CRF2 receptor agonists and their uses in therapy

Abstract

The present disclosure provides compounds that are peptides comprising the amino acid sequence of formula (I) as disclosed herein, or pharma- ceutically acceptable salts thereof. The compounds act as agonists of the corticotropin releasing factor receptor 2 (CRF2) and are useful in therapy, particularly in the treatment or prevention of cardiovascular disease, renal disease, obesity, diabetes, sarcopenia, particularly obesity-associated sarcopenia, heart failure, cachexia, and pulmonary hypertension.

Description

[Technical field]

[0001] The present disclosure relates to compounds that are agonists of the corticotropin releasing factor receptor 2 (CRF2) and their use in therapy, particularly in the treatment or prevention of cardiovascular disease, obesity, diabetes, sarcopenia, particularly obesity-related sarcopenia, cachexia, kidney disease, heart failure and pulmonary hypertension. [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] There are three known endogenous urocortins in mammals: UCN1, UCN2 and UCN3. Although highly homologous in sequence, these peptides differ in their binding to CRF1 and CRF2. CRF1 and CRF2 are non-selectively activated by corticotropin releasing hormone (CRH) and UCN1, whereas UCN2 and UCN3 are CRF2 selective agonists. In particular, UCN2 is a 38 amino acid peptide that selectively activates the CRF2 receptor, which includes the known isoforms CRF2-alpha (α), -beta (β) and -gamma (γ).

[0004] Urocortins and their receptors are involved in neurohumoral responses to various stresses and pathological conditions. In particular, urocortins have a positive effect on hemodynamics in both preclinical experimental heart failure models and in patients with heart failure or hypertension. Urocortins and CRF receptors are expressed in the heart, kidneys and blood vessels, with CRF2 being highly expressed and CRF1 being only slightly expressed, if at all (see Non-Patent Document 1). In experimental models, urocortins acting through CRF2 activation have been shown to improve cardiovascular function through a reduction in vascular resistance, improved renal function, and inotropic and relaxant effects on the heart. In clinical studies, UCN2 and UCN3 have been shown to have a direct vasorelaxant effect in healthy volunteers and patients with heart failure (see Non-Patent Document 2), whereas UCN2 has also been shown to increase cardiac output and reduce vascular resistance in patients with heart failure (see Non-Patent Document 3 and Non-Patent Document 4). Recombinant acetate of UCN3 has been shown to improve cardiac output and reduce vascular resistance in a multicenter study of patients with chronic stable heart failure (see Non-Patent Document 5).

[0005] Recent studies have demonstrated that UCN2 and / or UCN3 gene transfer into mice improves not only cardiac function but also glucose disposal (see Non-Patent Document 6). Furthermore, subcutaneous delivery of pegylated UCN2 has been shown to improve glucose tolerance and increase glucose uptake in skeletal muscle while reducing body weight (see Non-Patent Document 7). These findings suggest that urocortin may be useful not only for the treatment of cardiovascular disease, but also for the treatment of diseases such as diabetes and obesity.

[0006] Nevertheless, the extremely short half-life of urocortins is a major limitation in their therapeutic use (see Non-Patent Document 8). To date, urocortin therapy cannot be sustained without continuous intravenous infusion. However, management of patients with chronic diabetes or heart failure requires a therapy suitable for self-administration at home over the long term.

[0007] To overcome these limitations, various analogs of urocortin have been proposed. For example, US Pat. No. 5,399,633 (Alsina-Fernandez, Eli Lilly and Company) and US Pat. No. 5,499,633 disclose analogs of UCN2 that are said to be useful in treating diseases such as chronic kidney disease and type II diabetes.

[0008] However, there remains a need for improved CRF2 receptor agonists that are useful as therapeutic agents, particularly in the treatment and prevention of cardiovascular disease, obesity and diabetes. In particular, there is a need for selective CRF2 agonists that have desirable efficacy, pharmacokinetic properties (e.g., improved half-life) and / or physicochemical properties (e.g., improved stability and / or solubility), and that expand the potential for use in sarcopenia, kidney disease, particularly obesity-related sarcopenia, cachexia, heart failure and pulmonary hypertension. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2018013803 [Patent Document 2] International Publication No. 2022038179 [Non-patent literature]

[0010] [Non-Patent Document 1] Waser et al., Peptides, 2006, 27, 3029-3038 [Non-Patent Document 2] Stirrat et al., Br. J. Clin. Pharmacol.,2016,82, 974-982 [Non-Patent Document 3] Davis et al., Eur. Heart J., 2007,28,2589-2597 [Non-Patent Document 4] Chan et al., JACC: Heart Failure, 2013,1,433-441 [Non-Patent Document 5] Gheorghiade et al., Eur. J. Heart Fail.,2013,15, 679-89 [Non-Patent Document 6] Giamouridis et al., JACC: BasictoTranslational Science, 2018, 3, 2 [Non-Patent Document 7] Borg et al., Diabetes, 2019, 1403-1414 [Non-Patent Document 8] Davies et al., JACC, 2007, 49, 461-471 Summary of the Invention

[0011] In a first aspect, the present disclosure provides a compound of formula (I) (SEQ ID NO:1): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20- X21-X22-X23-X24-X25-X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38 (I) (In the formula, X1 is absent or isoleucine (I), isoleucine in the L- or D-configuration; X2 is valine (V) in the L- or D-configuration; X3 is leucine (L); X4 is serine (S), X5 is leucine (L); X6 is aspartic acid (D), X7 is valine (V) or D-valine (v); X8 is proline (P); X9 is isoleucine (I), X10 is lysine (K), alanine (A) or glycine (G), in particular lysine (K); X11 is leucine (L), isoleucine (I), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X12 is a lysine (K) with the epsilon-amino group of the lysine side chain covalently attached to the albumin binding moiety (also denoted here as (K*)); X13 is lysine (K), glutamine (Q) or alanine (A), in particular lysine (K) or glutamine (Q), more particularly lysine (K); X14 is isoleucine (I) or 2-aminoisobutyric acid (Aib); X15 is leucine (L), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X16 is leucine (L); X17 is glutamic acid (E) or lysine (K); X18 is glutamine (Q), X19 is glutamic acid (E); X20 is lysine (K), arginine (R) or alanine, in particular lysine (K) or arginine (R); X21 is glutamine (Q), X22 is lysine (K) or alanine (A), in particular alanine (A); X23 is lysine (K), alanine (A), glutamic acid (E) or 2-aminoisobutyric acid (Aib), in particular lysine (K), alanine (A) or 2-aminoisobutyric acid (Aib); X24 is glutamine (Q), X25 is arginine (R), alanine (A), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular arginine (R), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), X26 is glutamic acid (E) or 2-aminoisobutyric acid (Aib); X27 is glutamine (Q), X28 is alanine (A); X29 is glutamic acid (E); X30 is lysine (K) or threonine (T); X31 is asparagine (N), glutamine (Q) or alanine (A); X32 is lysine (K), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), glutamic acid (E), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx); X33 is glutamine (Q), X34 is isoleucine (I); X35 is leucine (L); X36 is alanine (A) or glutamic acid (E); X37 is glutamine (Q), X38 is valine, wherein when X1 is isoleucine, X7 is D-valine, and X32 is selected from valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex) or 1-aminocyclopropanecarboxylic acid (Cpx), wherein the isoleucine is optionally acetylated or N-methylated at the N-terminus, or a pharma- ceutically acceptable salt thereof.

[0012] In a second aspect of the disclosure, there is provided a pharmaceutical composition comprising a compound of the disclosure and a pharma- ceutically acceptable excipient, diluent or carrier.

[0013] The compounds and pharmaceutical compositions disclosed herein are useful in therapy and can be used to treat or prevent various diseases through agonism of the CRF2 receptor.Accordingly, in another aspect, the present disclosure relates to the use of the compounds and pharmaceutical compositions in therapy, particularly in the treatment or prevention of cardiovascular disease, obesity, diabetes, kidney disease, sarcopenia, particularly obesity-related sarcopenia, cachexia, heart failure and pulmonary hypertension. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present disclosure relates to compounds that are derivatives of UCN2 and are useful as CRF2 receptor agonists. The compounds exhibit desirable activity and selectivity at the CRF2 receptor, as well as improved pharmacokinetic properties and beneficial in vivo effects in relevant animal models. In addition, the compounds exhibit desirable physicochemical properties, such as desirable solubility and stability, making them excellent candidates for solution formulations for subcutaneous delivery. The compounds are useful in therapy, particularly for the treatment or prevention of cardiovascular disease, kidney disease, obesity, diabetes, sarcopenia, particularly obesity-related sarcopenia, cachexia, heart failure and pulmonary hypertension.

[0015] It has been found that the desirable properties of the UCN2 analogues disclosed in WO 2005 / 023901, in particular the property allowing for once-daily administration, are further improved by N-terminal modifications of said UCN2-like peptides (N-methylation, preferably acylation at Val2 or acetylation or N-terminal truncation by N-methylation) when combined with a further modification at position 32, which is shown to be key for the chemical stability of the peptide, as evidenced by the following data: Preferably, these N-terminal modifications and the modification at position 32 are further combined with D-valine at position 7, a further change that lowers the isoelectric point below 7, improving the solubility of the peptide at neutral pH. In particular, when the isoelectric point of the sequence is close to 7, mutations can be introduced at one or more positions where basic amino acids are present, such as positions 10, 13, 20, 22, 23 and 25 in particular, which has the advantage of a) lowering the isoelectric point below 6, thereby improving solubility at neutral pH, and b) at the same time significantly reducing the undesirable mast cell degranulation effects that lead to pseudo-allergic reactions often observed with peptides containing basic amino acids.

[0016] compound The compounds of the present disclosure are peptides comprising the amino acid sequence of formula (I) listed above, or a pharma- ceutically acceptable salt of said peptides.

[0017] In this disclosure, amino acids are referred to by their name, their commonly known three letter symbols, or the one letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Other commonly accepted three letter codes for amino acids may also be used, e.g., Aib for 2-aminoisobutyric acid. Unless otherwise specified, all amino acids used in the compounds of this disclosure are L-amino acids. Thus, for example, L-valine may be referred to as "valine," "V," or "Val," whereas D-valine may be clearly distinguished from it and represented as "v" or "D-val." In the one letter symbols, D-amino acids are represented by lower case letters, e.g., isoleucine is referred to as "i," valine is referred to as "v," serine is referred to as "s," leucine is referred to as "l," etc.

[0018] In an embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: X1 is absent or is isoleucine (I), isoleucine in the L- or D-configuration; X2 is valine (V), in the L- or D-configuration; X3 is leucine (L); X4 is serine (S); X5 is leucine (L); X6 is aspartic acid (D); X7 is valine (V) or D-valine (v); X8 is proline (P); X9 is isoleucine (I); X10 is lysine (K); X11 is leucine (L), isoleucine (I), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X12 is a lysine (K) with the epsilon-amino group of the lysine side chain covalently attached to the albumin binding moiety (K * ), X13 is lysine (K) or glutamine (Q); X14 is isoleucine (I) or 2-aminoisobutyric acid (Aib); X15 is leucine (L), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X16 is leucine (L); X17 is glutamic acid (E) or lysine (K); X18 is glutamine (Q), X19 is glutamic acid (E); X20 is lysine (K) or arginine (R); X21 is glutamine (Q), X22 is lysine (K); X23 is lysine (K), alanine (A), glutamic acid (E) or 2-aminoisobutyric acid (Aib); X24 is glutamine (Q), X25 is arginine (R), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X26 is glutamic acid (E) or 2-aminoisobutyric acid (Aib); X27 is glutamine (Q), X28 is alanine (A); X29 is glutamic acid (E); X30 is lysine (K) or threonine (T); X31 is asparagine (N), glutamine (Q) or alanine (A); X32 is lysine (K), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), glutamic acid (E), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx); X33 is glutamine (Q); X34 is isoleucine (I); X35 is leucine (L); X36 is alanine (A) or glutamic acid (E); X37 is glutamine (Q); X38 is valine, wherein when X1 is isoleucine, X7 is D-valine and X32 is selected from valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex) or 1-aminocyclopropanecarboxylic acid (Cpx), said isoleucine is optionally acetylated or N-methylated at the N-terminus, in particular acetylated at the N-terminus.

[0019] The above provisos regarding the selection of X32 when X1 is isoleucine and X7 is D-valine are applicable across the various embodiments disclosed herein, but do not apply to the following independent embodiments: In an embodiment of the above provisos, X1 is N-terminally acetylated or N-methylated isoleucine; In a particular embodiment of the above provisos, X1 is N-terminally acetylated isoleucine.

[0020] In some embodiments, when X1 is absent, X2 is valine, valine in the L- or D-configuration, particularly valine (V) in the L-configuration, which is optionally acylated or alkylated (e.g., N-methylated) at the N-terminus. In particular, when X1 is absent, X2 is valine, which is acylated at the N-terminus with a C1-20 alkanoyl group, more particularly, which is acylated at the N-terminus with a C1-10 alkanoyl group, even more particularly, which is acylated at the N-terminus with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, decanoyl, dodecanoyl, or tetradecanoyl, more particularly, which is acylated at the N-terminus with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, or heptanoyl.

[0021] In certain embodiments, when X1 is absent, X2 is valine, valine in the L- or D-configuration, particularly valine (V) in the L-configuration, which valine is N-terminally acylated or alkylated (preferably with an alkanoyl group as described hereinbefore), and X32 is selected from valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), glutamic acid (E), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx).

[0022] In certain embodiments, when X1 is absent, X2 is valine, valine in the L- or D-configuration, particularly valine (V) in the L-configuration, which valine is N-terminally acylated or alkylated (preferably with an alkanoyl group as described hereinbefore), and X32 is selected from valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx).

[0023] In another specific embodiment, when X1 is absent, X2 is valine, valine in the L-configuration or D-configuration, particularly valine (V) in the L-configuration, the valine is N-terminally alkylated or N-terminally acylated with a C1-20 alkanoyl group, more specifically, the valine is N-terminally acylated with a C1-10 alkanoyl group, even more specifically, the valine is N-terminally acylated with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, or heptanoyl, and X32 is selected from valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx).

[0024] In some embodiments, X7 is D-valine (v).

[0025] In certain embodiments, X11 is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL).

[0026] In some embodiments, X15 is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib).

[0027] In some embodiments, X23 is alanine (A), glutamic acid (E) or 2-aminoisobutyric acid (Aib).

[0028] In certain embodiments, X25 is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL).

