933]

[0934]

[0935] Table 19

[0936] This table highlights the significant impact of the presence of free carboxylic acid in the FA modification of K12. See, for example, examples containing the albumin-bound moiety -gGlu-C(O)(CH2). 14 Peptides 223, 225, and 226 of CH3, for example, contain -gGlu-C(O)(CH2). 14 COOH and -{AEEA}2-gGlu-C(O)(CH2) 18 A comparison of peptides 222 and 224, with COOH as the albumin-binding moiety. This is even more evident for edge-to-edge comparisons of peptides that differ from each other only in the presence of the free carboxylic acid (Table 20).

[0937]

[0938] Table 20

[0939] It was also observed (data not shown) that elongating the albumin-binding moiety linkers containing free carboxylic acids, such as -{AEEA}2-gGlu- and -{AEEA}2-(gGlu)2-, further improved the CRF2 selectivity of the peptide.

[0940] Example 19.11: DMPK protocol and results for these FA-modified peptides

[0941] In vitro plasma stability

[0942] In vitro plasma metabolic stability was investigated in male Sprague Dawley rats and humans. Test compounds were incubated at 3 mM at 37 °C for 2 h. At each time point (0, 0.25, 1, and 2 h), samples for analysis were prepared using a single-step protein precipitation technique by adding 150 μL of ethanol and 0.1% formic acid to 50 μL of plasma aliquots. The samples were vortexed and then centrifuged at 14,000 rpm for 15 min. The supernatant (100 μL) was collected, diluted with 100 μL of water and 0.1% formic acid, and analyzed by LC-HRMS (TripleTOF 6600+, AB Sciex). For each test compound, the area ratio at each time point was compared to the area ratio at 0 h and converted to a residual percentage.

[0943] Representative plasma stability data are provided in Table 21 below:

[0944]

[0945]

[0946] Table 21

[0947] Solubility and chemical stability

[0948] For Example 15 above, LC-UV was used instead of light scattering to assess the chemical stability of representative examples of these FA-modified peptides. Solubility and chemical stability were investigated in 100 mM phosphate buffer (pH 7.4) and 100 mM acetate buffer (pH 4.5). The test compound powder was dissolved in both buffers at a target concentration of 10 mg / mL and incubated at room temperature for 1 hour. After centrifugation at 2500 rcf for 15 minutes, 10 mL of the supernatant was diluted with 190 mL of incubation buffer and analyzed by LC-UV (Acquity UPLC-DAD, Waters). Solubility was calculated by comparing the peak area of ​​the test compound in the buffer sample with the peak area of ​​the same compound dissolved at 0.5 mg / mL in water:acetonitrile 1:1, 0.1% formic acid.

[0949] From the centrifuged supernatant, collect two additional 80 mL aliquots and dilute with 160 mL of incubation buffer. One aliquot is stored at 5°C, and the other at 40°C. After 28 days, analyze the samples by LC-UV. Calculate chemical stability as a percentage loss using the following equation:

[0950] - Chemical stability (loss %) = [(Purity after 28 days at 5°C) - (Purity after 28 days at 40°C)] x 100 / (Purity after 28 days at 5°C)

[0951] Purity % = [(Compound peak area) x 100 / (Total peak area)]

[0952] Representative buffer solubility data are provided in Table 22 below:

[0953]

[0954]

[0955] Table 22

[0956] Representative chemical stability data are provided in Table 23 below:

[0957]

[0958] Table 23

[0959] All sequences disclosed herein are listed in the attached sequence listing, the entire contents of which form part of this specification.

