Exendin-4 Derivatives as Dual GLP1/Glucagon Agonists

Description

FIELD OF THE INVENTION

The present invention relates to exendin-4 peptide analogues which - in contrast to the pure GLP-1 agonist exendin-4 - activate both the GLP1 and the Glucagon receptor and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.

BACKGROUND OF THE INVENTION

Exendin-4 is a 39 amino acid peptide which is produced by the salivary glands of the Gila monster (Heloderma suspectum) (Eng, J. et al., J. Biol. Chem., 267:7402-05,1992). Exendin-4 is an activator of the glucagon-like peptide-1 (GLP-1 ) receptor, whereas it does not activate significantly the glucagon receptor.

Exendin-4 shares many of the glucoregulatory actions observed with GLP-1 . Clinical and non-clinical studies have shown that exendin-4 has several beneficial antidiabetic properties including a glucose dependent enhancement in insulin synthesis and secretion, glucose dependent suppression of glucagon secretion, slowing down gastric emptying, reduction of food intake and body weight, and an increase in beta-cell mass and markers of beta cell function (Gentilella R et al., Diabetes Obes Metab., 1 1 :544-56, 2009; Norris SL et al., Diabet Med., 26:837-46, 2009; Bunck MC et al., Diabetes Care., 34:2041 -7, 201 1 ).

These effects are beneficial not only for diabetics but also for patients suffering from obesity. Patients with obesity have a higher risk of getting diabetes, hypertension, hyperlipidemia, cardiovascular and musculoskeletal diseases.

Relative to GLP-1 , exendin-4 is resistant to cleavage by dipeptidyl peptidase-4 (DPP4) resulting in a longer half-life and duration of action in vivo (Eng J., Diabetes, 45 (Suppl 2):152A (abstract 554), 1996).

Nevertheless, exendin-4 is chemically labile due to methionine oxidation in position 14 (Hargrove DM et al., Regul. Pept., 141 : 1 13-9, 2007) as well as deamidation and isomerization of asparagine in position 28 (WO 2004/035623).

The amino acid sequence of exendin-4 is shown as SEQ ID NO: 1

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

The amino acid sequence of GLP-1 (7-36)-amide is shown as SEQ ID NO: 2

HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

Liraglutide is a marketed chemically modified GLP-1 analog in which, among other modifications, a fatty acid is linked to a lysine in position 20 leading to a prolonged duration of action (Drucker DJ et al., Nature Drug Disc. Rev. 9, 267-268, 2010; Buse, J.B. et al., Lancet, 374:39-47, 2009).

The amino acid sequence of Liraglutide is shown as SEQ ID NO: 195.

HAEGTFTSDVSSYLEGQAAK((S)-4-Carboxy-4-hexadecanoylamino-butyryl-)

EFIAWLVRGRG-OH

Glucagon is a 29-amino acid peptide which is released into the bloodstream when circulating glucose is low. Glucagon's amino acid sequence is shown in SEQ ID NO: 3.

HSQGTFTSDYSKYLDSRRAQDFVQWLMNT-OH

During hypoglycemia, when blood glucose levels drop below normal, glucagon signals the liver to break down glycogen and release glucose, causing an increase of blood glucose levels to reach a normal level. Hypoglycemia is a common side effect of insulin treated patients with hyperglycemia (elevated blood glucose levels) due to diabetes. Thus,

glucagon's most predominant role in glucose regulation is to counteract insulin action and maintain blood glucose levels.

Hoist (Hoist, J. J. Physiol. Rev. 2007, 87, 1409) and Meier (Meier, J. J. Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1 , liraglutide and exendin-4, have 3 major pharmacological activities to improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (FPG and PPG): (i) increased glucose-dependent insulin secretion (improved first- and second-phase), (ii) glucagon suppressing activity under hyperglycemic conditions, (iii) delay of gastric emptying rate resulting in retarded absorption of meal-derived glucose.

Pocai et al. (Obesity 2012;20: 1566-1571 ; Diabetes 2009, 58, 2258) and Day et al. (Nat Chem Biol 2009;5: 749) describe that dual activation of the GLP-1 and glucagon receptors, e.g. by combining the actions of GLP-1 and glucagon in one molecule, leads to a therapeutic principle with anti-diabetic action and a pronounced weight lowering effect.

Peptides which bind and activate both the glucagon and the GLP-1 receptor (Hjort et al., Journal of Biological Chemistry, 269, 30121 -30124, 1994; Day JW et al., Nature Chem Biol, 5: 749-757, 2009) and suppress body weight gain and reduce food intake are described in patent applications WO 2008/071972, WO 2008/101017, WO 2009/155258, WO 2010/096052, WO 2010/096142, WO 201 1/075393, WO 2008/152403, WO 2010/070251 , WO 2010/070252, WO 2010/070253, WO 2010/070255, WO 201 1/160630, WO 201 1/006497, WO 201 1/152181 , WO 201 1/152182, WO 201 1/1 17415, WO 201 1/1 17416 and WO 2006/134340, the contents of which are herein incorporated by reference.