[0029] In some embodiments, X31 is glutamine (Q).

[0030] In some embodiments, X32 is selected from the group consisting of valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), glutamic acid (E), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-amino-amino-peptide (Pt), 1 ... and in particular, X32 is selected from valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran ... X is selected from 1-amino-2-phenyl-1-phenyl ... -diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex) or 1-aminocyclopropanecarboxylic acid (Cpx), in particular 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx), wherein the isoleucine is optionally acetylated or N-methylated at the N-terminus.

[0031] In more specific embodiments, X32 is 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cp ex), more particularly, X32 is selected from 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex).

[0032] In some embodiments, the amino acid residue at X38 is amidated.

[0033] In an independent embodiment, the present invention relates to a compound in which at least one of X10, X11, X13, X15, X20, X22, X23, X25, X31 and X32 is X10, which is alanine (A) or glycine (G); X11 which is isoleucine (I), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), more particularly alpha-methyl-leucine (αMeL); X13, which is glutamine (Q) or alanine (A); X15, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X20, which is arginine (R) or alanine (A); X22, which is alanine (A); X23, which is alanine (A), glutamic acid (E), or 2-aminoisobutyric acid (Aib); X25, which is alanine (A), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), more particularly alpha-methyl-leucine (αMeL); X31 being glutamine (Q) or alanine (A), in particular glutamine (Q), and Glutamic acid (E), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid ( X32 being 1-aminocyclopropanecarboxylic acid (Cpx) or 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), and 1-aminocyclohexanecarboxylic acid (Chx); The present invention provides a peptide comprising an amino acid sequence of formula (I) as defined above, selected from the group consisting of:

[0034] In a further independent embodiment, X7 is D-valine, X38 is amidated and at least one of X11, X15, X23, X25, X31 and X32 is X11, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL); X15, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X23, which is alanine (A), glutamic acid (E), or 2-aminoisobutyric acid (Aib); X25, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL); X31, which is glutamine (Q), and Glutamic acid (E), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (C X32 being 1-aminocyclopropanecarboxylic acid (Cpx), in particular X32 selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), and 1-aminocyclohexanecarboxylic acid (Chx); is selected as.

[0035] In another independent embodiment, X1 is an N-methylated or acetylated isoleucine (particularly an acetylated isoleucine) or is absent, and when absent, X2 is an acylated valine, X7 is a D-valine, X38 is amidated, and at least one of X11, X15, X23, X25, X31 and X32 is X11, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL); X15, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X23, which is alanine (A), glutamic acid (E), or 2-aminoisobutyric acid (Aib); X25, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL); X31, which is glutamine (Q), and Glutamic acid (E), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (C X32 being 1-aminocyclopropanecarboxylic acid (Cpx), in particular X32 selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), and 1-aminocyclohexanecarboxylic acid (Chx); is selected as.

[0036] In another independent embodiment, X7 is D-valine, X38 is amidated and X32 is glutamic acid (E), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1 -carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx), in particular X32 is selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), and 1-aminocyclohexanecarboxylic acid (Chx), and at least one of X11, X15, X23, X25 and X31 is X11, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL); X15, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X23, which is alanine (A), glutamic acid (E), or 2-aminoisobutyric acid (Aib); X25, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL), and X31, which is glutamine (Q); is selected as.

[0037] In another independent embodiment, X1 is N-methylated or acetylated isoleucine (particularly acetylated isoleucine) or is absent, and if absent, X2 is an acylated valine, X7 is D-valine, X38 is amidated, and X32 is selected from glutamic acid (E), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP). , 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx), in particular X32 is selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), and 1-aminocyclohexanecarboxylic acid (Chx), and at least one of X11, X15, X23, X25, and X31 is X11, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL); X15, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X23, which is alanine (A), glutamic acid (E), or 2-aminoisobutyric acid (Aib); X25, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL), and X31, which is glutamine (Q); is selected as.

[0038] In one embodiment, X1 is absent or is an isoleucine (I) acetylated or N-methylated at the N-terminus; X2 is valine (V), and when X1 is absent, the valine is acylated or alkylated at the N-terminus, in particular with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl or heptanoyl, more particularly with a pentanoyl group; X7 is D-valine (v); X9 is isoleucine (I), X10 is lysine (K); X11 is leucine (L) or alpha-methyl-leucine (αMeL); X14 is isoleucine (I); X15 is leucine (L); X23 is lysine (K), alanine (A), glutamic acid (E) or 2-aminoisobutyric acid (Aib); X25 is arginine (R), X26 is glutamic acid (E); X31 is asparagine (N); X32 is glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx), and in particular X32 is 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx). aminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), more specifically, X32 is selected from 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex).

[0039] In one embodiment, X1 is absent or is an isoleucine (I) that is acetylated or N-methylated at the N-terminus; X2 is valine (V), and when X1 is absent, the valine is acetylated or acylated at the N-terminus with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanol, hexanoyl, or heptanoyl, more specifically, acylated at the N-terminus with a pentanoyl group; X3 is leucine (L); X4 is serine (S), X5 is leucine (L); X6 is aspartic acid (D), X7 is valine (V) or D-valine (v), in particular D-valine (v); X8 is proline (P); X9 is isoleucine (I), X10 is lysine (K); X11 is leucine (L) or alpha-methyl-leucine (αMeL); X12 is a lysine (K) (also designated herein as (K*)) in which the epsilon-amino group of the lysine side chain is covalently attached to the albumin binding moiety; X13 is lysine (K) or glutamine (Q), in particular lysine (K); X14 is isoleucine (I); X15 is leucine (L); X16 is leucine (L) or lysine (K), in particular leucine (L); X17 is glutamic acid (E) or arginine (R), in particular glutamic acid (E); X18 is glutamine (Q), X19 is glutamic acid (E); X20 is lysine (K) or arginine (R), in particular lysine (K); X21 is glutamine (Q), X22 is lysine (K), X23 is lysine (K), alanine (A), glutamic acid (E) or 2-aminoisobutyric acid (Aib); X24 is glutamine (Q), X25 is arginine (R), X26 is glutamic acid (E); X27 is glutamine (Q), X28 is alanine (A), X29 is glutamic acid (E); X30 is threonine (T) or lysine (K), in particular threonine (T); X31 is asparagine (N); X32 is lysine (K), 2-aminoisobutyric acid (Aib), glutamic acid (E), alanine (A), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), or 1-aminocyclopropanecarboxylic acid (Cpx); X33 is glutamine (Q), X34 is isoleucine (I); X35 is leucine (L); X36 is alanine (A) or glutamic acid (E), in particular alanine (A); X37 is glutamine (Q), X38 is valine (V), wherein X1 is N-terminally acetylated or N-methylated isoleucine (I), X7 is D-valine, and X32 is selected from 2-aminoisobutyric acid (Aib), glutamic acid (E), alanine (A), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), or 1-aminocyclopropanecarboxylic acid (Cpx). In particular, X32 is selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), or 1-aminocyclopropanecarboxylic acid (Cpx), more particularly, when X1 is N-terminally acetylated or N-methylated isoleucine (I), X32 is 2-aminoisobutyric acid (Aib); The albumin binding moiety may comprise the following group: -{AEEA}2-gGlu-C(O)(CH2) 16 COOH, -{AEEA}2-gGlu-C(O)(CH2) 18 COOH, -{AEEA}-gGlu-C(O)(CH2) 16 COOH, -{AEEA}-gGlu-C(O)(CH2) 18 COOH, -gGlu-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 16 COOH, -gGlu-C(O)(CH2) 18 COOH, and -{gGlu}2-C(O)(CH2) 18 COOH, or a pharma- ceutically acceptable salt thereof.

[0040] In one embodiment, X1 is absent or is an isoleucine (I) that is acetylated or N-methylated at the N-terminus; X2 is valine (V), and when X1 is absent, the valine is acylated or alkylated at the N-terminus, in particular with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl or heptanoyl, more particularly with a pentanoyl group; X7 is D-valine (v); X9 is isoleucine (I), X10 is lysine (K); X11 is leucine (L) or alpha-methyl-leucine (αMeL); X14 is isoleucine (I); X15 is leucine (L); X23 is lysine (K), glutamic acid (E) or alanine (A); X25 is arginine (R), X26 is glutamic acid (E); X31 is asparagine (N); X32 is glutamic acid (E), 2-aminoisobutyric acid (Aib), or 4-amino-piperidine-4-carboxylic acid (4-Pip); wherein when X1 is N-terminally acetylated or N-methylated isoleucine (I), X32 is selected from 2-aminoisobutyric acid (Aib) or 4-amino-piperidine-4-carboxylic acid (4-Pip).

[0041] In one embodiment, X1 does not exist, X2 is valine (V) whose N-terminus is methylated or acylated with a group selected from a propanoyl group, a butanoyl group, a pentanoyl group, or an isopropanoyl group; X32 is selected from glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx).

[0042] In one embodiment, X1 is an N-terminally acetylated or N-methylated isoleucine (I); X2 is valine (V), X7 is D-valine (v); X9 is isoleucine (I), X10 is lysine (K); X11 is leucine (L); X14 is isoleucine (I); X15 is leucine (L); X23 is lysine (K), alanine (A), or 2-aminoisobutyric acid (Aib); X25 is arginine (R), X26 is glutamic acid (E); X31 is asparagine (N); X32 is glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx), and in particular X32 is 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx). aminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), more specifically, X32 is selected from 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex).

[0043] In one embodiment, X1 is absent or isoleucine (I); X2 is valine (V), X7 is D-valine (v); X9 is isoleucine (I), X10 is lysine (K); X11 is leucine (L), α-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular X11 is leucine (L) or α-methyl-leucine (αMeL), X14 is isoleucine (I) or glutamine (Q), in particular X14 is isoleucine (I); X15 is leucine (L); X16 is leucine (L); X17 is glutamic acid (E) or lysine (K), in particular X17 is glutamic acid (E); X23 is lysine (K), alanine (A) or 2-aminoisobutyric acid (Aib), in particular X23 is lysine (K); X25 is arginine (R), X26 is glutamic acid (E); X30 is lysine (K) or threonine (T), in particular X30 is threonine (T); X31 is asparagine (N); X32 is a nucleotide sequence of lysine (K), glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecapsule (1H-Cyclohexyl)-2-pyridine-4-carboxylate ... X32 is selected from lysine (K), 2-aminoisobutyric acid (Aib), glutamic acid (E), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), wherein when X1 is absent, X2 is optionally N-terminally methylated or acylated with a group selected from an acetyl group, a propanoyl group, a butanoyl group, a pentanoyl group, or an isopropanoyl group; When X1 is isoleucine (I), X32 is glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx), in particular, X32 is 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino X32 is 2-aminoisobutyric acid (Aib), glutamic acid (E), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), more specifically, X32 is 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), even more specifically, X32 is 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip).

[0044] As noted above, the compounds of the disclosure comprise a modified lysine (K) residue at the position designated X12 of Formula (I) with an albumin binding moiety covalently attached to the epsilon-amino group of the lysine side chain.

[0045] The term "albumin binding moiety" as used herein refers to a moiety that can bind to albumin by covalent or non-covalent bonds. In embodiments, the albumin binding moiety can bind to albumin by non-covalent bonds. The albumin binding moiety may comprise or consist of a group selected from fatty acids, phthalocyanines, coumarins, flavonoids, tetracyclines, naphthalenes, aryl carboxylic acids, heteroaryl carboxylic acids, lipids, alkylamines, cyclic or linear tetrapyrroles and their organometallic compounds, halo-substituted aromatic derivatives, organic dyes, and derivatives of tryptophan and thyroxine.

[0046] In certain embodiments, the albumin binding moiety comprises a C10-C24 fatty acid group attached to the epsilon-amino group of a lysine side chain, either by a direct bond or by a linker. As used herein, the term "C10-C24 fatty acid" refers to a carboxylic acid having 10 to 24 carbon atoms. The C10-C24 fatty acid can be a saturated monoacid or a saturated diacid. "Saturated" means that the fatty acid does not contain a carbon-carbon double bond or a carbon-carbon triple bond.

[0047] Examples of saturated C10-C24 fatty acids include capric acid (decanoic acid, C10 monoacid), lauric acid (dodecanoic acid, C12 monoacid), dodecanedioic acid (DDDA) (C12 diacid), myristic acid (tetradecanoic acid, C14 monoacid), tetradecanedioic acid (C14 diacid), pentadecylic acid (pentadecanoic acid, C15 monoacid), pentadecanedioic acid (C15 diacid), palmitic acid (hexadecanoic acid, C16 monoacid), hexadecanedioic acid (C16 diacid), margaric acid (heptadecanoic acid, C17 monoacid), heptadecanedioic acid (C17 diacid), stearic acid (octadecanoic acid, C1 8 monoacid), octadecanedioic acid (C18 diacid), nonadecylic acid (nonadecanoic acid, C19 monoacid), nonadecanedioic acid (C19 diacid), alachadic acid (eicosanoic acid, C20 monoacid), eicosane diacid (C20 diacid), heneicosane acid (henicosane acid, C21 monoacid), heneicosane diacid (C21 diacid), behenic acid (docosane acid, C22 monoacid), docosane diacid (C22 diacid), tricosane acid (tricosane acid, C23 monoacid), tricosane diacid (C23 diacid), lignoceric acid (tetracosane acid, C24 monoacid), and tetracosane diacid (C24 diacid).

[0048] In certain embodiments, the C10-C24 fatty acid group is a C12-C24 fatty acid, in particular a C12-C20 fatty acid, more particularly a fatty acid selected from the group consisting of lauric acid (dodecanoic acid, C12 monoacid), dodecanedioic acid (DDDA) (C12 diacid), myristic acid (tetradecanoic acid, C14 monoacid), tetradecanedioic acid (C14 diacid), palmitic acid (hexadecanoic acid, C16 monoacid), hexadecanedioic acid (C16 diacid), stearic acid (octadecanoic acid, C18 monoacid), octadecanedioic acid (C18 diacid), alachadic acid (eicosanoic acid, C20 monoacid) and eicosandioic acid (C20 diacid).

[0049] The C10-C24 fatty acid may be directly attached to the epsilon-amino group of the lysine side chain. Alternatively, the C10-C24 fatty acid may be attached to the epsilon-amino group of the lysine side chain via a linker. The linker may comprise one or more groups selected from [2-(2-aminoethoxy)ethoxy]acetyl (referred to herein as "AEEA"), glycine (Gly), N-methylglycine (N-MeGly) and gamma-glutamic acid (gGlu).