[0960] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. Furthermore, the materials, methods, and examples given are illustrative only and not restrictive. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should be understood that although this application has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the claims. sequence list <110> Sanofi <120> CRF2 receptor agonists and their therapeutic uses <130> IIC230175 <150> EP20315387.9 <151> 2020-08-19 <160> 227 <170> BiSSAP 1.3.6 <210> 1 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_1 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 1 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Glu Lys Glu Lys Gln Gln Ala Glu Thr Asn Ala 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 2 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_2 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 2 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Glu Lys Glu Lys Gln Gln Ala Glu Thr Asn Ala 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 3 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_3 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 3 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Glu Lys Glu Lys Gln Gln Ala Glu Lys Asn Ala 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 4 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_4 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 4 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Glu Lys Glu Lys Gln Gln Ala Glu Thr Asn Ala 20 25 30 Lys Ile Leu Ala Gln Val 35 <210> 5 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_5 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 5 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Gln Arg Gln Arg Lys Glu Arg Gln Gln Ala Glu Thr Asn Ala 20 25 30 Arg Ile Leu Ala Arg Val 35 <210> 6 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_6 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 6 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Gln Arg Gln Arg Lys Glu Arg Gln Gln Ala Glu Lys Asn Ala 20 25 30 Arg Ile Leu Ala Arg Val 35 <210> 7 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_7 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 7 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Arg Glu Gln Ala Glu Lys Asn Ala 20 25 30 Arg Ile Leu Ala Arg Val 35 <210> 8 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_8 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 8 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Lys Lys Lys Gln Arg Gln Lys Ala Lys Thr Ala Ala 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 9 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_9 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 9 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Lys Lys Gln Arg Gln Lys Ala Lys Thr Ala Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 10 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_10 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 10 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Lys Lys Gln Arg Gln Lys Ala Lys Thr Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 11 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_11 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 11 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Lys Lys Lys Gln Arg Gln Lys Ala Lys Thr Asn Ala 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 12 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_12 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 12 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Arg Lys Gln Lys Gln Gln Ala Lys Thr Asn Ala 20 25 30 Lys Ile Leu Ala Arg Val 35 <210> 13 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_13 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 13 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Phe 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Leu Leu Glu Gln Ile 35 <210> 14 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_14 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 14 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Arg Lys Gln Lys Gln Lys Ala Lys Thr Asn Ala 20 25 30 Lys Ile Leu Ala Arg Val 35 <210> 15 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_15 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 15 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Lys Leu Phe 1 5 10 15 Lys Gln Ala Lys Gln Lys Lys Gln Arg Gln Lys Ala Lys Thr Asn Ala 20 25 30 Gln Ile Leu Ala Arg Val 35 <210> 16 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_16 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 16 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Gln Arg Gln Arg Lys Glu Arg Gln Gln Ala Glu Lys Asn Ala 20 25 30 Arg Ile Leu Ala Arg Val 35 <210> 17 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_17 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 17 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 18 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_18 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 18 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 19 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_19 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 19 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Xaa Glu Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 20 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_20 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 20 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Xaa Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> twenty one <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_21 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> variants <222> 25 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> twenty one Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Xaa Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> twenty two <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_22 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> twenty two Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Gln Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> twenty three <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_23 <220> <221> variants <222> 7 <223> D-valine (D) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> variants <222> 26 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> twenty three Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Arg Xaa Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> twenty four <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_24 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> twenty four Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 25 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_25 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 25 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Lys Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Lys Arg Lys Glu Arg Glu Lys Ala Glu Lys Asn Ala 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 26 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_26 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> variants <222> 27 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 26 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Lys Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Lys Arg Lys Glu Arg Glu Xaa Ala Glu Lys Asn Ala 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 27 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_27 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 27 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Lys Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Lys Arg Lys Glu Arg Glu Gln Ala Glu Lys Asn Ala 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 28 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_28 <220> <221> variants <222> 7 <223> D-valine (d) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 28 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Lys Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Lys Arg Lys Glu Arg Glu Lys Ala Glu Lys Ala Ala 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 29 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_29 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> variants <222> 27 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 29 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Lys Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Lys Arg Lys Glu Arg Glu Xaa Ala Glu Lys Ala Ala 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 30 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_30 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 30 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Lys Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Lys Arg Lys Glu Arg Glu Gln Ala Glu Lys Ala Ala 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 31 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_31 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 31 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Arg Glu Gln Ala Glu Lys Asn Xaa 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 32 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_32 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 32 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Arg Glu Gln Ala Glu Lys Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 33 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_33 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14CH3". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 33 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Arg Glu Gln Ala Glu Lys Asn Thr 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 34 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_34 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 34 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Lys Lys Gln Arg Gln Lys Ala Lys Thr Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 35 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_35 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 35 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 36 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_36 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 36 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Xaa Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 37 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_37 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 37 Ile Val Leu Ser Leu Asp Val Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Lys Glu Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 38 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_38 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 38 Ile Val Leu Ser Leu Asp Val Pro Thr Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Xaa Glu Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 39 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_39 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 39 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Arg Lys Glu Arg Gln Gln Ala Glu Thr Asn Ala 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 40 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_40 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 40 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Arg Lys Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 41 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_41 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 41 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Arg Lys Glu Arg Gln Gln Ala Glu Lys Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 42 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_42 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 42 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Arg Xaa Glu Arg Gln Gln Ala Glu Lys Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 43 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_43 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 43 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Lys Gln Lys Lys Leu Arg Ala Gln Ala Glu Thr Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 44 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_44 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 44 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Lys Gln Lys Lys Glu Arg Ala Gln Ala Glu Thr Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 45 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_45 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 45 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Lys Gln Lys Xaa Leu Lys Ala Gln Ala Glu Thr Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 46 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_46 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 46 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Lys Gln Lys Xaa Leu Arg Ala Gln Ala Glu Thr Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 47 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_47 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 47 Ile Val Leu Ser Leu Asp Xaa Pro Thr Lys Leu Lys Lys Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Lys Arg Xaa Glu Arg Glu Lys Ala Glu Lys Ala Ala 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 48 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_48 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 48 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Arg Xaa Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 49 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_49 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 49 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Arg Xaa Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 50 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_50 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 50 Ile Val Leu Ser Leu Asp Val Pro Thr Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Arg Xaa Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 51 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_51 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 51 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Leu Leu Glu Gln Ile 35 <210> 52 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_52 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 52 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 53 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_53 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 53 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 54 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_54 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 54 Phe Thr Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 55 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_55 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 55 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Lys Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 56 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_56 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 56 Phe Thr Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 57 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_57 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 57 Phe Thr Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Lys Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 58 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_58 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 58 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Phe 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Leu Leu Glu Gln Ile 35 <210> 59 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_59 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 59 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Leu Leu Glu Gln Ile 35 <210> 60 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_60 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 60 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 61 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_61 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 61 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 62 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_62 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 62 Phe Thr Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 63 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_63 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 63 Phe Thr Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 64 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_64 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 64 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Lys Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 65 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_65 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 65 Phe Thr Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Gln Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 66 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_66 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 66 Phe Thr Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Gln Lys Gln Lys Lys Glu Arg Gln Lys Ala Glu Thr Asn Val 20 25 30 Gln Leu Leu Glu Arg Val 35 <210> 67 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_67 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 67 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 68 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_68 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 68 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 69 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_69 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 14 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 69 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Xaa Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 70 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_70 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 70 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 71 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_71 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 14 <223> 2-Aminoisobutyric acid (Aib) <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 71 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Xaa Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 72 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_72 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 72 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 73 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_73 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 73 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Gln Lys Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 74 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_74 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 74 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 75 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_75 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 75 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 76 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_76 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 76 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 77 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_77 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 77 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Lys Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 78 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_78 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 78 Ile Val Leu Ser Leu Asp Val Pro Thr Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 79 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_79 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 79 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Lys Xaa Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 80 