In addition, triple co-agonist peptides which not only activate the GLP-1 and the glucagon receptor but also the GIP receptor are described in WO 2012/0881 16 and by VA Gault et al. (Biochem Pharmacol, 85, 16655-16662, 2013; Diabetologia, 56, 1417-1424, 2013).

Bloom et al. (WO 2006/134340) disclose that peptides which bind and activate both the glucagon and the GLP-1 receptor can be constructed as hybrid molecules from glucagon and exendin-4, where the N-terminal part (e.g. residues 1 -14 or 1 -24) originates from glucagon and the C-terminal part (e.g. residues 15-39 or 25-39) originates from exendin- DE Otzen et al. (Biochemistry, 45, 14503-14512, 2006) disclose that N- and C-terminal hydrophobic patches are involved in fibrillation of glucagon due to the hydrophobicity and/or high β-sheet propensity of the underlying residues.

Krstenansky et al. (Biochemistry, 25, 3833-3839, 1986) show the importance of the residues 10-13 of glucagon for its receptor interactions and activation of adenylate cyclase. In the exendin-4 derivatives described in this invention, several of the underlying residues are different from glucagon. In particular residues Tyr10 and Tyr13 , which are known to contribute to the fibrillation of glucagon (DE Otzen, Biochemistry, 45, 14503-14512, 2006) are replaced by Leu in position 10 and Gin, a non-aromatic polar amino acid, in position 13, leading to exendin-4 derivatives with potentially improved biophysical properties.

Furthermore, compounds of this invention are exendin-4 derivatives with fatty acid acylated residues in position 14. This fatty acid functionalization in position 14 results in exendin-4 derivatives with high activity not only at the GLP-1 receptor but also at the glucagon receptor when compared to the corresponding non-acylated exendin-4 derivatives. In addition, this modification results in an improved pharmacokinetic profile.

Compounds of this invention are more resistant to cleavage by neutral endopeptidase (NEP) and dipeptidyl peptidase-4 (DPP4), resulting in a longer half-life and duration of action in vivo when compared with GLP-1 and glucagon. Furthermore, the compounds are stabilized versus other proteases, among those cathepsin D.

Compounds of this invention are preferably soluble not only at neutral pH, but also at pH 4.5. This property potentially allows co-formulation for a combination therapy with an insulin or insulin derivative and preferably with a basal insulin like insulin glargine/Lantus®.

BRIEF SUMMARY OF THE INVENTION

Provided herein are exendin-4 derivatives which potently activate the GLP1 and the

glucagon receptor. In these exendin-4 derivatives - among other substitutions -methionine at position 14 is replaced by an amino acid carrying an -NH2 group in the side chain, which is further substituted with an unpolar residue (e.g. a fatty acid optionally combined with a linker).

The invention provides a peptidic compound having the formula (I):

R1 - Z - R2 (I)

wherein Z is a peptide moiety having the formula (II)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-X16-X17-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-X35-Pro-Pro-Pro- X39-X40 (II)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin, His and a-amino- functionalized Gin, wherein Gin may be functionalized in that an H of the a-NH2 group is substituted by (Ci-C4)-alkyl,

X14 represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is functionalized by -C(O)-R5, -C(O)O-R5, - C(O)NH-R5, -S(O)2-R5 or R5, preferably by -C(O)-R5, wherein R5 may be a moiety comprising up to 50 or up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S and/or P,

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser, Glu and Lys,

X17 represents an amino acid residue selected from Arg, Glu, Gin, Leu, Aib and Lys, X18 represents an amino acid residue selected from Arg, Ala and Lys,

X20 represents an amino acid residue selected from Gin, Arg, Lys, His, Glu and Aib, X21 represents an amino acid residue selected from Asp, Leu and Glu,

X28 represents an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Ala and Asp,

X29 represents an amino acid residue selected from Gly, Ala, D-Ala and Thr,

X35 represents an amino acid residue selected from Ala, Glu, Arg and Lys,

X39 represents Ser or is absent and

X40 is absent or represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is optionally functionalized by -C(O)- R5, -C(O)O-R5, -C(O)NH-R5, -S(O)2-R5 or R5, preferably by -C(O)-R5, wherein R5 may be a moiety comprising up to 50 or up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S and/or P,

R1 represents the N-terminal group of the peptidic compound and is selected from NH2 and mono- or bisfunctionalized NH2,

R2 represents the C-terminal group of the peptidic compound and is selected from

(i) OH or functionalized OH and

(ii) NH2 or mono- or bisfunctionalized NH2,

or a salt or solvate thereof.