[0050] In some embodiments, the albumin binding moiety has formula (II): -YZC(O)R 1 (II) (In the formula, Y is AEEA, {AEEA}2, {AEEA}3, Gly, {Gly}2, {Gly}3, N-MeGly, {N-MeGly}2, {N-MeGly}3 or absent; Z is gGlu, {gGlu}2 or absent, and R 1 -(CH2)xCOOH or -(CH2) x CH3 (wherein x is an integer of 10 to 22).

[0051] In an embodiment of the albumin binding moiety of formula (II), Y is {AEEA} or {AEEA}2 and Z is gGlu or {gGlu}2.

[0052] In an embodiment of the albumin binding moiety of formula (II), Y is absent and Z is gGlu.

[0053] In embodiments of the albumin binding moiety of formula (II), Y and Z are both absent.

[0054] In an embodiment of the albumin binding moiety of formula (II), R1 is -(CH2) x COOH (wherein x is an integer from 12 to 18).

[0055] In an embodiment of the albumin binding moiety of formula (II), Y is {AEEA} or {AEEA}2, Z is gGlu or {gGlu}2, and R 1 Ha-(CH2) x COOH (wherein x is an integer from 12 to 18).

[0056] In certain embodiments, the albumin binding moiety comprises the following group: -{AEEA}-gGlu-C(O)(CH2) 10 COOH, -{AEEA}-gGlu-C(O)(CH2) 12 COOH, -{AEEA}-gGlu-C(O)(CH2) 14 COOH, -{AEEA}-gGlu-C(O)(CH2) 16 COOH, -{AEEA}-gGlu-C(O)(CH2) 18 COOH, -{AEEA}2-gGlu-C(O)(CH2) 10 COOH, -{AEEA}2-gGlu-C(O)(CH2) 12 COOH, -{AEEA}2-gGlu-C(O)(CH2) 14 COOH, -{AEEA}2-gGlu-C(O)(CH2) 16 COOH, -{AEEA}2-gGlu-C(O)(CH2) 18 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 10 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 12 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 16 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2)18 COOH, -gGlu-C(O)(CH2) 10 COOH, -gGlu-C(O)(CH2) 12 COOH, -gGlu-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 16 COOH, -gGlu-C(O)(CH2) 18 COOH, -{gGlu}2-C(O)(CH2) 10 COOH, -{gGlu}2-C(O)(CH2) 12 COOH, -{gGlu}2-C(O)(CH2) 14 COOH, -{gGlu}2-C(O)(CH2) 16 COOH, and -{gGlu}2-C(O)(CH2) 18 COOH, is selected from.

[0057] In certain embodiments, the albumin binding moiety comprises the following group: -{AEEA}2-gGlu-C(O)(CH2) 10 COOH, -{AEEA}2-gGlu-C(O)(CH2) 12 COOH, -{AEEA}2-gGlu-C(O)(CH2) 14 COOH, -{AEEA}2-gGlu-C(O)(CH2) 16 COOH, -{AEEA}2-gGlu-C(O)(CH2) 18 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 10 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 12 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 14 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 16 COOH, -{AEEA}2-{gGlu}2-C(O)(CH2) 18 COOH, -gGlu-C(O)(CH2) 10 COOH, -gGlu-C(O)(CH2) 12 COOH, -gGlu-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 16 COOH, and -gGlu-C(O)(CH2) 18 COOH, is selected from.

[0058] In certain embodiments, the albumin binding moiety comprises the following group: -{AEEA}2-gGlu-C(O)(CH2) 16 COOH, -{AEEA}2-gGlu-C(O)(CH2) 18 COOH, -{AEEA}-gGlu-C(O)(CH2) 16 COOH, -{AEEA}-gGlu-C(O)(CH2) 18 COOH, -gGlu-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 16 COOH, -gGlu-C(O)(CH2) 18 COOH, -{gGlu}2-C(O)(CH2) 16 COOH, and -{gGlu}2-C(O)(CH2) 18 COOH, is selected from.

[0059] In certain embodiments, the albumin binding moiety comprises the following group: -{AEEA}2-gGlu-C(O)(CH2) 16 COOH, -{AEEA}2-gGlu-C(O)(CH2) 18 COOH, -{AEEA}-gGlu-C(O)(CH2) 16 COOH, -{AEEA}-gGlu-C(O)(CH2) 18 COOH, -gGlu-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 16 COOH, -gGlu-C(O)(CH2) 18 COOH, and -{gGlu}2-C(O)(CH2) 18 COOH, is selected from.

[0060] The chemical structures and IUPAC names of some examples of these groups are shown in Table 1 below, where R indicates the point of attachment of each group to the epsilon-amino group of the lysine residue at X12.

[0061] Table 1 [Table 1] JPEG2025508820000002.jpg196110JPEG2025508820000003.jpg19698JPEG2025508820000004.jpg196105JPEG2025508820000005.jpg19610 8JPEG2025508820000006.jpg19393JPEG2025508820000007.jpg193111JPEG2025508820000008.jpg19396JPEG2025508820000009.jpg19349

[0062] In some embodiments, the albumin binding moiety is -gGlu-C(O)(CH2) 12COOH, -gGlu-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 16 COOH, -gGlu-C(O)(CH2) 18 COOH, -{AEEA}2-gGlu-C(O)(CH2) 12 COOH, -{AEEA}2-gGlu-C(O)(CH2) 16 COOH, -{AEEA}2-gGlu-C(O)(CH2) 18 COOH and -{AEEA}2-{gGlu}2-C(O)(CH2) 16 COOH.

[0063] In certain embodiments, the albumin binding moiety is -gGlu-C(O)(CH2) 12 COOH, -gGlu-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 16 COOH, -{AEEA}2-gGlu-C(O)(CH2) 16 COOH and -{AEEA}2-{gGlu}2-C(O)(CH2) 16 COOH.

[0064] In another specific embodiment, the albumin binding moiety is -gGlu-C(O)(CH2) 14 COOH, -gGlu-C(O)(CH2) 16 COOH and -{AEEA}2-gGlu-C(O)(CH2) 16 COOH.

[0065] In one embodiment, the compound is a peptide comprising the amino acid sequence of any one of SEQ ID NOs: 1-244, except for a comparison peptide in which X1 is isoleucine and the isoleucine is neither acetylated nor N-methylated at the N-terminus, or a pharma- ceutically acceptable salt thereof.

[0066] In some embodiments, the compound is a peptide comprising the amino acid sequence of any one of SEQ ID NOs: 19, 33, 34, 40, 43, 47, 51, 54, 55, 57, 64, 80, 92, 93, 96, 98, 100, 104, 110, 113, 118, 125, 131, 132, 136, 144, 145, 189, 190, 193, 203, 206, 210, 212, 213, 215, 217, 218, 219, 222, 230, 231, 233, 234, 235, 236, 237, 238, 241, 242, 243, or a pharma- ceutically acceptable salt thereof.

[0067] In some embodiments, the compound is a peptide comprising the amino acid sequence of any one of SEQ ID NOs: 40, 51, 57, 64, 80, 98, 110, 206, 212, 213, 215, 218, 231, 235, 237, 238, 243, or a pharma- ceutically acceptable salt thereof.

[0068] In one embodiment, the compound is a peptide of the amino acid sequence of formula (I), or a pharma- ceutically acceptable salt thereof, wherein optionally the amino acid residue at X1 is acetylated and optionally the amino acid residue at X38 is amidated.

[0069] In certain embodiments, the compound is a peptide of the amino acid sequence of formula (I), or a pharma- ceutically acceptable salt thereof, wherein: X1 does not exist, X2 is valine (V), and when the valine is acylated or alkylated at the N-terminus, the N-terminus is particularly acylated with a C1-10 alkanoyl group, more specifically, the N-terminus is acylated with a C1-10 alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, or heptanoyl; X7 is D-valine (v); X9 is isoleucine (I), X10 is lysine (K); X11 is leucine (L) or alpha-methyl-leucine (αMeL); X14 is isoleucine (I); X15 is leucine (L); X23 is lysine (K), glutamic acid (E), alanine (A) or 2-aminoisobutyric acid (Aib); X25 is arginine (R), X26 is glutamic acid (E); X31 is asparagine (N); X32 is glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx); and optionally, the amino acid residue at X38 is amidated.

[0070] In certain embodiments, the compound is a peptide of the amino acid sequence of formula (I), or a pharma- ceutically acceptable salt thereof, wherein: X1 is an N-terminally acetylated or N-methylated isoleucine (I); X2 is valine (V), X7 is D-valine (v); X9 is isoleucine (I), X10 is lysine (K); X11 is leucine (L); X14 is isoleucine (I); X15 is leucine (L); X23 is lysine (K), glutamic acid (E), alanine (A) or 2-aminoisobutyric acid (Aib); X25 is arginine (R), X26 is glutamic acid (E); X31 is asparagine (N); X32 is selected from glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclohexane-1-carboxylic acid (Cpex). chloropropanecarboxylic acid (Cpx), in particular 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex) or 1-aminocyclopropanecarboxylic acid (Cpx), and optionally, the amino acid residue at X38 is amidated.

[0071] In some embodiments, the compound is a peptide of any one of SEQ ID NOs: 1-145 or 152-244, or a pharma- ceutically acceptable salt thereof. These peptides are listed in Table 2 below, where K * indicates a modified lysine residue at X12, Ra indicates an albumin binding moiety, Ac- indicates that the N-terminus is acetylated, NMe- indicates that the N-terminus is N-methylated, propanoyl- indicates that the N-terminus is alkylated with a propanoyl group, butanoyl- indicates that the N-terminus is alkylated with a butanoyl group, pentanoyl- indicates that the N-terminus is alkylated with a pentanoyl group, and -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide.

[0072] As used herein, a peptide acetylated at the N-terminus is generally represented as follows: [ka] (wherein Pep refers to the peptide structure).

[0073] As used herein, a peptide N-terminally acylated with a propanoyl group is generally represented as follows: [ka] (wherein Pep refers to the peptide structure).

[0074] As used herein, a peptide N-terminally acylated with a butanoyl group is generally represented as follows: [ka] (wherein Pep refers to the peptide structure).

[0075] As used herein, a peptide N-terminally acylated with a propanoyl group is generally represented as follows: [ka] (wherein Pep refers to the peptide structure).

[0076] As used herein, a peptide N-terminally acylated with an isopentanoyl group is generally represented as follows: [ka] (wherein Pep refers to the peptide structure).

[0077] Table 2 [Table 2] JPEG2025508820000016.jpg217156JPEG2025508820000017.jpg220157JPEG2025508820000018.jpg22015 7JPEG2025508820000019.jpg220157JPEG2025508820000020.jpg220157JPEG2025508820000021.jpg22015 3JPEG2025508820000022.jpg220154JPEG2025508820000023.jpg220154JPEG2025508820000024.jpg22015 8JPEG2025508820000025.jpg220148JPEG2025508820000026.jpg220157JPEG2025508820000027.jpg22014 7JPEG2025508820000028.jpg220147JPEG2025508820000029.jpg220147JPEG2025508820000030.jpg22014 9JPEG2025508820000031.jpg220156JPEG2025508820000032.jpg220148JPEG2025508820000033.jpg22015 4JPEG2025508820000034.jpg220152JPEG2025508820000035.jpg220152JPEG2025508820000036.jpg22015 7JPEG2025508820000037.jpg220151JPEG2025508820000038.jpg220158JPEG2025508820000039.jpg22087

[0078] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:19): Ac-IVLSLDVPIKαMeLK * QILLKQERQKKQREQAEKNAibQILEQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0079] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:33): Ac-VLSLDvPIKLK * KILLEQEKQKKQREQAETNKQILAQV-NH2 (In the formula, K residue at position 11 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0080] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:34): VLSLDvPIKLK * KILLEQEKQKKQREQAETNKQILAQV-NH2 (In the formula, K residue at position 11 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0081] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:40): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:43): Ac-IVLSLDVPIKαMeLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0083] In one embodiment, the compound has the following amino acid sequence (SEQ ID NO:47): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0084] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:51): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAbuQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0085] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:54): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNαMeKQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0086] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:55): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNDapQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0087] In one comparative embodiment, the compound has the following amino acid sequence (SEQ ID NO:56): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNEQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:57): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETN4-PipQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0089] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:64): NMeIVLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0090] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:80): Pentanoyl-VLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 11 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Pentanoyl- indicates that the N-terminal amino acid residue is acylated with a pentanoyl group), or a pharma- ceutically acceptable salt thereof.

[0091] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:92): Ac-VLSLDvPIKLK * KILLEQEKQKKQREQAETNKQILAQV-NH2 (In the formula, K residue at position 11 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:93): VLSLDvPIKLK * KILLEQEKQKKQREQAETNKQILAQV-NH2 (In the formula, K residue at position 11 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide), or a pharma- ceutically acceptable salt thereof.

[0093] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:96): Butanoyl-VLSLDVPIKLK * KILLEQEKQKKQREQAETNKQILAQV-NH2 (In the formula, K residue at position 11 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and butanoyl- indicates that the N-terminal amino acid residue is acylated with a butanoyl group), or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:100): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0095] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:104): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAbuQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0096] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:110): Ac-IVLSLDvPIKαMeLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0097] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:113): NMeIVLSLDvPIKLK * KILLEQEKQKKQREQAETNAQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0098] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:118): NMeIVLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K *) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0099] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:125): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 14 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0100] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:131): Ac-IVLSLDvPIKLK * KILLEQEKQKAQREQAETN4PipQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0101] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:132): Ac-IVLSLDvPIKLK * KILLEQEKQKAibQREQAETN4PipQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:136): Ac-IVLSLDdvPIKLK * KILLEQEKQKKQREQAETNCpxQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0103] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:144): NMeIVLSLDvPIKLK * KILLEQEKQKAQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:145): NMeIVLSLDvPIKLK * KILLEQEKQKAibQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0105] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:189): Ac-IVLSLDvPIKLK * KILLEQEKQKAQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:190): Ac-IVLSLDvPIKLK * KILLEQEKQKAibQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:193): Pentanoyl-VLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 11 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Pentanoyl- indicates that the N-terminal amino acid residue is acylated with a pentanoyl group), or a pharma- ceutically acceptable salt thereof.