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_80 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 80 Ile Val Leu Ser Leu Asp Val Pro Thr Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 81 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_81 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 81 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Lys Xaa Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 82 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_82 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 82 Ile Val Leu Ser Leu Asp Val Pro Thr Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Val 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 83 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_83 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 83 Ile Val Leu Ser Leu Asp Xaa Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 84 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_84 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 84 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 85 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_85 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 85 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 86 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_86 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 86 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Lys Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 87 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_87 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 87 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Lys Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 88 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_88 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 88 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Lys Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 89 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_89 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 89 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Lys Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 90 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_90 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 90 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Lys Thr Asn Val 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 91 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_91 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 91 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Lys Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 92 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_92 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 92 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 93 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_93 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 93 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Lys Thr Asn Val 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 94 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_94 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 94 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Glu Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 95 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_95 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 95 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Glu Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 96 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_96 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 96 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Glu Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 97 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_97 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 97 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 98 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_98 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 98 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Lys Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 99 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_99 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 99 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 100 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_100 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> variants <222> 32 <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 100 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Xaa 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 101 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_101 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 101 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Lys Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 102 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_102 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 102 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 103 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_103 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 103 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 104 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_104 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 104 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 105 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_105 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 105 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 106 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_106 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 106 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 107 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_107 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 107 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 108 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_108 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 108 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Gln Lys Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 109 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_109 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 109 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Lys Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 110 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_110 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 110 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 111 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_111 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 111 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 112 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_112 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 112 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 113 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_113 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 113 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 114 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_114 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 114 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 115 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_115 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 115 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 116 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_116 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 116 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 117 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_117 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 117 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 118 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_118 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 118 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Gln Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 119 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_119 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 119 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Gln Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 120 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_120 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 120 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 121 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_121 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 121 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 122 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_122 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 122 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 123 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_123 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 123 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 124 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_124 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 124 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 125 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_125 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 125 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 126 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_126 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 126 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Lys Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 127 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_127 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 127 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Lys Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 128 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_128 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 128 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Ala Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 129 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_129 