The compounds of the invention are GLP-1 and glucagon receptor agonists as determined by the observation that they are capable of stimulating intracellular cAMP formation.

According to another embodiment, the compounds of the invention, particularly with a lysine at position 14 which is further substituted with a lipophilic residue, exhibit at least a relative activity of 0.1 %, more preferably of 0.2%, more preferably of 0.3% and even more preferably of 0.4% compared to that of GLP-1 (7-36) at the GLP-1 receptor. Furthermore, the compounds exhibit at least a relative activity of 0.1 %, more preferably of 0.2% or of 0.3% or of 0.4% and even more preferably of 0.5% compared to that of natural glucagon at the glucagon receptor.

The term "activity" as used herein preferably refers to the capability of a compound to activate the human GLP-1 receptor and the human glucagon receptor. More preferably the term "activity" as used herein refers to the capability of a compound to stimulate intracellular cAMP formation. The term "relative activity" as used herein is understood to refer to the capability of a compound to activate a receptor in a certain ratio as compared to another receptor agonist or as compared to another receptor. The activation of the receptors by the agonists (e.g. by measuring the cAMP level) is determined as described herein, e.g. as described in the examples.

According to one embodiment, the compounds of the invention have an EC50 for hGLP-1 receptor of 450 pmol or less, preferably of 200 pmol or less; more preferably of 150 pmol or less, more preferably of 100 pmol or less, more preferably of 90 pmol or less, more preferably of 80 pmol or less, more preferably of 70 pmol or less, more preferably of 60 pmol or less, more preferably of 50 pmol or less, more preferably of 40 pmol or less, more preferably of 30 pmol or less, more preferably of 25 pmol or less, more preferably of 20 pmol or less, more preferably of 15 pmol or less, more preferably of 10 pmol or less, more preferably of 9 pmol or less, more preferably of 8 pmol or less, more preferably of 7 pmol or less, more preferably of 6 pmol or less, and more preferably of 5 pmol or less.

According to another embodiment, the compounds of the invention have an EC50 for hGlucagon receptor of 500 pmol or less, preferably of 200 pmol or less; more preferably of 150 pmol or less, more preferably of 100 pmol or less, more preferably of 90 pmol or less, more preferably of 80 pmol or less, more preferably of 70 pmol or less, more preferably of 60 pmol or less, more preferably of 50 pmol or less, more preferably of 40 pmol or less, more preferably of 30 pmol or less, more preferably of 25 pmol or less, more preferably of 20 pmol or less, more preferably of 15 pmol or less, more preferably of 10 pmol or less.

According to another embodiment, the compounds of the invention have an EC50 for hGLP-1 receptor of 450 pmol or less, preferably of 200 pmol or less; more preferably of 150 pmol or less, more preferably of 100 pmol or less, more preferably of 90 pmol or less, more preferably of 80 pmol or less, more preferably of 70 pmol or less, more preferably of 60 pmol or less, more preferably of 50 pmol or less, more preferably of 40 pmol or less, more preferably of 30 pmol or less, more preferably of 25 pmol or less, more preferably of 20 pmol or less, more preferably of 15 pmol or less, more preferably of 10 pmol or less, more preferably of 9 pmol or less, more preferably of 8 pmol or less, more preferably of 7 pmol or less, more preferably of 6 pmol or less, and more preferably of 5 pmol or less, and/or an EC5o for hGlucagon receptor of 500 pmol or less, preferably of 200 pmol or less; more preferably of 150 pmol or less, more preferably of 100 pmol or less, more preferably of 90 pmol or less, more preferably of 80 pmol or less, more preferably of 70 pmol or less, more preferably of 60 pmol or less, more preferably of 50 pmol or less, more preferably of 40 pmol or less, more preferably of 30 pmol or less, more preferably of 25 pmol or less, more preferably of 20 pmol or less, more preferably of 15 pmol or less, more preferably of 10 pmol or less.

In still another embodiment,the EC50 for both receptors i.e. for the hGLP-1 receptor and the hGlucagon receptor, is 100 pmol or less, more preferably 90 pmol or less, more preferably 80 pmol or less, more preferably 70 pmol or less, more preferably 60 pmol or less, more preferably 50 pmol or less, more preferably 40 pmol or less, more preferably 30 pmol or less, more preferably 25 pmol or less, more preferably 20 pmol or less, more preferably 15 pmol or less, more preferably 10 pmol or less. The EC5o for hGLP-1 receptor and hGlucagon receptor may be determined as described in the Methods herein and as used to generate the results described in Example 9.