[0108] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:203): Ac-IVLSLDvPIKLK *KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}-gGlu-C(O)(CH2) 16 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0109] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:206): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:210): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNThpQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:212): Ac-IVLSLDvPIKLK * KILLEQEKQKAQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:213): Ac-IVLSLDvPIKLK * KILLEQEKQKEQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:215): NMeIVLSLDvPIKLK * KILLEQEKQKAibQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0114] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:217): NMeIVLSLDvPIKLK * KILLEQEKQKAQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0115] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:218): NMeIVLSLDvPIKLK * KILLEQEKQKEQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0116] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:219): Pentanoyl-VLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 11 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Pentanoyl- indicates that the N-terminal amino acid residue is acylated with a pentanoyl group), or a pharma- ceutically acceptable salt thereof.

[0117] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:222): Pentanoyl-VLSLDvPIKLK * KILLEQEKQKAQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 11 (K * Glu-C(O)(CH2) is a Glu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Pentanoyl- indicates that the N-terminal amino acid residue is acylated with a pentanoyl group), or a pharma- ceutically acceptable salt thereof.

[0118] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:230): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}-gGlu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0119] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:231): Ac-IVLSLDvPIKLK * KILLEQEKQKEQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}-gGlu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0120] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:233): NMeIVLSLDvPIKLK * KILLEQEKQKEQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K *) has an epsilon-amino group in its side chain -{AEEA}-gGlu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0121] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:234): NMeIVLSLDvPIKLK * KILLEQEKQKAibQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}-gGlu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:235): Pentanoyl-VLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 11 (K * ) has an epsilon-amino group in its side chain -{AEEA}-gGlu-C(O)(CH2) 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Pentanoyl- indicates that the N-terminal amino acid residue is acylated with a pentanoyl group), or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:236): Ac-IVLSLDvPIKLK * KILLEQEKQKEQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0124] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:237): NMeIVLSLDvPIKLK * KILLEQEKQKEQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0125] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:238): Ac-IVLSLDvPIKLK *KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-gGlu-C(O)(CH2). 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0126] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:241): Ac-IVLSLDvPIKLK * KILLEQEKQKEQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu is a Glu-like molecule whose epsilon-amino side group is -{gGlu}2-C(O)(CH2). 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:242): NMeIVLSLDvPIKLK * KILLEQEKQKEQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu is a Glu-like molecule whose epsilon-amino side group is -{gGlu}2-C(O)(CH2). 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and NMe- indicates that the N-terminal amino acid residue is N-methylated), or a pharma- ceutically acceptable salt thereof.

[0128] In some embodiments, the compound has the following amino acid sequence (SEQ ID NO:243): Ac-IVLSLDvPIKLK * KILLEQEKQKKQREQAETNAibQILAQV-NH2 (In the formula, K residue at position 12 (K * Glu is a Glu-like molecule whose epsilon-amino side group is -{gGlu}2-C(O)(CH2). 18 It is chemically modified to be covalently bonded to COOH. -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide; and Ac- indicates that the N-terminal amino acid residue is acetylated), or a pharma- ceutically acceptable salt thereof.

[0129] The compounds of the present disclosure can be prepared and used in the form of pharmaceutically acceptable salts.Pharmaceutically acceptable salts and their preparation methods are well known in the art (see, for example, Stahl, et al. "Handbook of Pharmaceutical Salts: Properties, Selection and Use", Second Revised Edition, Wiley-VCH, 2011, and Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 1977, 66, 1).Examples of pharmaceutically acceptable salts include trifluoroacetate, sodium salt, acetate and hydrochloride.

[0130] Synthesis of compounds A variety of methods can be used to prepare the compounds of the present disclosure. Compounds can be prepared by synthesis in solution or on a solid support, followed by isolation and purification. Alternatively, peptides can be prepared by gene expression in a host cell into which a DNA sequence encoding the peptide has been introduced. Gene expression can also be achieved without the use of cell lines. Methods can also be used in combination.

[0131] In particular, the compounds can be prepared by solid phase synthesis on a suitable resin, which is a well-established methodology (see, for example, Stewart and Young, "Solid Phase Peptide Synthesis", Pierce Chemical Co., Rockford, III., 1984, and Atherton and Sheppard, "Solid Phase Peptide Synthesis: A Practical Approach", Oxford-IRL Press, New York, 1989).

[0132] Standard manual or automated solid-phase synthesis procedures can be used to prepare the compounds. Automated peptide synthesizers are commercially available, for example, from Applied Biosystems (Foster City, Calif.) and Protein Technologies Inc. (Tucson, Ariz.). Reagents for solid-phase synthesis are readily available from commercial sources. Solid-phase synthesizers can be used to block interfering groups, protect amino acids during reaction, couple, deprotect, and cap unreacted amino acids according to the manufacturer's instructions.

[0133] Solid phase synthesis can be initiated by attaching an N-terminally protected amino acid with a carboxy terminus to an inert solid support carrying a cleavable linker. The solid support can be any polymer that allows the coupling of the first amino acid, for example trityl, chlorotrityl, Wang or Rink resins, where the linkage of the carboxy group (or carboxamide group in the case of Rink resin) to the resin (if the Fmoc strategy is used) is acid sensitive. The support must be stable under the conditions used to deprotect the α-amino group during peptide synthesis.

[0134] After the first N-terminally protected amino acid is coupled to the solid support, the α-amino protecting group of the amino acid is removed using a reagent such as trifluoroacetic acid (TFA) or piperidine. The remaining protected amino acids are then coupled sequentially in the order represented by the peptide sequence using an appropriate amide coupling reagent, or added as preformed dipeptides, tripeptides, or tetrapeptides. Examples of coupling reagents include benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), hexafluorophosphate benzotriazole tetramethyluronium (HBTU), hexafluorophosphate azabenzotriazole tetramethyluronium (HATU), diisopropyl-carbodiimide (DIC), 1-hydroxybenzotriazole (HOBt), and 1-hydroxy-7-azabenzotriazole, and combinations thereof. Typically, the coupling is carried out at room temperature in an inert solvent such as dimethylformamide (DMF), N-methylpyrrolidone (NMP), or dichloromethane (DCM).

[0135] Usually, the reactive side groups of amino acids are protected with suitable blocking groups. These protecting groups are removed after the desired peptide is assembled, and they can be removed simultaneously with cleavage of the desired product from the resin under the same conditions. Protecting groups and procedures for their introduction 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 fluorenylmethoxycarbonyl (Fmoc).

[0136] The albumin binding moiety can be introduced by selectively functionalizing the lysine (K) residue at the position designated X12. Thus, the deprotected lysine residue can be selectively functionalized with the albumin binding moiety, since the lysine residue may contain a side chain protecting group that can be selectively removed, whereas other side chain protecting groups remain intact. Attachment of the albumin binding moiety to the epsilon-amino group of the lysine side chain can be achieved by an acylation reaction or other suitable reaction known in the art.

[0137] As an illustration, lysine residues can be protected with the 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl ("ivDde") protecting group, which is labile to highly nucleophilic bases such as 4% hydrazine in DMF (see Chhabra et al., Tetrahedron Lett. 1998, 39, 1603). Thus, if the N-terminal amino group and all side chain functional groups are protected with acid-labile protecting groups, the ivDde group can be selectively removed using a highly nucleophilic base. The resulting free amino group can then be coupled to an albumin binding moiety, for example by acylation. Alternatively, lysine residues may be protected with the (4-methoxyphenyl)diphenylmethyl ("Mmt") protecting group, which is labile to very weak acids such as acetic acid and trifluoroethanol in dichloromethane (see Dubowchik et al., Tetrahedron Lett., 1997, 38(30), 5257). Thus, if the N-terminal amino group and all side chain functional groups are protected with protecting groups that are only labile 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 coupled to an albumin binding moiety, for example by acylation.

[0138] Alternatively, the albumin binding moiety can be introduced with lysine during peptide synthesis by using a pre-functionalized building block as a coupling partner. An example of a pre-functionalized building block is Fmoc-L-Lys[gGlu(OtBu)-C(O)(CH2) 18 -C(O)OtBu]-OH, Fmoc-L-Lys[gGlu(OtBu)-C(O)(CH2) 16 -C(O)OtBu]-OH, Fmoc-L-Lys[gGlu(OtBu)-C(O)(CH2) 14 -C(O)OtBu]-OH and Fmoc-L-Lys[{AEEA}2-gGlu(OtBu)-C(O)(CH2) 16 -C(O)OtBu]-OH.

[0139] If necessary, the N-terminus of the peptide chain may be modified, for example by acetylation. For the synthesis of C-terminal amide peptides, in Fmoc synthesis a resin incorporating the Rink amide 4-methylbenzhydrylamine (MBHA) or Rink amide AM linker is typically used, whereas in tBoc synthesis an MBHA resin is generally used.

[0140] Once synthesis is complete, the peptide is cleaved from the solid support with concomitant side-chain deprotection using standard procedures, which can be accomplished using King's cocktail (King et al., Int. J. Peptide Protein Res., 1990, 36, 255-266) or similar cleavage cocktails known in the art.

[0141] The raw material can be purified by chromatography (e.g., preparative RP-HPLC) if necessary. Crude peptides are typically purified using RP-HPLC on a C8 or C18 column using a water-acetonitrile gradient in 0.05%-0.1% trifluoroacetic acid (TFA). The purity of the peptide can be verified by analytical RP-HPLC. The identity of the peptide can be verified by mass spectrometry. Compounds can also be isolated in solid form (e.g., as a dry powder) using techniques such as lyophilization.

[0142] The present disclosure also relates to intermediate compounds used in the synthesis of the present compounds. In particular, compounds are provided which are peptides comprising the amino acid sequence of formula (I) as disclosed herein, in which residues X1 to X11 and X13 to X38 have the meanings given in relation to formula (I) and X12 is lysine (K) or a salt thereof. The above compounds can be used as intermediates in the preparation of compounds of the present disclosure and can be obtained by attaching an albumin binding moiety to the epsilon-amino group of the lysine side chain of X12. The addition of the albumin binding moiety may be performed while the peptide is still attached to the solid phase. After the addition of the albumin binding moiety, the peptide may be released from the resin and purified.

[0143] Specific processes for preparing the compounds of this disclosure are described in the Examples below. The specific synthetic steps of each pathway described can be combined in various ways to prepare the compounds. The reagents and starting materials are readily available or can be prepared by methods known in the art.

[0144] Pharmaceutical Compositions Also disclosed herein are pharmaceutical compositions comprising a compound of the present disclosure and a pharma- ceutically acceptable carrier or excipient.

[0145] The pharmaceutical composition may comprise about 0.1% to about 99.9% by weight of the compound of the present disclosure and about 99.9% to about 0.1% by weight of one or more pharma- ceutically acceptable carriers, excipients, or diluents. In one example, the pharmaceutical composition comprises about 5% to about 75% by weight of the compound of the present disclosure, with the remainder being suitable pharmaceutical carriers, diluents, or excipients. Methods for preparing pharmaceutical compositions are known to those skilled in the art or are apparent to those skilled in the art from literature, such as, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press.

[0146] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents.

[0147] The pharmaceutical composition may be suitable for administration by oral, inhalation or parenteral routes, such as subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal administration. In particular, the pharmaceutical composition may be suitable for subcutaneous administration. In certain embodiments, the pharmaceutical composition is a ready-to-use composition suitable for administration by pen or auto-injector.

[0148] The compounds may exhibit desirable solubility, chemical stability, and / or physical stability, especially in solvents at physiological pH values ​​and solvents containing antimicrobial preservatives such as phenol or meta-cresol, and as a result, the compounds may be particularly suitable for use in pharmaceutical compositions in solution form.

[0149] In certain embodiments, the pharmaceutical composition is a solution comprising a solvent, a compound of the disclosure, and an antimicrobial preservative selected from phenol and meta-cresol dissolved in the solvent, where the compound of the disclosure is 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 where the solution has a pH measured at 25° C. of 6 to 8 (e.g., pH 7.0 or pH 7.4).

[0150] Therapeutic Use The compounds of the present disclosure are useful in therapy and can be used to treat or prevent various diseases.Accordingly, in another aspect, the present disclosure relates to the use of the compounds in therapy and to a therapeutic method of administering an effective amount of the compounds of the present disclosure to a patient.The present disclosure also relates to the use of the compounds for the manufacture of a medicament for use in therapy.The compounds are particularly useful in the therapy of diseases that can be treated or prevented by agonism of CRF2 receptor.

[0151] As used herein, the term "therapy" refers to the treatment or prevention of a disease in a patient.

[0152] The term "treat" or "treating" as used herein includes inhibiting, suppressing, slowing, halting or reversing the progression or severity of an existing disease in a patient. Treating may eliminate the disease, prevent or slow the disease in a patient, inhibit or slow the onset of new disease in a patient, reduce the frequency or severity of symptoms and / or recurrences in a currently or previously affected patient, and / or prolong or increase the patient's lifespan. In particular, treating a disease may result in curing, shortening the duration, ameliorating, slowing, or inhibiting the progression or worsening of the disease or its symptoms.

[0153] The term "prevent" or "preventing" as used herein refers to inhibiting or delaying the onset or progression of a disease in a patient.

[0154] As used herein, the term "disease" refers to any condition or disorder that damages or interferes with the normal function of a cell, tissue or organ.

[0155] As used herein, the term "patient" refers to a mammal, such as a human, mouse, guinea pig, rat, dog or cat. In certain embodiments, the patient is a human patient.

[0156] The term "effective amount" as used herein refers to an amount or dose of the compound of the present disclosure that, when administered to a patient in one or more doses, produces the desired effect in the patient. The effective amount can be easily determined by the attending diagnostician by using known techniques and observing the results obtained under similar circumstances. In determining the effective amount for a patient, the attending diagnostician will consider several factors, including, but not limited to, the species of mammal, its size, age and general health; the specific disease or disease involved; the severity of the disease or the extent or involvement of the disease; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the pharmaceutical drug administered; the selected dosing regimen; the use of concomitant drugs; and other relevant circumstances.

[0157] The compounds of the present disclosure can be effective over a wide range of administration. For example, the unit dose can be in the range of about 0.1 μg to about 50 mg per kg of body weight. For example, in the case of oral administration, the unit dose can be in the range of about 500 μg / kg to about 50 mg / kg. In the case of parenteral administration routes, for example subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal administration, the unit dose can be in the range of about 0.1 μg / kg to about 300 μg / kg, and in the case of inhalation as an administration route, the unit dose can be in the range of about 1 μg / kg to about 1 mg / kg, particularly in the range of about 30 μg / kg to about 300 μg / kg.

[0158] In embodiments, the compound is administered in a daily, weekly, bimonthly or monthly dose.