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 129 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 130 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_130 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 130 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 131 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_131 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 131 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 132 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_132 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 132 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 133 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_133 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 133 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 134 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_134 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 134 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 135 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_135 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 135 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 136 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_136 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 136 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Gln Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 137 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_137 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 137 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 138 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_138 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 138 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 139 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_139 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 139 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 140 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_140 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 140 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 141 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_141 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 141 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 142 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_142 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 142 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 143 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_143 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 143 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Lys Gln Lys Lys Gln Arg Gln Lys Ala Lys Thr Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 144 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_144 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 144 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Lys Ala Lys Thr Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 145 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_145 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 145 Phe Thr Leu Ser Leu Asp Val Pro Thr Lys Ile Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Lys Ala Lys Lys Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 146 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_146 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 146 Phe Thr Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Lys Ala Lys Lys Asn Lys 20 25 30 Gln Ile Leu Glu Arg Val 35 <210> 147 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_147 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 147 Ile Val Leu Ser Leu Asp Xaa Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 148 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_148 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 148 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 149 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_149 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 149 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 150 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_150 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 150 Ile Val Leu Ser Leu Asp Xaa Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 151 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_151 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 151 Ile Val Leu Ser Leu Asp Xaa Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 152 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_152 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 152 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 153 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_153 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 153 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Glu Lys Glu Lys Gln Gln Ala Glu Thr Asn Ala 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 154 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_154 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 154 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Glu Lys Glu Lys Gln Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 155 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_155 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 155 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Lys Gln Glu Lys Glu Lys Gln Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 156 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_156 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 156 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Ala 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 157 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_157 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 157 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 158 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_158 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 158 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 159 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_159 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 159 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Glu Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 160 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_160 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 160 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Glu Xaa Glu Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 161 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_161 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 161 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Glu Xaa Glu Arg Glu Gln Ala Glu Lys Asn Glu 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 162 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_162 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 162 Ile Val Leu Ser Leu Asp Xaa Pro Ile Glu Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 163 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_163 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 163 Ile Val Leu Ser Leu Asp Xaa Pro Ile His Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 164 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_164 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 164 Ile Val Leu Ser Leu Asp Xaa Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 165 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_165 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 165 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Ala Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Glu 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 166 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_166 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 166 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Glu 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 167 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_167 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 167 Ile Val Leu Ser Leu Asp Xaa Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Glu 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 168 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_168 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 168 Ile Val Leu Ser Leu Asp Xaa Pro Ile Glu Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Glu 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 169 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_169 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 169 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Glu Xaa Gln Arg Glu Gln Ala Glu Lys Asn Glu 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 170 <211> 38 <212> PRT <213> Artificial sequence <220> <221> MOD_RES <222> 1 <223> acetylation <220> <223> Compound Seq_170 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 170 Ile Val Leu Ser Leu Asp Xaa Pro Ile Glu Leu Lys Gln Ile Leu Leu 1 5 10 15 Glu Gln Glu Arg Gln Glu Xaa Gln Arg Glu Gln Ala Glu Lys Asn Glu 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 171 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_171 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-{gGlu}2-C(O)(CH2)16COOH <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 171 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 172 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_172 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-{gGlu}2-C(O)(CH2)16COOH <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 172 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 173 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_173 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)18COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 173 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 174 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_174 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-{gGlu}2-C(O)(CH2)16COOH <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 