The compounds of the invention have the ability to reduce the intestinal passage, to increase the gastric content and/or to reduce the food intake of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods. The results of such experiments are described in Examples 1 1 and 12. Preferred compounds of the invention may increase the gastric content of mice, preferably of female NMRI-mice, if administered as a single dose, preferably subcutaneous dose, of 0.02 mg/kg body weight by at least 25%, more preferably by at least 30%, more preferably by at least 40%, more preferably by at least 50%, more preferably by at least 60%, more preferably by at least 70%, more preferably by at least 80%.

Preferably, this result is measured 1 h after administration of the respective compound and 30 mins after administration of a bolus, and/or reduces intestinal passage of mice, preferably of female NMRI-mice, if administered as a single dose, preferably subcutaneous dose, of 0.02 mg/kg body weight at least by 45%; more preferably by at least 50%, more preferably by at least 55%, more preferably by at least 60%, and more preferably at least 65%; and/or reduces food intake of mice, preferably of female NMRI-mice, over a period of 22 h, if administered as a single dose, preferably subcutaneous dose of 0.01 mg/kg body weight by at least 10%, more preferably 15%, and more preferably 20%.

The compounds of the invention have the ability to reduce blood glucose level, and/or to reduce HbA1 c levels of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods. The results of such experiments are described in Examples 14 and 17.

Preferred compounds of the invention may reduce blood glucose level of mice, preferably in female leptin-receptor deficient diabetic db/db mice over a period of 24 h, if administered as a single dose, preferably subcutaneous dose, of 0.01 mg/kg body weight by at least 4 mmol/L; more preferably by at least 6 mmol/L, more preferably by at least 8 mmol/L. If the dose is increased to 0.1 mg/kg body weight a more pronounced reduction of blood glucose levels can be observed in mice over a period of 24 h, if administered as a single dose, preferably subcutaneous dose. Preferably the compounds of the invention lead to a reduction by at least 7 mmol/L; more preferably by at least 9 mmol/L, more preferably by at least 1 1 mmol/L. The compounds of the invention preferably reduce the increase of HbA1 c levels of mice over a period of 4 weeks, if administered at a daily dose of 0.01 mg/kg to about the ignition value.

The compounds of the invention also have the ability to reduce body weight of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods and in Examples 13 and 16.

It was found that peptidic compounds of the formula (I), particularly those with a lysine at position 14 which is further substituted with a lipophilic residue, showed increased glucagon receptor activation compared to derivatives having the original methionine (from exendin-4) at position 14. Furthermore, oxidation (in vitro or in vivo) of methionine is not possible anymore.

In one embodiment the compounds of the invention have a high solubility at acidic and/or physiological pH values, e.g., at pH 4.5 and/or at pH 7.4 at 25°C, in another embodiment at least 0.5 mg/ml and in a particular embodiment at least 1 .0 mg/ml.

Furthermore, according to one embodiment, the compounds of the invention preferably have a high stability when stored in solution. Preferred assay conditions for determining the stability is storage for 7 days at 25°C in solution at pH 4.5 or pH 7. The remaining amount of peptide is determined by chromatographic analyses as described in the Examples. Preferably, after 7 days at 25°C in solution at pH 4.5 or pH 7, the remaining peptide amount is at least 80%, more preferably at least 85%, even more preferably at least 90% and even more preferably at least 95%.

Preferably, the compounds of the present invention comprise a peptide moiety Z (II) which is a linear sequence of 39-40 amino carboxylic acids, particularly a-amino carboxylic acids linked by peptide, i.e. carboxamide bonds.

In an embodiment R1 is selected from -NH2, -NH[(CrC5)alkyl], -N[(Ci-C5)alkyl]2> -NH[(C0-C4)alkylene-(C3-C8)cycloalkyl], NH-C(O)-H, NH-C(O)-(C C5)-alkyl, NH-C(O)-(C0-C3)alkylene-(C3-C8)cycloalkyl, in which alkyl or cycloalkyl is unsubstituted or up to 5-fold substituted by -OH or halogen selected from F, CI, Br and I, preferably F.

In an embodiment R2 is selected from -OH, -O-(CrC2o)alkyl, -O(C0-C8)alkylene-(C3-C8)cycloalkyl, -NH2, -NH[(C C30)alkyl], -N[(CrC30)alkyl]2, -NH[(C0-C8)alkylene-(C3-C8)cycloalkyl], -N[(C0-C8)alkylene-(C3-C8)cycloalkyl]2, -NH[(CH2-CH2-O)1-4o-(CrC4)alkyl], -NH-(C3-C8)heterocyclyl or -NH-(C0-C8)alkylene-aryl, wherein aryl is selected from phenyl and naphthyl, preferably phenyl, or a (C3-C8)-heterocyclyl containing 1 N-atom and optionally two additional heteroatoms selected from O, N or S, particularly selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl und homopiperidinyl. Moreover alkyl or cycloalkyl as described above is unsubstituted or up to 5-fold substituted by -OH or halogen selected from F, CI, Br and I, preferably F.