[0159] The compounds may be administered in combination with one or more additional therapeutic agents. As used herein, the term "in combination with" refers to administration of the compounds of the present disclosure with one or more additional therapeutic agents either simultaneously, sequentially, or in a single combined formulation.

[0160] The compounds of the present disclosure can be administered orally or by parenteral routes, such as subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal administration, or by inhalation.

[0161] In certain embodiments, the compound is administered by subcutaneous administration. The compound may be administered by a doctor, a nurse, or may be self-administered using an injection device. It is understood that the gauge size and the amount of injection volume are determined by a skilled practitioner. In one embodiment, the amount of injection volume is 2 ml or less, for example 1 ml or less. In another embodiment, a needle gauge of 27 or more, for example 29 or more, is used. Administration can be accomplished using an auto-injector or a multiple delivery device.

[0162] The compounds of the present disclosure may be useful in the treatment of diseases that can be treated or prevented by agonism of the CRF2 receptor.

[0163] The compounds are particularly useful for the treatment or prevention of cardiovascular disease, obesity and diabetes. Accordingly, embodiments of the present disclosure relate to the use of the compounds in the treatment or prevention of cardiovascular disease, obesity, diabetes, sarcopenia, particularly obesity-related sarcopenia, cachexia, heart failure and pulmonary hypertension in a patient.

[0164] The present disclosure also relates to a method of treating or preventing cardiovascular disease, obesity, diabetes, kidney disease, sarcopenia, particularly obesity-related sarcopenia, cachexia, heart failure and pulmonary hypertension in a patient, the method comprising administering to the patient an effective amount of a compound of the present disclosure. Further, the present disclosure relates to the use of a compound in the manufacture of a medicament for treating or preventing cardiovascular disease, obesity, diabetes, kidney disease, sarcopenia, particularly obesity-related sarcopenia, cachexia, heart failure and pulmonary hypertension in a patient.

[0165] Examples of cardiovascular diseases that can be treated or prevented using the compounds include heart failure, hypertension, dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, and stroke.The effect of the compounds in these conditions may be the result of or related to the effect on body weight, or may be independent of body weight.In certain embodiments, the compounds are used to treat or prevent heart failure alone or in addition to standard treatments, including but not limited to angiotensin enzyme inhibitors, angiotensin II receptor antagonists, angiotensin receptor / neprilysin inhibitors (ARNi), beta-blockers, mineralocorticoid antagonists, SGLT1 inhibitors, SGLT2 inhibitors, and diuretics.

[0166] The compounds may also be useful for the treatment or prevention of obesity and other disorders caused by or characterized by excess weight, such as obesity-related inflammation, obesity-related sarcopenia, obesity-related gallbladder disease, and obesity-induced sleep apnea. In adult patients, obesity is defined as a body mass index (BMI) of 30 kg / m or less. 2 BMI can be defined as greater than or equal to 100 mg / kg. BMI is a simple index of weight to height that is commonly used to classify overweight and obesity in adults. It is defined as an individual's weight in kilograms divided by the square of their height in meters, and is therefore expressed in kg / m2. The compound may be administered in combination with one or more additional therapeutic agents useful for treating obesity. Alternatively or additionally, treatment may be combined with diet and exercise.

[0167] The compounds can also be used to treat or prevent diabetes, particularly type II diabetes.The compounds can be administered alone or in combination with one or more additional therapeutic agents useful for the treatment of diabetes, such as one or more agents selected from metformin, thiazolidinedione (TZD), sulfonylurea (SU), dipeptidyl peptidase-IV (DPP-IV) inhibitors, glucagon-like peptide-1 (GLP1) agonists, and sodium glucose cotransporter (SGLT) inhibitors.Alternatively or additionally, treatment can be combined with diet and exercise.The compounds can also be used to treat or prevent hyperglycemia, type I diabetes, and impaired glucose tolerance.

[0168] The compounds may also be useful in the treatment or prevention of other diseases, such as metabolic syndrome, kidney disease, degenerative diseases (e.g., neurodegenerative diseases) or diseases associated with nausea or vomiting. In particular, the compounds may be useful in the treatment or prevention of sarcopenia, particularly obesity-related sarcopenia, cachexia, heart failure and pulmonary hypertension, either alone or in addition to standard treatments.

[0169] The present invention is further described by the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope or content of the present disclosure in any way. EXAMPLES

[0170] Abbreviation In the examples and elsewhere herein, certain abbreviations are used: "AA" stands for amino acid, "AEEA" refers to [2-(2-aminoethoxy)ethoxy]acetyl; "Aib" refers to 2-aminoisobutyric acid, "AUC" stands for area under the curve. "cAMP" stands for cyclic adenosine monophosphate, "Boc" refers to tert-butyloxycarbonyl, "BOP" refers to (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; "BSA" stands for bovine serum albumin. "tBu" stands for tertiary butyl. "DCM" refers to dichloromethane "Dde" refers to 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl "IvDde" refers to 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methyl-butyl "DIC" stands for N,N'-diisopropylcarbodiimide. "DIPEA" stands for N,N-diisopropylethylamine. "DMEM" refers to Dulbecco's modified Eagle's medium. "DMF" refers to dimethylformamide. "DMSO" refers to dimethyl sulfoxide. "EDT" stands for ethanedithiol. "FA" stands for formic acid, "FBS" stands for fetal bovine serum. "Fmoc" stands for fluorenylmethyloxycarbonyl. "gGlu" refers to gamma-glutamic acid (γE); "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; "HBSS" stands for Hanks' Balanced Salt Solution. "HBTU" refers to 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; "HEPES" refers to 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid. "HOAt" refers to 1-hydroxy-7-azabenzotriazole; "HOBt" refers to 1-hydroxybenzotriazole. "HOSu" refers to N-hydroxysuccinimide; "HPLC" stands for high performance liquid chromatography. "hr" refers to time, "HTRF" stands for homogeneous time-resolved fluorescence; "IBMX" refers to 3-isobutyl-1-methylxanthine, "iv" refers to intravenous "kDa" stands for kilodaltons. "LC / MS" stands for liquid chromatography / mass spectrometry. "Mmt" refers to monomethoxytrityl "MS" refers to mass spectrometry; "OtBu" stands for O-tert-butyl. "Palm" refers to palmitoyl, "Pbf" refers to 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl "PBS" stands for phosphate buffered saline. "PK" stands for pharmacokinetics; "RP-HPLC" stands for reversed-phase high-performance liquid chromatography. "sc" refers to subcutaneous "SEM" refers to standard error of the mean, "Stea" refers to stearyl, "TIPS" stands for triisopropylsilane. "TFA" stands for trifluoroacetic acid. "Trt" refers to trityl, and "UV" refers to ultraviolet light.

[0171] Materials and Methods In the synthetic procedures described in the examples, the following starting materials and methods were used.

[0172] For the synthesis of all peptide amides, Rink Amide AM Resin LL 0.29 mmol / g (4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamide-norleucylaminomethyl resin, Novabiochem) (100–200 mesh) was used.

[0173] Fmoc-protected natural amino acids were purchased from Novabiochem, Iris Biotech, Bachem or Chem-Impex 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-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-Val-OH.

[0174] Additionally, the following amino acids were purchased from Novabiochem, IrisBiotech, Bachem, Chem-ImpexInternational, FluoroChem, GLBiochem, Alchem ​​Pharmtech or AurumPharmatech: Fmoc-L-Lys(Dde)-OH, Fmoc-Aib-OH, Fmoc-D-Val-OH, Fmoc-D-Ile-OH, Fmoc-D-Leu-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-N-Methyl-L-Ile, Fmoc-L-Abu-OH, Fmoc-L-Asn(Me2)-OH, Fmoc-L-HSer(Trt)-OH, N-Boc-4-( Fmoc-amino)piperidine-4-carboxylic acid, Fmoc-L-Nva-OH, Fmoc-α-Me-L-Lys(Boc)-OH, Fmoc-α-Me-L-Leu-OH, Fmoc-L-Dap(Boc)-OH, Fmoc-4-amino-tetrahydropyran-4-carboxylic acid, 1-(Fmoc-amino)cyclohexanecarboxylic acid, Fmoc-1-aminocyclopentane-1-carboxylic acid, 1-(Fmoc-amino)cyclopropanecarboxylic acid.

[0175] The following side chain building blocks were obtained from Iris Biotech, TCI, Merck, BLD pharm: Fmoc-AEEA-OH, Fmoc-L-Glu-OtBu, tetradecanedioic acid (HO-C(O)(CH2) 12 COOH), 16-(tert-butoxy)-16-oxohexadecanoic acid (HO-C(O)(CH2) 16 COOtBu), 18-(Tert-butoxy)-18-oxooctadecanoic acid (HO-C(O)(CH2) 16 COOtBu), icosandioic acid (HO-C(O)(CH2) 18 COOH).

[0176] Propionic acid, butyric acid, valeric acid, 3-methylbutanoic acid, tert-butoxycarbonyl tert-butyl carbonate and acetic anhydride were purchased from TCI, FluoroChem, Fluka or Sigma-Aldrich.

[0177] The crude peptides were purified on a preparative HPLC Waters system equipped with a C4 column, specifically: Reprosil (Dr. Maish) Gold C4 Prep, 250x40 mm, 120 Å, 5 μm.

[0178] Acetonitrile + 0.1% TFA and water + 0.1% TFA were used as eluents. Fractions containing the product were collected and lyophilized to give the purified product, typically as the TFA salt.

[0179] Ion exchange from TFA to HCl was performed with the following protocol: 10 equivalents of HCl 50 mM were added to the peptide. A final concentration of 1 mg / ml was reached by diluting the sample with H2O / ACN 80:20. After lyophilization, the peptide was dissolved in H2O / ACN 80:20 and lyophilized again. The completeness of the ion exchange was confirmed by 19F NMR.

[0180] Crude and purified peptides were analyzed by ultra-performance liquid chromatography with UV and mass spectrometry detection (UPLC-UV-MS). Analytical UPLC was performed according to one of the following methods:

[0181] Method A: Detection at 214 nm Column: Acquity Waters BEH C4, 300Å, 1.7 μm (2.1x100 mm), 45°C Solvent: HO + 0.1% TFA:ACN + 0.1% TFA (flow rate 0.4 ml / min) Gradient: 70:30 (0 min) → 70:30 (1 min) → 50:50 (5 min) → 10:90 (5.2 min) → 10:90 (5.5 min) → 70:30 (5.7 min) → 70:30 (6 min) Mass spectrometer: Waters SQ Detector (electrospray ionization, positive ion detection mode)

[0182] Method B: Detection at 214 nm Column: Acquity Waters BEH C4, 300Å, 1.7 μm (2.1x100 mm), 45°C Solvent: HO + 0.1% TFA:ACN + 0.1% TFA (flow rate 0.4 ml / min) Gradient: 65:35 (0 min) → 65:35 (1 min) → 45:55 (5 min) → 10:90 (5.2 min) → 10:90 (5.5 min) → 65:35 (5.7 min) → 65:35 (6 min) Mass spectrometer: Waters SQ Detector (electrospray ionization, positive ion detection mode)

[0183] Example 1: General synthesis procedure for SEQ ID NOs: 1-145 The synthesis of all peptides (SEQ ID NOs: 1-145) was carried out by standard Fmoc stepwise solid phase synthesis (SPPS) on a Liberty Blue microwave synthesizer (CEM corp.). Assembly was carried out using Rink amide AM Resin LL 0.29 mmol / g on a 0.1 mmol scale with DIC / Oxyma activation. DMF was used as the solvent. The sequences were assembled with single couplings except for arginine and amino acids introduced after the alpha-methylated amino acids (double couplings). For the modified lysine side chain, Fmoc-L-Lys(Dde)-OH was used at position 12.

[0184] The following conditions were used: Standard deprotection: 20% piperidine in DMF, 120 sec x 2, 90°C Wash: DMF 4 times. Standard single coupling: 5 eq. AA 0.4 M / 5 eq. DIC 1M / 5 eq. Oxyma 1M, 120 sec, 90 °C Wash: DMF 4 times.

[0185] At the end of the assembly, the N-terminus of the peptide was modified according to the peptide sequence as reported in Examples 2-9.

[0186] Removal of the Dde group of Lys12 was achieved by dropwise addition of hydrazine monohydrate 2% and washing the resin with DMF / DCM / DMF (6 / 6 / 6 times each).

[0187] After removal of the Dde group, the resin was treated according to peptide sequence side chain derivatization as reported in Examples 2-9.

[0188] Cleavage of the peptide from the resin was carried out for 1.5-2.5 h using the following cleavage cocktail: TFA 87.5%, phenol 5%, water 5%, TIPS 2.5%. The resin used for the synthesis was such that the C-terminus was cleaved from the resin as a primary amide.

[0189] The cleavage mixture was collected by filtration, and the crude peptide was precipitated in methyl tert-butyl ether, centrifuged, the supernatant removed, fresh diethyl ether added to the peptide, and centrifuged again; this process was repeated twice, and the crude peptide was then lyophilized.

[0190] Peptides were analyzed by analytical UPLC and verified by ESI+mass spectrometry. Crude peptides were purified by conventional preparative RP-HPLC purification procedures.

[0191] Example 2: Synthesis of peptide of SEQ ID NO: 125 The compound of SEQ ID NO: 125 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)-phenoxyacetamide-norleucylaminomethyl resin) (100-200 mesh) was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. At position 12, Fmoc-L-Lys(Dde)-OH was used in a solid phase synthesis protocol.

[0192] At the end of the assembly, the N-terminus of the peptide was reacted with acetic anhydride (10 equivalent excess relative to the resin loading, Sigma-Aldrich) in DMF, the mixture was shaken at room temperature for 30 min, and the reaction was monitored by the Kaiser test.

[0193] The Dde protecting group of Lys12 was removed as reported in Example 1.

[0194] The γ-carboxyl terminus of glutamic acid was coupled to the epsilon-amino group of Lys using Fmoc-L-Glu-OtBu (4 equivalent excess relative to the resin loading) by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of glutamic acid was removed by treatment with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on peptide resin aliquots at the completion of Fmoc deprotection and was positive.

[0195] The attachment of the albumin binding moiety was performed using 18-(Tert-butoxy)-18-oxooctadecanoic acid (HO-C(O)(CH2)) by the DIC / HOAt method in DMF. 16 COOtBu) (5 equivalent excess relative to the loading of the resin). The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0196] The peptide was cleaved from the resin as described in Example 1. The crude product was purified by preparative RP-HPLC on a Reprosil Gold C4 Prep (Dr Maisch), 250x40 mm, 120 Å, 5 μm, using an acetonitrile / water gradient (containing 0.1% TFA). The purified peptide was analyzed by LC / MS as reported in Example 10.