174 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 175 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_175 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)18COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 175 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 176 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_176 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-{gGlu}2-C(O)(CH2)16COOH <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 176 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 177 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_177 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-{gGlu}2-C(O)(CH2)16COOH <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 177 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 178 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_178 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)18COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 178 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 179 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_179 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 179 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 180 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_180 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 180 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 181 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_181 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 181 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 182 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_182 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 182 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 183 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_183 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-C(O)(CH2)16COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 183 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 184 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_184 <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-C(O)(CH2)16COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 184 Ile Val Leu Ser Leu Asp Xaa Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 185 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_185 <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)16COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 185 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Gln Lys Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 186 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Compound Seq_186 <220> <221> variants <222> 1 <223> Isoleucine (I) or phenylalanine (F) <220> <221> variants <222> 2 <223> Valine (V) or threonine (T) <220> <221> variants <222> 7 <223> Valine (V) or D-valine (V) <220> <221> variants <222> 9 <223> Isoleucine (I) or threonine (T) <220> <221> variants <222> 10 <223> Lysine (K), glutamic acid (E), histidine (H), or glycine (G) <220> <221> variants <222> 11 <223> Isoleucine (I) or leucine (L) <220> <221> variants <222> 12 <223> Lysine (K), wherein the ε-amino group of the lysine side chain Covalently bound to the albumin binding site <220> <221> variants <222> 13 <223> Glutamine (Q) or Lysine (K) <220> <221> variants <222> 14 <223> Isoleucine (I), lysine (K), or 2-aminoisobutyric acid (Aib) <220> <221> variants <222> 16 <223> Leucine (L) or phenylalanine (F) <220> <221> variants <222> 17 <223> Glutamic acid (E) or lysine (K) <220> <221> variants <222> 19 <223> Alanine (A), glutamic acid (E), or glutamine (Q) <220> <221> variants <222> 20 <223> Lysine (K) or arginine (R) <220> <221> variants <222> twenty one <223> Glutamine (Q) or lysine (K) <220> <221> variants <222> twenty two <223> Lysine (K), arginine (R), or glutamic acid (E) <220> <221> variants <222> twenty three <223> Lysine (K) or 2-aminoisobutyric acid (Aib) <220> <221> variants <222> twenty four <223> Glutamine (Q), 2-aminoisobutyric acid (Aib), leucine (L) or Glutamic acid (E) <220> <221> variants <222> 25 <223> Arginine (R), lysine (K), or 2-aminoisobutyric acid (Aib) <220> <221> variants <222> 26 <223> Alanine (A), glutamic acid (E), 2-aminoisobutyric acid (Aib) or Glutamine (Q) <220> <221> variants <222> 27 <223> Glutamine (Q), 2-aminoisobutyric acid (Aib), or lysine (K) <220> <221> variants <222> 29 <223> Glutamic acid (E) or lysine (K) <220> <221> variants <222> 30 <223> Lysine (K) or threonine (T) <220> <221> variants <222> 31 <223> Asparagine (N) or alanine (A) <220> <221> variants <222> 32 <223> Lysine (K), alanine (A), valine (V), threonine (T), glutamic acid (E) Or 2-aminoisobutyric acid (Aib) <220> <221> variants <222> 33 <223> Arginine (R), lysine (K), or glutamine (Q) <220> <221> variants <222> 34 <223> Isoleucine (I) or leucine (L) <220> <221> variants <222> 36 <223> Alanine (A) or glutamic acid (E) <220> <221> variants <222> 37 <223> Glutamine (Q) or arginine (R) <220> <221> variants <222> 38 <223> Isoleucine (I) or valine (V) <400> 186 Xaa Xaa Leu Ser Leu Asp Xaa Pro Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa 1 5 10 15 Xaa Gln Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Ala Xaa Xaa Xaa Xaa 20 25 30 Xaa Xaa Leu Xaa Xaa Xaa 35 <210> 187 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final _seq_187; AA; sequence list Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "--gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 187 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 188 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final _seq_188; AA; sequence list Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "--gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 188 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 189 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final _seq_189; AA; sequence list Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 189 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Gln Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 190 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_190; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 190 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Glu Gln Val 35 <210> 191 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_191; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 191 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Glu Lys Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 192 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_192; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 192 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Gln Arg Gln Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 193 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_193; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 193 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 194 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final _seq_194 of the sequence list; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 194 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Thr Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 195 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_195; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 195 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Gln Gln Ala Glu Thr Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 196 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_196; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty four <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 196 Ile Val Leu Ser Leu Asp Val Pro Ile Gly Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Lys Xaa Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 197 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_197; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 197 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Ala Arg Gln Lys Xaa Gln Arg Ala Gln Ala Glu Lys Asn Lys 20 25 30 Arg Ile Leu Glu Arg Val 35 <210> 198 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_198; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-gGlu-C(O)(CH2)14COOH". <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 198 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 199 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_199; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue modified at X12, and Ra represents... The albumin-binding portion, Ra, is "-{AEEA}2-{gGLU}2-C(O)(CH2)14COOH <220> <221> variants <222> twenty three <223> 2-Aminoisobutyric acid (Aib) <220> <221> MOD_RES <222> 38 <223> The C-terminal amino acid residue is amidated to form a primary amide. <400> 199 Ile Val Leu Ser Leu Asp Val Pro Ile Lys Leu Lys Gln Ile Leu Leu 1 5 10 15 Lys Gln Glu Arg Gln Lys Xaa Gln Arg Glu Gln Ala Glu Lys Asn Lys 20 25 30 Gln Ile Leu Ala Gln Val 35 <210> 200 <211> 38 <212> PRT <213> Artificial sequence <220> <223> >CRP-001 210819 The final sequence list _seq_200; AA; Synthesized Constructs > <220> <221> variants <222> 7 <223> D-valine (v) <220> <221> variants <222> 12 <223> K* represents the lysine residue ...

Claims

1. A compound being a peptide of any one of SEQ ID NO 1 to 184, 187 to 222 and 224 to 227 or a pharmaceutically acceptable salt thereof.

2. A compound, which is a peptide of any one of SEQ ID NO 3, 7, 35, 83, 130, 135, 136, 137, 138, 139, 140, 141, 142, 147, 149, 151, 152, 171, 172, 173 and 174, or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the compound of claim 1 or 2 and a pharmaceutically acceptable excipient.

4. A pharmaceutical composition comprising the compound of claim 1 or 2 and a pharmaceutically acceptable diluent.

5. A pharmaceutical composition comprising the compound of claim 1 or 2 and a pharmaceutically acceptable carrier.

6. The compound of claim 1 or 2 or the pharmaceutical composition of claim 3, 4 or 5, in a method of treating or preventing cardiovascular disease, obesity or diabetes in a patient.

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