In one embodiment, the N-terminal group R1 is NH2. In a further embodiment, the C-terminal group R2 is NH2. In still a further embodiment the N-terminal group R1 and the C-terminal group R2 are NH2.

In one embodiment position X14 represents an amino acid residue with a functionalized -NH2 side chain group, such as functionalized Lys, Orn, Dab, or Dap, more preferably functionalized Lys, and X40 represents an amino acid residue with a functionalized -NH2 side chain group, such as functionalized Lys, Orn, Dab, or Dap, more preferably functionalized Lys.

An amino acid residue with an -NH2 side chain group, e.g. Lys, Orn, Dab or Dap, may be functionalized in that at least one H atom of the -NH2 side chain group is replaced by -C(O)-R5, -C(O)O-R5, -C(O)NH-R5, -S(0)2-R5 or R5, preferably by -C(O)-R5, wherein R5 may be a moiety comprising up to 50 or up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S and/or P.

In certain embodiments, R5 may comprise a lipophilic moiety, e.g. an acyclic linear or branched saturated hydrocarbon group, wherein R5 particularly comprises an acyclic linear or branched (C4-C3o) saturated or unsaturated hydrocarbon group, and/or a cyclic saturated, unsaturated or aromatic group, particularly a mono-, bi-, or tricyclic group comprising 4 to 14 carbon atoms and 0, 1 , or 2 heteroatoms selected from N, O, and S, e.g. cyclohexyl, phenyl, biphenyl, chromanyl, phenanthrenyl or naphthyl, wherein the acyclic or cyclic group may be unsubstituted or substituted e.g. by halogen, -OH and/or CO2H.

More preferred groups R5 may comprise a lipophilic moiety, e.g. an acyclic linear or branched (Ci2-C22) saturated or unsaturated hydrocarbon group. The lipophilic moiety may be attached to the -NH2 side chain group by a linker in all stereoisomeric forms, e.g. a linker comprising one or more, e.g. 2, amino acid linker groups such as γ-aminobutyric acid (GABA), ε-aminohexanoic acid (ε-Ahx), γ-Glu and/or β-Ala. In one embodiment the lipophilic moiety is attached to the -NH2 side chain group by a linker. In another embodiment the lipophilic moiety directly attached to the -NH2 side chain group. Specific examples of amino acid linker groups are ( -Ala)i-4, (y-Glu)i-4, (£-Ahx) -4, or (GABA) -4. Preferred amino acid linker groups are β-Ala, γ-Glu, β-Αΐ3-β-Αΐ3 and y-Glu-y-Glu.

Specific preferred examples for -C(O)-R5 groups are listed in the following Table 1 , which are selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, 4-Hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-, Hexadecanoyl-, (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl-, (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-propionylamino]-propionylamino}-butyryl-, (S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2- ((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6^

(S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-, (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl-, (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylannino)-butyryl-, (S)-4-Carboxy-4-tetradecanoylamino-butyryl-, (S)-4-(1 1 -Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl-, (S)-4-Carboxy-4-[1 1 -((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylannino]-butyryl-, (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, (S)-4-Carboxy-4-docosanoylamino-butyryl-, (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl- (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-Carboxy-4-icosanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-, 3-(3-Octadecanoylamino-propionylannino)-propionyl-, 3-(3-Hexadecanoylamino-propionylannino)-propionyl-, 3-Hexadecanoylamino-propionyl-, (S)-4-Carboxy^-KRH-iiSR.SS R.eR.QR.10S,12S,13R,14R,17R)-3,7,12-trihydroxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-[(R)-4-((3R,5RJ8RJ9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylannino)-butyryl-, Tetradecanoyl-, 1 1 -Carboxy-undecanoyl-, 1 1 -Benzyloxycarbonyl-undecanoyl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-tetradecanoylamino-butyrylannino)-butyryl-, 6-[Hydroxy-(naphthalene-2-yloxy)-phosphoryloxy]-hexanoyl-, 6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-, 4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-, 4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylannino]-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2- (2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-hepta-decanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetyl, (S)-4-Carboxy-4-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-butyrylamino}-butyrylamino)-butyryl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-1 H-tetrazol-5-yl-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-carboxy-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)-decanoylamino]-butyrylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylannino}-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(7-carboxy-heptanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(1 1 -carboxy-undecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamm butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(13-carboxy-tridecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, and (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-.