[0197] Example 3: Synthesis of peptide of SEQ ID NO:9 The compound of SEQ ID NO:9 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)-phenoxyacetamide-norleucylaminomethyl resin) (100-200 mesh) was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. At position 12, Fmoc-L-Lys(Dde)-OH was used in a solid phase synthesis protocol.

[0198] At the end of the assembly, the N-terminus of the peptide was reacted with 3-methylbutanoic acid (4 equivalent excess relative to the resin loading, Sigma-Aldrich) by the DIC / HOAt method in DMF, the mixture was shaken at room temperature for 1 h, and the reaction was monitored by the Kaiser test.

[0199] The Dde protecting group of Lys12 was removed as reported in Example 1.

[0200] The γ-carboxyl terminus of glutamic acid was coupled to the epsilon-amino group of Lys using Fmoc-L-Glu-OtBu (4 equivalent excess relative to the resin loading) by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of glutamic acid was removed by treatment with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on peptide resin aliquots upon completion of Fmoc deprotection and was positive.

[0201] The attachment of the albumin binding moiety was performed using 16-(tert-butoxy)-16-oxohexadecanoic acid (HO-C(O)(CH2)) by the DIC / HOAt method in DMF. 16COOtBu) (5 equivalent excess relative to the loading of the resin). The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0202] The peptide was cleaved from the resin as described in Example 1. The crude product was purified by preparative RP-HPLC on a Reprosil Gold C4 Prep (Dr Maisch), 250x40 mm, 120 Å, 5 μm, using an acetonitrile / water gradient (containing 0.1% TFA). The purified peptide was analyzed by LC / MS as reported in Example 10.

[0203] Example 4: Synthesis of peptide of SEQ ID NO:7 The compound of SEQ ID NO: 7 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)-phenoxyacetamide-norleucylaminomethyl resin) (100-200 mesh) was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. At position 12, Fmoc-L-Lys(Dde)-OH was used in a solid phase synthesis protocol.

[0204] At the end of the assembly, the N-terminus of the peptide was acylated with butyric acid (4 equivalent excess relative to the resin loading, TCI) by the DIC / HOAt method in DMF, the mixture was shaken at room temperature for 1 h, and the reaction was monitored by the Kaiser test.

[0205] The Dde protecting group of Lys12 was removed as reported in Example 1.

[0206] The γ-carboxyl terminus of glutamic acid was coupled to the epsilon-amino group of Lys using Fmoc-L-Glu-OtBu (4 equivalent excess relative to the resin loading) by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of glutamic acid was removed by treatment with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on peptide resin aliquots at the completion of Fmoc deprotection and was positive.

[0207] The attachment of the albumin binding moiety was performed using 16-(tert-butoxy)-16-oxohexadecanoic acid (HO-C(O)(CH2)) by the DIC / HOAt method in DMF. 16 COOtBu) (5 equivalent excess relative to the loading of the resin). The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0208] The peptide was cleaved from the resin as described in Example 1. The crude product was purified by preparative RP-HPLC on a Reprosil Gold C4 Prep (Dr Maisch), 250x40 mm, 120 Å, 5 μm, using an acetonitrile / water gradient (containing 0.1% TFA). The purified peptide was analyzed by LC / MS as reported in Example 10.

[0209] Example 5: Synthesis of peptide of SEQ ID NO:86 The compound of SEQ ID NO: 86 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)-phenoxyacetamide-norleucylaminomethyl resin) (100-200 mesh) was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. At position 12, Fmoc-L-Lys(Dde)-OH was used in a solid phase synthesis protocol.

[0210] At the end of the assembly, the N-terminus of the peptide was acylated with valeric acid (4 equivalent excess relative to the resin loading, Sigma-Aldrich) by the DIC / HOAt method in DMF, the mixture was shaken at room temperature for 1 h, and the reaction was monitored by the Kaiser test.

[0211] The Dde protecting group of Lys12 was removed as reported in Example 1.

[0212] The γ-carboxyl terminus of glutamic acid was coupled to the epsilon-amino group of Lys using Fmoc-L-Glu-OtBu (4 equivalent excess relative to the resin loading) by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of glutamic acid was removed by treating with 20% (v / v) piperidine / DMF solution twice for 5 min (25 ml each). The resin was washed with NMP / DCM / NMP (6 / 6 / 6 times each). Kaiser test was performed on an aliquot of peptide resin at the completion of Fmoc deprotection and was positive.

[0213] The binding of the albumin-binding moiety was confirmed by the DIC / HOAt method in NMP using tetradecanedioic acid (HO-C(O)(CH2) 12COOH) (5 equivalent excess relative to the loading of the resin). The mixture was shaken at room temperature for 1 hour and the reaction was monitored by Kaiser test. The resin was filtered and washed with NMP / DCM / NMP (6 / 6 / 6 times each).

[0214] The peptide was cleaved from the resin as described in Example 1. The crude product was purified by preparative RP-HPLC on a Reprosil Gold C4 Prep (Dr Maisch), 250x40 mm, 120 Å, 5 μm, using an acetonitrile / water gradient (containing 0.1% TFA). The purified peptide was analyzed by LC / MS as reported in Example 10.

[0215] Example 6: Synthesis of peptide of SEQ ID NO: 42 The compound of SEQ ID NO: 42 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)-phenoxyacetamide-norleucylaminomethyl resin) (100-200 mesh) was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. At position 12, Fmoc-L-Lys(Dde)-OH was used in a solid phase synthesis protocol.

[0216] At the end of the assembly, the N-terminus of the peptide was reacted with acetic anhydride (10 equivalent excess relative to the resin loading, Sigma-Aldrich) in DMF, the mixture was shaken at room temperature for 30 min, and the reaction was monitored by the Kaiser test.

[0217] The Dde protecting group of Lys12 was removed as reported in Example 1.

[0218] Fmoc-AEEA-OH (4 equivalent excess relative to the resin loading) was coupled to the epsilon-amino group of Lys by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of AEEA was removed by treating the resin with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on an aliquot of peptide resin upon completion of Fmoc deprotection and was positive.

[0219] A second Fmoc-AEEA-OH was coupled to the deprotected amino group by the DIC / HOAt method in DMF, followed by deprotection from Fmoc as reported above.

[0220] The γ-carboxyl terminus of glutamic acid was coupled to the deprotected amino group using Fmoc-L-Glu-OtBu (4 equivalent excess relative to the resin loading) by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of glutamic acid was removed by treating with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on peptide resin aliquots at the completion of Fmoc deprotection and was positive.

[0221] The attachment of the albumin binding moiety was performed using 16-(tert-butoxy)-16-oxohexadecanoic acid (HO-C(O)(CH2)) by the DIC / HOAt method in DMF. 16 COOtBu) (5 equivalent excess relative to the loading of the resin). The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0222] The peptide was cleaved from the resin as described in Example 1. The crude product was purified by preparative RP-HPLC on a Reprosil Gold C4 Prep (Dr Maisch), 250x40 mm, 120 Å, 5 μm, using an acetonitrile / water gradient (containing 0.1% TFA). The purified peptide was analyzed by LC / MS as reported in Example 10.

[0223] Example 7: Synthesis of peptide of SEQ ID NO:94 The compound of SEQ ID NO: 94 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)-phenoxyacetamide-norleucylaminomethyl resin) (100-200 mesh) was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. At position 12, Fmoc-L-Lys(Dde)-OH was used in a solid phase synthesis protocol.

[0224] At the end of the assembly, the N-terminus of the peptide was acylated with propionic acid (4 equivalent excess relative to the resin loading, Sigma-Aldrich) by the DIC / HOAt method in DMF, the mixture was shaken at room temperature for 1 h, and the reaction was monitored by the Kaiser test.

[0225] The Dde protecting group of Lys12 was removed as reported in Example 1.

[0226] Fmoc-AEEA-OH (4 equivalent excess relative to the resin loading) was coupled to the epsilon-amino group of Lys by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of AEEA was removed by treating the resin with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on an aliquot of peptide resin upon completion of Fmoc deprotection and was positive.

[0227] A second Fmoc-AEEA-OH was coupled to the deprotected amino group by the DIC / HOAt method in DMF, followed by deprotection from Fmoc as reported above.

[0228] The γ-carboxyl terminus of glutamic acid was coupled to the deprotected amino group using Fmoc-L-Glu-OtBu (4 equivalent excess relative to the resin loading) by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of glutamic acid was removed by treating with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on peptide resin aliquots at the completion of Fmoc deprotection and was positive.

[0229] The attachment of the albumin binding moiety was performed using 18-(Tert-butoxy)-18-oxooctadecanoic acid (HO-C(O)(CH2)) by the DIC / HOAt method in DMF. 16 COOtBu) (5 equivalent excess relative to the loading of the resin). The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0230] The peptide was cleaved from the resin as described in Example 1. The crude product was purified by preparative RP-HPLC on a Reprosil Gold C4 Prep (Dr Maisch), 250x40 mm, 120 Å, 5 μm, using an acetonitrile / water gradient (containing 0.1% TFA). The purified peptide was analyzed by LC / MS as reported in Example 10.

[0231] Example 8: Synthesis of comparative peptide comp3 of SEQ ID NO: 146 The peptide sequence: IVLSLDvPIKLK * QILLKQERQKKQREQAEKNKQILEQV-NH2 (SEQ ID NO: 146) (In the formula, K residue at position 12 (K * ) has an epsilon-amino group in its side chain -{AEEA}2-{gGlu}2-C(O)(CH2). 14 It is chemically modified to be covalently bonded to COOH. A comparative compound (comp3) with -NH2 indicates that the C-terminal amino acid residue is amidated as a primary amide 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)-phenoxyacetamide-norleucylaminomethyl resin) (100-200 mesh) was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. At position 12, Fmoc-L-Lys(Dde)-OH was used in a solid phase synthesis protocol.

[0232] At the end of the assembly, the N-terminus of the peptide was protected using tert-butoxycarbonyl tert-butyl carbonate (10 equivalent excess relative to the resin loading, FluoroChem) in DMF, the mixture was shaken at room temperature for 30 min, and the reaction was monitored by the Kaiser test.

[0233] The Dde protecting group of Lys12 was removed as reported in Example 1.

[0234] Fmoc-AEEA-OH (4 equivalent excess relative to the resin loading) was coupled to the epsilon-amino group of Lys by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of AEEA was removed by treating the resin with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on an aliquot of peptide resin upon completion of Fmoc deprotection and was positive.

[0235] A second Fmoc-AEEA-OH was coupled to the deprotected amino group by the DIC / HOAt method in DMF, followed by deprotection from Fmoc as reported above.

[0236] The γ-carboxyl terminus of glutamic acid was coupled to the deprotected amino group using Fmoc-L-Glu-OtBu (4 equivalent excess relative to the resin loading) by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of glutamic acid was removed by treating with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on peptide resin aliquots at the completion of Fmoc deprotection and was positive.

[0237] A second Fmoc-L-Glu-OtBu was coupled to the deprotected amino group by the DIC / HOAt method in DMF, followed by deprotection from Fmoc as reported above. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0238] The attachment of the albumin binding moiety was performed using 16-(tert-butoxy)-16-oxohexadecanoic acid (HO-C(O)(CH2)) by the DIC / HOAt method in DMF. 16 COOtBu) (5 equivalent excess relative to the loading of the resin). The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0239] The peptide was cleaved from the resin as described in Example 1. The crude product was purified by preparative RP-HPLC on a Reprosil Gold C4 Prep (Dr Maisch), 250x40 mm, 120 Å, 5 μm, using an acetonitrile / water gradient (containing 0.1% TFA). The purified peptide was analyzed by LC / MS as reported in Example 10.

[0240] Example 9: Synthesis of peptide of SEQ ID NO: 41 The compound of SEQ ID NO: 41 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)-phenoxyacetamide-norleucylaminomethyl resin) (100-200 mesh) was used. An automated Fmoc synthesis strategy was applied with DIC / Oxyma activation. At position 12, Fmoc-L-Lys(Dde)-OH was used in a solid phase synthesis protocol.

[0241] At the end of the assembly, the N-terminus of the peptide was reacted with acetic anhydride (10 equivalent excess relative to the resin loading, Sigma-Aldrich) in DMF, the mixture was shaken at room temperature for 30 min, and the reaction was monitored by the Kaiser test.

[0242] The protecting group of Lys12 was removed as reported in Example 1.

[0243] The γ-carboxyl terminus of glutamic acid was coupled to the deprotected amino group using Fmoc-L-Glu-OtBu (4 equivalent excess relative to the resin loading) by the DIC / HOAt method in DMF. The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each). The Fmoc group of glutamic acid was removed by treating with 20% (v / v) piperidine / DMF solution three times for 3 min. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each). Kaiser test was performed on peptide resin aliquots at the completion of Fmoc deprotection and was positive.

[0244] A second Fmoc-L-Glu-OtBu was coupled to the deprotected amino group by the DIC / HOAt method in DMF, followed by deprotection from Fmoc as reported above. The resin was washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0245] The attachment of the albumin binding moiety was performed using 16-(tert-butoxy)-16-oxohexadecanoic acid (HO-C(O)(CH2)) by the DIC / HOAt method in DMF. 16 COOtBu) (5 equivalent excess relative to the loading of the resin). The mixture was shaken at room temperature for 1 h and the reaction was monitored by Kaiser test. The resin was filtered and washed with DMF / DCM / DMF (6 / 6 / 6 times each).

[0246] The peptide was cleaved from the resin as described in Example 1. The crude product was purified by preparative RP-HPLC on a Reprosil Gold C4 Prep (Dr Maisch), 250x40 mm, 120 Å, 5 μm, using an acetonitrile / water gradient (containing 0.1% TFA). The purified peptide was analyzed by LC / MS as reported in Example 10.

[0247] Example 10: Synthesis of further peptides The following peptides were synthesized according to the procedures described in Examples 1 to 9. In addition to the comparative peptide comp3 above, two further comparative peptides are included: comp1 of SEQ ID NO: 147 and comp2 of SEQ ID NO: 148, respectively.

[0248] [Table 3] Table legend: K* = position of side chain derivatization, v = D-valine, Ra = K * Side chain derivatization of R * The structure is reported in Figure 1

[0249] The calculated and measured masses and retention times of these peptides are shown in Table 3 below, along with the masses and retention times of the compounds of Examples 2-9.

[0250] Table 3 [Table 4] JPEG2025508820000042.jpg240107JPEG2025508820000043.jpg242108JPEG2025508820000044.jpg242108 JPEG2025508820000045.jpg242108JPEG2025508820000046.jpg242108JPEG2025508820000047.jpg185161

[0251] Example 11: Evaluation of activity at the human CRF2α receptor Agonism of the compounds for human corticotropin releasing factor 2α (CRF2α receptor) was determined by a functional assay measuring cAMP modulation upon treatment of TeloHEAC cells stably expressing the human CRF2α receptor.

[0252] Compounds were dissolved at 0.5 mM in 100% DMSO and serially diluted (1:2) in 100% DMSO to 16 steps. 20 nL of each dilution was then transferred to a 384-well assay plate using an acoustic droplet ejection device. 5 μL of compound buffer (1×HBSS, 20 mM HEPES) was added to each well.

[0253] Before use, frozen cells were quickly thawed at 37°C and washed (5 min at 900 rpm) with 20 mL of cell buffer (1x HBSS, 20 mM HEPES). Cells were resuspended in cell buffer supplemented with 2 mM IBMX and the cell density was adjusted to 2 M cells / ml.

[0254] 5 μL of cells (final cell density: 10000 cells / well) were dispensed into compound-containing 384-well assay plates and incubated at 37° C. for 30 minutes.

[0255] cAMP levels were determined in treated cells using the Cisbio 62AM4PEC kit according to the manufacturer's instructions. Finally, the fluorescence ratio between 665 / 620 nm was measured after incubating the plates at room temperature for 1 hour.

[0256] Percent activity values ​​(E%) were calculated by setting 100 nM Ucn2 (UCN2) as 100%. The in vitro potency of compounds was quantified by determining the concentration that caused 50% activation of the maximal response compared to Ucn2 (EC50).

[0257] Representative EC50 values ​​are presented in Table 4 below.

[0258] Table 4 [Table 5] JPEG2025508820000049.jpg24569JPEG2025508820000050.jpg24369JPEG2025508820 000051.jpg24369JPEG2025508820000052.jpg24369JPEG2025508820000053.jpg24369

[0259] Example 12: Evaluation of activity at the anti-target CFR1R receptor Assessment of activity at the anti-target CFR1R receptor will be performed using a procedure similar to that described for the TeloHEAC cell line.

[0260] CRF1R-overexpressing CHO-K1 cell line clone 2 was purchased from PerkinElmer.

[0261] Cells were grown in 10 cm dishes at 37° C. / 5% CO2 in medium (F12 (Hams) / 10% FBS / 400 μg / ml G418) until near confluence. At that stage, cells were harvested and resuspended at 10 million / mL in culture medium without G418 and with 10% DMSO. 1 mL vial aliquots were gradually frozen in isopropanol to −80° C. and then transferred to liquid nitrogen for storage. These vials were used to perform the experiments according to the procedure reported in the previous paragraph, with the exception of the compound used in the control wells to define 100% activation (100 nM Sauvagine) and the cell density (final cell density: 4000 cells / well).

[0262] Representative EC50 values ​​are presented in Table 5 below.

[0263] Table 5 [Table 6] JPEG2025508820000055.jpg24084JPEG2025508820000056.jpg24187JPEG2025508820000057.jpg24187 JPEG2025508820000058.jpg23787JPEG2025508820000059.jpg23987JPEG2025508820000060.jpg179130

[0264] Example 13: Evaluation of activity in rat CRF2α The A7R5 rat aortic smooth muscle cell line used in this study was purchased from ATCC.

[0265] Cells were grown in 10 cm dishes at 37° C. / 5% CO2 in culture medium (DMEM / 10% FBS) until near confluence, at which stage cells were harvested and resuspended at 10 million / mL in culture medium containing 5% DMSO. 1 mL vial aliquots were gently frozen in isopropanol to −80° C. and then transferred to liquid nitrogen for storage.

[0266] Using these vials, experiments were performed following the procedure reported in the previous paragraph, with the exception of the compound (100 nM sauvagin) used in the control wells to define 100% activation, and the cell density (final cell density: 5000 cells / well).

[0267] Representative EC50 values ​​compared to comparative peptide 11 (SEQ ID NO:85 in Table 2) are presented in Table 6 below.

[0268] Table 6 [Table 7] JPEG2025508820000062.jpg9083

[0269] Example 14: Evaluation of the solubility, chemical stability, catabolic stability and PK properties of peptides according to the invention The effect on the solubility, chemical stability, catabolic stability and PK properties of the peptides according to the invention was investigated by solubility, chemical stability, plasma and SC extract stability and pharmacokinetic studies. As comparative peptides, the following peptides (Table 7) were included in the assay:

[0270] Table 7 [Table 8] Generic: v=D-valine, K * = Position of side chain derivatization

[0271] in vitro plasma stability In vitro plasma metabolic stability was studied in male Sprague Dawley rats and humans. Test compounds were incubated at 3 μM for 2 h at 37°C. At each time point (0 h, 0.25 h, 1 h, and 2 h), samples were prepared for analysis by one-step protein precipitation by adding 150 μL of ethanol, 0.1% formic acid to a 50 μL plasma aliquot. Samples were mixed homogeneously by vortexing and then centrifuged at 14000 rpm for 15 min. Supernatants (100 μL) were collected, diluted with 100 μL of water, 0.1% formic acid, and analyzed by LC-HRMS (TripleTOF6600+, AB Sciex). For each test compound, the area ratio at each time point was compared to the area ratio at time 0 and converted to a percentage remaining.

[0272] Plasma stability was initially included in the ADME screening funnel. However, all compounds showed high stability in human, rat and minipig or dog plasma. Some representative examples are shown (Table 8). The good stability results indicate that differences in N-terminal protecting groups or linkers did not affect stability.

[0273] Plasma stability data for representative compounds in humans, rats and minipigs or dogs:

[0274] Table 8 [Table 9] JPEG2025508820000065.jpg42160

[0275] In vitro stability of subcutaneous tissue supernatants and identification of metabolites The in vitro metabolic stability of subcutaneous tissue supernatants (SCts) was studied in male Sprague Dawley rats. Test compounds were incubated at 3 mM for 2 h at 37°C. At each time point (0 h, 0.25 h, 1 h, and 2 h), samples were prepared for analysis by one-step protein precipitation by adding 150 μL of ethanol, 0.1% formic acid to a 50 μL aliquot of SCts. Samples were mixed homogeneously by vortexing and then centrifuged at 14000 rpm for 15 min. Supernatants (100 μL) were collected, diluted with 100 μL of water, 0.1% formic acid, and analyzed by LC-HRMS using either a TripleTOF 6600+ (Sciex) or an Orbitrap Q Exactive (Thermo). For each test compound, the area ratio at each time point was compared to the area ratio at 0 h and converted to a percentage remaining.

[0276] Software-assisted in vitro metabolite identification of SCts stability samples was performed using either Metabolite Pilot (Sciex) or Biopharma Finder (Thermo). In addition, metabolite identification using Metabolite Pilot was performed on plasma samples of CompY after SC administration at 1 mg / kg in rats.

[0277] Representative SCts stability data are presented in Table 9. The first analog of the comparative peptide tested had poor metabolic stability in rat SCts (<5% remaining at 2 hours). Identification of the in vitro soft spots of Comp X and Comp Y, as well as ID of the in vivo metabolites of Comp Y, identified the N-terminus as the major metabolic soft spot both in vitro (rat) and in vivo.

[0278] Acetylation or N-methylation of Ile1 at the N-terminus significantly improved rat SCts stability (>50% remaining at 2 hours). Finally, N-terminal stabilization improved the SC pharmacokinetic profile in rats (see Pharmacokinetics section below). All tested compounds showed good SCts stability in all species investigated (human, rat, minipig and dog), confirming that N-terminal modifications improved SCts stability. Additionally, the chemical nature of the Lys12 linker (e.g. gEC16OH, gEC20OH, PEG2-gE-C20OH and PEG2-PEG2-gE-C20OH) did not significantly affect the stability of these peptides.

[0279] Representative rat SCts stability data.

[0280] Table 9 [Table 10] JPEG2025508820000067.jpg64152

[0281] Solubility and Chemical Stability Solubility and chemical stability were studied in 100 mM phosphate buffer (pH 7.4) and 100 mM acetate buffer (pH 4.5). Powders of test compounds were dissolved in both buffers at a target concentration of 10 mg / mL and incubated at room temperature for 1 h. After centrifugation at 2500 rcf for 15 min, 10 μL of the supernatant was diluted with 190 μL 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 samples with the peak area of ​​the same compound dissolved at 0.5 mg / mL in 1:1 water:acetonitrile, 0.1% formic acid.

[0282] Two additional 80 μL aliquots were collected from the centrifuged supernatant and diluted with 160 μL of incubation buffer. One aliquot was stored at 5° C. and the other at 40° C. Samples were analyzed by LC-UV after 14 or 28 days. Chemical stability was calculated as % loss using the following formula: Chemical stability (as % loss) = [(purity after 14 or 28 days at 5°C) - (purity after 28 days at 40°C)] x 100 / (purity after 28 days at 5°C) % Purity = [(compound peak area) x 100 / (total peak area)]

[0283] Representative buffer stability data are presented in Table 10 below. Solubility was generally good at both pHs (data not shown), with most peptides approaching the target concentration (10 mg / mL). The peptides showed good chemical stability at pH 4.5, but some relevant degradation was observed at pH 7.4, likely related to isomerization of Asn31 (observed and confirmed by high resolution mass spectrometry). To block or reduce this degradation pathway, bulky amino acids were introduced in place of Lys32. Notably, the use of Aib, Abu and 4-Pip provided good chemical stabilization with no observed loss of purity after 2 weeks.

[0284] Table 10 [Table 11] JPEG2025508820000069.jpg23593

[0285] Pharmacokinetics The pharmacokinetics of UCN-2 derivatives was studied in male Sprague Dawley rats after subcutaneous administration (SC) of 0.05, 0.1, 0.3 or 1 mg / kg. Peptides were formulated as a solution in 10 mM phosphate (pH 7.4) buffer + glycerol 85% (2.3% v / v). Plasma samples obtained from dosed animals were prepared for analysis by a one-step protein precipitation method by adding 200 μL of methanol, 0.1% trifluoroacetic acid to a 50 μL aliquot of each subject sample. Samples were mixed homogeneously by vortexing and then centrifuged at 16000 rpm for 15 min. Supernatants (200 μL) were analyzed by LC-MSMS. Pharmacokinetic parameters were calculated using established non-compartmental methods. The area under the plasma concentration curve versus time (AUC) was determined using Watson LIMS (version 7.6) with linear trapezoidal interpolation for ascending slopes and logarithmic trapezoidal interpolation for descending slopes. The portion of the AUC from the final measurable concentration to infinity was estimated from the equation Ct / kel, where Ct represents the final measurable concentration and kel is the elimination rate constant. kel was determined from the concentration curve versus time by linear regression on the terminal phase of a semi-log plot.

[0286] Consistent with what was observed for the chemical stability data, stabilization of the N-terminus by acetylation or N-methylation of Ile-1 improved the PK properties, or when Ile-1 was removed from Val-2 by acetylation, the half-life in rats was extended up to 8.6 hours (data not shown).

[0287] Substitution of lysine-32 with bulky residues (e.g., Aib, Abu, or 4-Pip) further improved catabolic stability. Data for some representative peptides are presented in Table 11. Compared to Comp Y, there was a significant increase in half-life at much lower doses.

[0288] Furthermore, consistent with the stronger albumin binding typically observed with peptides with longer fatty acid chains, the C20-OH analog had a longer SC half-life compared to the C16-OH and C18-OH analogs.

[0289] Table 11. Rat PK results of representative peptides compared to Comp Y [Table 12] JPEG2025508820000071.jpg240126JPEG2025508820000072.jpg30126

[0290] Example 15: Evaluation of the degranulation ability of peptides according to the invention in human LAD2 cells Non-allergic (anaphylactoid) reactions are acute adverse drug reactions that can worsen the patient's condition and lead to potentially life-threatening effects. The main mechanism is direct stimulation of mast cells or basophils to release anaphylactic mediators such as histamine and β-hexosaminidase. A recent study by McNeil et al. (McNeil BD et al., Nature, 12, 519 (2015)) reported that MrgprX2, a specific membrane receptor on human mast cells, plays a major role in non-allergic reactions induced by small molecule drugs, including neuromuscular blockers and insect venoms, neuropeptides and peptide therapeutics.

[0291] Laboratory of Allergic Diseases 2 (LAD2) cells are a human mast cell line commonly used to study anaphylactic and anaphylactoid reactions because their biological properties are identical to those of primary human mast cells, including functional expression of the MrgprX2 receptor.

[0292] LAD2 cells were derived from CD34+ cells isolated from a patient with invasive mastocytosis with no detectable KIT mutation (Kirshenbaum et al., Leukemia Res. 27, 677 (2003)). LAD2 cells stably express IgE receptor type 1 (FceR1), exhibit a granular phenotype, and have been reported to be more sensitive to degranulating peptides than primary human mast cells (Kulka et al., Immunology 123, 398 (2008)).

[0293] Therefore, the LAD2 cell line appears to closely resemble normal human mast cells. Degranulation of LAD2 cells is quantified fluorometrically via the release of anaphylactic mediators such as β-hexosaminidase.

[0294] Human LAD2 cells were obtained following a license agreement with the NIH and cultured according to the NIH instructions.

[0295] LAD2 cells (20,000 cells / well in 96-well plates and 10,000 cells / well in 384-well plates) were incubated with compounds for 30 min. β-hexosaminidase released in the supernatants and cell lysates was quantified using the fluorogenic substrate 4-methylumbelliferyl-N-acetyl-bD-glucosaminide.

[0296] On the day of the assay, lyophilized peptides were dissolved in DMSO and / or PBS (1x, pH 7.4) to obtain a stock solution. This stock solution was used to prepare a working serial dilution such that the final concentrations in the assay ranged from 50, 100 or 300 μM to 0.1 or 0.001 μM. Each peptide was tested in biological replicates. When compounds were dissolved in DMSO, the final solvent concentration in the assay was 0.5% (v / v).

[0297] The percentage of degranulation, expressed as % of β-hexosaminidase release, was calculated by dividing the fluorescence signal of the supernatant by the sum of the signal from the supernatant and cell pellet (lysed in Triton X-100, 1% final) and multiplying by 100.