Further preferred are stereoisomers, particularly enantiomers of these groups, either S- or R-enantiomers. The term "R" in Table 1 is intended to mean the attachment site of -C(O)-R5 at the peptide back bone, i.e. particularly the ε-amino group of Lys.

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According to one embodiment, R5 is selected from the group consisting of (S)-4-carboxy-4-hexadecanoylamino-butyryl (γΕ-χ53), (S)-4-carboxy-4-octadecanoylamino-butyryl (γΕ-x70), 4-hexadecanoylamino-butyryl (GABA-x53), 4-{3-[(R)-2,5,7I8-tetramethyl-2-((4R,8R)- 4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylam (GABA-x60), 4-octadecanoylamino-butyryl (GABA-x70), 4-((Z)-octadec-9-enoylamino)-butyryl (GABA- x74), 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl (Phosphol ), Hexadecanoyl (x53), (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl (x52), 5 (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)- propionylamino]-propionylannino}-butyryl (γΕ-χ59), (S)-4-Carboxy-4-{3-[(R)-2,5,7,8- tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]^

propionylamino}-butyryl (γΕ-χ60), (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12- dienoylamino)-butyryl (γΕ-χ61 ), (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-10 tetrahydroxy-pentanoylamino)-hexanoylannino]-butyryl (γΕ-χ64), (S)-4-Carboxy-4- ((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-butyryl (γΕ-χ65), (S)-4- carboxy-4-tetradecanoylamino-butyryl (γΕ-χ69), (S)-4-(1 1 -Benzyloxycarbonyl- undecanoylamino)-4-carboxy-butyryl (γΕ-χ72), (S)-4-carboxy-4-[1 1 -((2S,3R,4R,5R)- 2,3,4,5,6-pentahydroxy-hexylcarbannoyl)-undecanoylannino]-butyryl (γΕ-χ73), (SHI S Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl (γΕ-χ74), (S)-4-Carboxy-4-(4-dodecyloxy- benzoylamino)-butyryl (γΕ-χ75), (S)-4-Carboxy-4-henicosanoylamino-butyryl (γΕ-χ76), (S)-4-Carboxy-4-docosanoylamino-butyryl (γΕ-χ77), (S)-4-Carboxy-4-((Z)-nonadec-10- enoylamino)-butyryl (γΕ-χ79), (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl (γΕ- x80), (S)-4-Carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl (γΕ-χ81 ), (S)-4-20 Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl (γΕ-χ82), (S)-4-Carboxy-4- icosanoylamino-butyryl (γΕ-χ95), (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino- butyrylamino)-butyryl (γΕ-γΕ-χ53), (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino- butyrylamino)-butyryl (γΕ-γΕ-χ70), and 3-(3-Octadecanoylamino-propionylannino)- propionyl( -Ala- -Ala-x70).

25

According to another embodiment, R5 is selected from the group consisting of (S)-4- carboxy-4-octadecanoylamino-butyryl (γΕ-χ70), (S)-4-carboxy-4-hexadecanoylamino- butyryl (γΕ-χ53), and hexadecanoyl (x53).

30 According to yet another embodiment, R5 is (S)-4-carboxy-4-hexadecanoylamino-butyryl (γΕ-χ53).

In some embodiments of the invention, position X14 and/or X40 represents Lysine (Lys). According to some embodiments, Lys at position 14 and optionally at position 40 is

functionalized, e.g. with a group -C(O)R5 as described above. In other embodiments, X40 is absent and X14 is Lys functionalized with -C(O)-R5, -C(O)O-R5, -C(O)NH-R5, -S(O)2-R5 or R5, preferably by -C(O)-R5, wherein R5 is as defined above. In particular, X14 is Lys functionalized with C(O)-R5, wherein R5 is selected from the group consisting of (S)-4-carboxy-4-hexadecanoylamino-butyryl (γΕ-χ53), (S)-4-carboxy-4-octadecanoylamino-butyryl (γΕ-χ70), 4-hexadecanoylamino-butyryl (GABA-x53), 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-(GABA-x60), 4-octadecanoylamino-butyryl (GABA-x70), 4-((Z)-octadec-9-enoylamino)-butyryl (GABA-x74), 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl (Phosphol ), Hexadecanoyl (x53), (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl (x52), (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-propionylamino]-propionylamino}-butyryl (γΕ-χ59), (S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl (γΕ-χ60), (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl (γΕ-χ61 ), (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl (γΕ-χ64), (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-butyryl (γΕ-χ65), (S)-4-carboxy-4-tetradecanoylamino-butyryl (γΕ-χ69), (S)-4-(1 1 -Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl (γΕ-χ72), (S)-4-carboxy-4-[1 1 -((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl (γΕ-χ73), (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl (γΕ-χ74), (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl (γΕ-χ75), (S)-4-Carboxy-4-henicosanoylamino-butyryl (γΕ-χ76), (S)-4-Carboxy-4-docosanoylamino-butyryl (γΕ-χ77), (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl (γΕ-χ79), (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl (γΕ-x80), (S)-4-Carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl (γΕ-χ81 ), (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl (γΕ-χ82), (S)-4-Carboxy-4-icosanoylamino-butyryl (γΕ-χ95), (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl (γΕ-γΕ-χ53), (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl (γΕ-γΕ-χ70), and 3-(3-Octadecanoylamino-propionylamino)-propionyl( -Ala- -Ala-x70).