[0298] Dose-response curves were generated by plotting the % of β-hexosaminidase release relative to the total release from Triton-treated cells (y-axis) versus the concentration of peptide tested (x-axis). Mast cell degranulation (MCD) EC50 values ​​and standard errors were calculated using XLfit 5.5.0.5 based on the following formula: 4-parameter sigmoid model: f=(A+((BA) / (1+((C / x)^D)))) (Where A=Emin, B=Emax, C=EC50 and D=slope)

[0299] The potency (EC50) at the highest concentration and % β-hexosaminidase release of all peptides tested in LAD2 cells are summarized in Table 12 below.

[0300] Substance P and icatibant were included as positive controls, and GLP-1 as a negative control. Prior art peptides Comp 10 (SEQ ID NO: 56), Comp Y (SEQ ID NO: 149) and Comp X (SEQ ID NO: 151) were also included in the study.

[0301] Table 12. MCD data for representative peptides compared to Comp Y and Comp X. [Table 13] JPEG2025508820000074.jpg17452

[0302] Example 16: Evaluation of effects on blood pressure The effect of the compounds on systolic blood pressure was determined in a telemetry study in Sprague Dawley rats at a dose of 0.1 mg / kg SC.

[0303] Rats were pre-implanted with telemetry devices (DSI (Saint-Paul, USA), HD-S10, HD-S11 or HDS21) and allowed to recover for a minimum of 2 weeks before treatment with vehicle or the various peptides. Blood pressure (BP) was recorded through a catheter inserted into the abdominal aorta. The device body was placed in the abdomen. Animals were allowed to recover from surgery for at least 10 days before the first administration of test drug or vehicle.

[0304] Chronically instrumented rats in the telemetry study were housed individually immediately after surgery and then paired with non-instrumented peers after recovery.

[0305] Systolic blood pressure was recorded 1 h before treatment (basal period), after which subcutaneous administration of test compound or its vehicle was performed and signals were continuously recorded for up to 48 h, analyzed and expressed as % change from baseline.

[0306] Representative data are presented below in Table 13, where "Duration of Action" indicates the last time point at which an effect on BP was still observed (n=2 animals / peptide).

[0307] Table 13 [Table 14] JPEG2025508820000076.jpg189117

[0308] All sequences disclosed herein are listed in Table 2, with the accompanying list of sequences including albumin binding moieties also shown in Table 2. The contents of this list are incorporated herein in their entirety.

[0309] 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 are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention belongs. Although the present disclosure has been described in conjunction with its detailed description, it should be understood that the above description is intended to illustrate, but not to limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the claims.

Claims

1. Formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20- X21-X22-X23-X24-X25-X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38 (I) (In the formula, X1 is absent or isoleucine (I), isoleucine in the L- or D-configuration; X2 is valine (V), either in the L- or D-configuration; X3 is leucine (L), X4 is serine (S), X5 is leucine (L), X6 is aspartic acid (D), X7 is valine (V) or D-valine (v); X8 is proline (P), X9 is isoleucine (I), X10 is lysine (K), alanine (A) or glycine (G); X11 is leucine (L), isoleucine (I), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X12 is a lysine (K) with the epsilon-amino group of the lysine side chain covalently attached to the albumin binding moiety (here, (K * ) (also written as X13 is lysine (K), glutamine (Q) or alanine (A); X14 is isoleucine (I) or 2-aminoisobutyric acid (Aib); X15 is leucine (L), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X16 is leucine (L), X17 is glutamic acid (E) or lysine (K); X18 is glutamine (Q), X19 is glutamic acid (E), X20 is lysine (K), arginine (R) or alanine (A); X21 is glutamine (Q), X22 is lysine (K) or alanine (A); X23 is lysine (K), alanine (A), glutamic acid (E) or 2-aminoisobutyric acid (Aib); X24 is glutamine (Q), X25 is arginine (R), alanine (A), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X26 is glutamic acid (E) or 2-aminoisobutyric acid (Aib); X27 is glutamine (Q), X28 is alanine (A), X29 is glutamic acid (E), X30 is lysine (K) or threonine (T); X31 is asparagine (N), glutamine (Q) or alanine (A); X32 is lysine (K), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), glutamic acid (E), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx); X33 is glutamine (Q), X34 is isoleucine (I), X35 is leucine (L), X36 is alanine (A) or glutamic acid (E); X37 is glutamine (Q), X38 is valine (V), wherein when X1 is isoleucine, X7 is D-valine, and X32 is selected from valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex) or 1-aminocyclopropanecarboxylic acid (Cpx), wherein the isoleucine is optionally acetylated or N-methylated at the N-terminus, in particular when X1 is isoleucine, the isoleucine is acetylated or N-methylated at the N-terminus, or a pharma- ceutically acceptable salt thereof.

2. X1 is absent or is an isoleucine (I) acetylated or N-methylated at the N-terminus; when X2 is valine (V) and X1 is absent, said valine is acylated or alkylated at the N-terminus, in particular with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl or heptanoyl, more particularly with a pentanoyl group; X7 is D-valine (v); X9 is isoleucine (I), X10 is lysine (K), X11 is leucine (L) or alpha-methyl-leucine (αMeL); X14 is isoleucine (I), X15 is leucine (L); X20 is lysine (K), X23 is lysine (K), alanine (A), glutamic acid (E) or 2-aminoisobutyric acid (Aib); X25 is arginine (R), X26 is glutamic acid (E), X31 is asparagine (N); X32 is glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx), in particular, X32 is 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or 1-aminocyclopropanecarboxylic acid (Cpx). aminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex); more specifically, X32 is selected from 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex); 2. The compound of claim 1, wherein when X1 is N-terminally acetylated or N-methylated isoleucine (I), X7 is D-valine, and X32 is selected from valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex), or a pharma- ceutically acceptable salt thereof.

3. At least one of X10, X11, X13, X15, X20, X22, X23, X25, X31, and X32 is X10, which is alanine (A) or glycine (G); X11 which is isoleucine (I), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), more particularly alpha-methyl-leucine (αMeL); X13, which is glutamine (Q) or alanine (A); X15, which is alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib); X20, which is arginine (R) or alanine (A); X22, which is alanine (A); X23, which is alanine (A), glutamic acid (E) or 2-aminoisobutyric acid (Aib); X25, which is alanine (A), alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), in particular alpha-methyl-leucine (αMeL) or 2-aminoisobutyric acid (Aib), more particularly alpha-methyl-leucine (αMeL); X31 being glutamine (Q) or alanine (A), in particular glutamine (Q), and X32 being glutamic acid (E), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cpex) or 1-aminocyclopropanecarboxylic acid (Cpx), in particular X32 selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP) and 1-aminocyclohexanecarboxylic acid (Chx); 3. The compound according to claim 1 or 2, selected as:

4. X1 is absent or is an isoleucine (I) that is acetylated or N-methylated at the N-terminus; when X2 is valine (V) and X1 is absent, said valine is acylated or alkylated at the N-terminus, in particular with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl or heptanoyl, more particularly with a pentanoyl group; X7 is D-valine (v); X9 is isoleucine (I), X10 is lysine (K), X11 is leucine (L) or alpha-methyl-leucine (αMeL); X14 is isoleucine (I), X15 is leucine (L); X20 is lysine (K), X23 is lysine (K), X25 is arginine (R), X26 is glutamic acid (E), X31 is asparagine (N); The compound according to any one of claims 1 to 3, wherein when X32 is glutamic acid (E), 2-aminoisobutyric acid (Aib) or 4-amino-piperidine-4-carboxylic acid (4-Pip) and X1 is N-terminally acetylated or N-methylated isoleucine (I), X7 is D-valine and X32 is selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP) or 4-amino-piperidine-4-carboxylic acid (4-Pip), in particular when X1 is N-terminally acetylated or N-methylated isoleucine (I), X7 is D-valine and X32 is selected from 2-aminoisobutyric acid (Aib) or 4-amino-piperidine-4-carboxylic acid (4-Pip).

5. X1 does not exist, X2 is valine (V) whose N-terminus is acetylated or alkylated with a group selected from N-methyl, propanoyl, butanoyl, pentanoyl, or isopropanoyl; X32 is a nucleotide sequence of glutamic acid (E), valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP), 1-aminocyclohexanecarboxylic acid (Chx), 1-aminocyclopentane-1-carboxylic acid (Cp Compounds according to any one of claims 1 to 4, wherein X32 is selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP) or 4-amino-piperidine-4-carboxylic acid (4-Pip), more particularly, X32 is selected from 2-aminoisobutyric acid (Aib) or 4-amino-piperidine-4-carboxylic acid (4-Pip).

6. The compound according to any one of claims 1 to 5, wherein the compound is a peptide of the amino acid sequence of formula (I), and when X1 is absent, X2 is valine, valine in the L- or D-configuration, in particular valine in the L-configuration (V), and the valine is acylated or alkylated at the N-terminus, in particular the valine is acylated at the N-terminus with a C1-20 alkanoyl, more particularly the valine is acylated at the N-terminus with a C1-10 alkanoyl, even more particularly the valine is acylated at the N-terminus with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, decanoyl, dodecanoyl or tetradecanoyl, more particularly the valine is acylated at the N-terminus with an alkanoyl group selected from ethanoyl, methanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl or heptanoyl.

7. The compound is a peptide of the amino acid sequence of formula (I), and when X1 is absent, X2 is valine, valine in the L-configuration or D-configuration, in particular valine (V) in the L-configuration, said valine being acylated or alkylated at the N-terminus, and X32 is selected from the group consisting of valine (V), threonine (T), 2-aminoisobutyric acid (Aib), alanine (A), 2-aminobutyric acid (Abu), norvaline (Nva), α-methyl-lysine (αMeK), 2,3-diaminopropionic acid (Dap), 4-amino-piperidine-4-carboxylic acid (4-Pip), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP 7. The compound according to claim 1, wherein X32 is selected from 2-aminoisobutyric acid (Aib), 2-aminobutyric acid (Abu), 4-amino-tetrahydro-2H-pyran-4-yl-acetic acid (ThP) or 4-amino-piperidine-4-carboxylic acid (4-Pip), more particularly, X32 is selected from 2-aminoisobutyric acid (Aib) or 4-amino-piperidine-4-carboxylic acid (4-Pip).

8. The albumin binding moiety has the formula (II): -YZC(O)R 1 (II) (In the formula, Y is AEEA, {AEEA} 2 , {AEEA} 3 , Gly, {Gly} 2 , {Gly} 3 , N-MeGly, {N-MeGly} 2 , {N-MeGly} 3 or absent, AEEA represents [2-(2-aminoethoxy)ethoxy]-acetyl, Z is gGlu, {gGlu} 2 or absent, and R 1 Ha-(CH 2 ) x COOH or -(CH 2 ) x CH 3 8. The compound according to any one of claims 1 to 7, which is a group of the formula: wherein x is an integer from 10 to 22.

9. The albumin binding moiety comprises the following group: -{AEEA}-gGlu-C(O)(CH). 2 ) 10 COOH -{AEEA}-gGlu-C(O)(CH). 2 ) 12 COOH -{AEEA}-gGlu-C(O)(CH). 2 ) 14 COOH -{AEEA}-gGlu-C(O)(CH). 2 ) 16 COOH -{AEEA}-gGlu-C(O)(CH). 2 ) 18 COOH -{AEEA} 2 -gGlu-C(O)(CH). 2 ) 10 COOH -{AEEA} 2 -gGlu-C(O)(CH). 2 ) 12 COOH -{AEEA} 2 -gGlu-C(O)(CH). 2 ) 14 COOH -{AEEA} 2 -gGlu-C(O)(CH). 2 ) 16 COOH -{AEEA} 2 -gGlu-C(O)(CH). 2 ) 18 COOH -{AEEA} 2 -{gGlu} 2 -C(O)(CH 2 ) 10 COOH -{AEEA} 2 -{gGlu} 2 -C(O)(CH 2 ) 12 COOH -{AEEA} 2 -{gGlu} 2 -C(O)(CH 2 ) 14 COOH -{AEEA} 2 -{gGlu} 2 -C(O)(CH 2 ) 16 COOH -{AEEA} 2 -{gGlu} 2 -C(O)(CH 2 ) 18 COOH -gGlu-C(O)(CH 2 ) 10 COOH、 -gGlu-C(O)(CH 2 ) 12 COOH、 -gGlu-C(O)(CH 2 ) 14 COOH、 -gGlu-C(O)(CH 2 ) 16 COOH、 -gGlu-C(O)(CH 2 ) 18 COOH、 -{gGlu} 2 -C(O)(CH 2 ) 10 COOH、 -{gGlu} 2 -C(O)(CH 2 ) 12 COOH、 -{gGlu} 2 -C(O)(CH 2 ) 14 COOH、 -{gGlu} 2 -C(O)(CH 2 ) 16 COOH, and -{gGlu} 2 -C(O)(CH 2 ) 18 COOH、 9. The compound of claim 8, selected from:

10. The albumin binding moiety is -gGlu-C(O)(CH 2 ) 12 COOH, -gGlu-C(O)(CH 2 ) 14 COOH, -gGlu-C(O)(CH 2 ) 16 COOH, -gGlu-C(O)(CH 2 ) 18 COOH, -{AEEA} 2 -gGlu-C(O)(CH 2 ) 12 COOH, -{AEEA} 2 -gGlu-C(O)(CH 2 ) 16 COOH, -{AEEA} 2 -gGlu-C(O)(CH 2 ) 18 COOH and -{AEEA} 2 -{gGlu} 2 -C(O)(CH 2 ) 16 9. The compound of claim 8, wherein said compound is COOH.

11. 2. The compound of claim 1, wherein the compound is a peptide of any one of SEQ ID NOs: 19, 33, 34, 40, 43, 47, 51, 54, 55, 57, 64, 80, 92, 93, 96, 98, 100, 104, 110, 113, 118, 125, 131, 132, 136, 144, 145, 189, 190, 193, 203, 206, 210, 212, 213, 215, 217, 218, 219, 222, 230, 231, 233, 234, 235, 236, 237, 238, 241, 242, 243, or a pharma- ceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharma- ceutically acceptable excipient, diluent or carrier.

13. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use in therapy.

14. A compound according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13, for use in a method for treating or preventing cardiovascular disease, obesity, diabetes, sarcopenia, in particular obesity-related sarcopenia, cachexia, heart failure and pulmonary hypertension in a patient.

15. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use as an agonist of the corticotropin releasing factor receptor 2 (CRF2).

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