A further embodiment relates to a group of compounds, wherein

R1 is NH2,

R is NH2 or

R1 and R2 are NH2.

A further embodiment relates to a group of compounds, wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin, His and a-amino- functionalized Gin, wherein Gin may be functionalized in that an H of the a-NH2 group is substituted by (Ci -C4)-alkyl,

X14 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group is functionalized by -C(O)-R5,

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser, Lys and Glu,

X17 represents an amino acid residue selected from Arg, Glu, Gin, Leu and Lys, X18 represents an amino acid residue selected from Arg and Ala,

X20 represents an amino acid residue selected from Gin, Arg, Lys and Aib,

X21 represents an amino acid residue selected from Asp, Leu and Glu,

X28 represents an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Asp and Ala,

X29 represents an amino acid residue selected from Gly, Ala, D-Ala and Thr, X35 represents an amino acid residue selected from Ala or Glu,

X39 is Ser or is absent,

X40 is either absent or represents Lys, wherein the -NH2 side chain group can be functionalized by -C(O)-R5 and

-C(O)-R5 is as defined above.

A further embodiment relates to a group of compounds, wherein

X2 represents an amino acid residue selected from D-Ser and Aib,

X3 represents Gin,

X14 represents an amino acid residue selected from Lys and Orn, wherein the -NH2 side chain group is functionalized by -C(O)-R5,

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser and Glu,

X17 represents an amino acid residue selected from Arg, Gin and Lys,

X18 represents an amino acid residue selected from Arg and Ala,

X20 represents an amino acid residue selected from Gin, Arg, Lys and Aib,

X21 represents an amino acid residue selected from Asp, Leu and Glu,

X28 represents an amino acid residue selected from Asn, Arg, Lys, Aib, Ser and Ala,

X29 represents an amino acid residue selected from Gly, Ala or Thr,

X35 represents Ala,

X39 is Ser or is absent,

X40 is either absent or represents Lys, wherein the -NH2 side chain group can be functionalized by -C(O)-R5 and

-C(O)-R5 is as defined above.

A further embodiment relates to a group of compounds, wherein

X20 represents an amino acid residue selected from Gin, Lys and Aib.

A further embodiment relates to a group of compounds, wherein

X2 represents an amino acid residue selected from D-Ser and Aib,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized by one of the groups selected from 3-(3-octadecanoylamino-propionyl-amino)-propionyl-, 4-hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12- trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4- octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, hexadecanoyl-, (S)-4-carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4- carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-carboxy-4- henicosanoylamino-butyryl-, (S)-4-carboxy-4-docosanoylamino-butyryl-, (S)-4- carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-carboxy-4-(4-decyloxy- benzoylamino)-butyryl-, (S)-4-carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)- amino]-butyryl-, (S)-4-carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4- carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4- carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-, (S)-4- carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)- chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4-carboxy-4-((9Z,12Z)- octadeca-9,12-dienoylamino)-butyryl-, (S)-4-carboxy-4-octadecanoylamino- butyryl- and (S)-4-carboxy-4-hexadecanoylamino-butyryl-,

X15 represents Glu,

X16 represents Ser,

X17 represents an amino acid residue selected from Arg, Gin and Lys,

X18 represents Ala,

X20 represents Gin,

X21 represents Asp,

X28 represents Ala,

X29 represents Gly,

X35 represents Ala,

X39 is Ser

X40 is absent.

A further embodiment relates to a group of compounds of formula (I), wherein

X2 represents Aib,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-Carboxy-4-hexadecanoylamino-butyryl- and (S)-4-Carboxy-4- octadecanoylamino-butyryl-;

X15 represents an amino acid residue selected from Asp and Glu,

X16 represents an amino acid residue selected from Ser and Glu,

X17 represents an amino acid residue selected from Gin and Lys,

X18 represents Ala,

X20 represents an amino acid residue selected from Gin and Lys,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents Ala,

X29 represents an amino acid residue selected from Gly and D-Ala,

X35 represents Ala,

X39 is Ser,

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X2 represents an amino acid residue selected from D-Ser and Aib,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-Carboxy-4-octadecanoylamino-butyryl-;

X15 represents Asp,

X16 represents Ser,

X17 represents Arg,

X18 represents Arg,

X20 represents Gin,

X21 represents Asp,

X28 represents Ala,

X29 represents an amino acid residue selected from Gly and D-Ala,

X35 represents Ala,

X39 is Ser,

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X2 represents D-Ser,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group can be functionalized, particularly by (S)-4-carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12- trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4- carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-, (S)-4-carboxy-4- tetradecanoylamino-butyryl-, (S)-4-carboxy-4-octadecanoylamino-butyryl-, 2- ((S)-4-carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy- pentanoylamino)-propionylamino]-propionylamino}-butyryl-, 2-{(S)-4-carboxy-4- [6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)- hexanoylamino]-butyryl-, 2-[(S)-4-carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5- tetrahydroxy-pentanoylamino)-butyryl-, 2-[(S)-4-(1 1 -benzyloxycarbonyl- undecanoylamino)-4-carboxy-butyryl-, 2-{(S)-4-carboxy-4-[1 1 -((2S,3R,4R,5R)- 2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl-;

X15 represents Asp,

X16 represents Ser,

X17 represents Arg,

X18 represents Arg,

X20 represents Gin,

X21 represents Asp,

X28 represents Asn,

X29 represents Gly, X35 represents Ala, X39 is Ser,

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X2 represents D-Ser,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-;

X15 represents an amino acid residue selected from Glu or Asp,

X16 represents Ser,

X17 represents Arg,

X18 represents Arg,

X20 represents Gin,

X21 represents Asp,

X28 represents an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu and Asp,

X29 represents an amino acid residue selected from Gly, Ala, D-Ala and Thr, X35 represents an amino acid residue selected from Ala, Glu, Arg and Lys,

X39 is Ser,

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X2 represents D-Ser,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-;

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser and Glu,

X17 represents an amino acid residue selected from Arg, Glu, Lys and Aib,

X18 represents an amino acid residue selected from Arg, Lys and Ala,

X20 represents an amino acid residue selected from Gin, Lys and Aib,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents an amino acid residue selected from Ala and Asn,

X29 represents Gly,

X35 represents Ala,

X39 is Ser,

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X2 represents D-Ser,

X3 represents Gin,

X14 represents Orn or Dab, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl-;

X15 represents Glu,

X16 represents Ser,

X17 represents Arg,

X18 represents Arg,

X20 represents Gin,

X21 represents Asp,

X28 represents Ala,

X29 represents Gly,

X35 represents Ala,

X39 is Ser,

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X2 represents D-Ser,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-;

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents Ser,

X17 represents an amino acid residue selected from Arg and Lys,

X18 represents an amino acid residue selected from Arg and Ala,

X20 represents Gin,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents an amino acid residue selected from Ala and Asn,

X29 represents Gly,

X35 represents Ala,

X39 represents Ser or is absent,

X40 is absent or represents Lys, wherein the -NH2 side chain group is optionally functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl- and R2 is NH2, NH(Ci-Ci8) alkyl, which are unsubstituted or monosubstituted by OH or 3- fold-substituted by F, N[(C C6) alkyl]2, NH(CH2-CH2-O)1-24-(C C4) alkyl-COOH, NH-pyrrolidine (N-pyrrolidin-1 -yl-amido), NH-benzyl (N-benzyl-amido) or N- morpholine (1 -morpholin-4-yl), particularly by NH2, NH-CH2-CH3, NH-(CH2)2- CH3, NH-C(CH3)3, NH-CH2-CF3, NH-(CH2)12-OH, NH-(CH2)13-CH3, NH-(CH2)14- CH3, NH-(CH2)15-CH3, NH-(CH2)17-CH3, NH(CH2-CH2-O)4-CH2-CH2-COOH, NH(CH2-CH2-O)24-CH2-CH2-COOH, NH-N(CH2)4, NH-CH2-C6H5, N(CH2-CH2)2O.

A further embodiment relates to a group of compounds, wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin, His, Asn and Na-methylated Gin [Gin (a-NHCH3)],

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-;

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser and Lys,

X17 represents an amino acid residue selected from Arg and Glu,

X18 represents an amino acid residue selected from Arg and Ala,

X20 represents an amino acid residue selected from Gin, Arg and Aib,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents an amino acid residue selected from Ala and Asn,

X29 represents Gly,

X35 represents Ala,

X39 is Ser,

X40 is absent.

A further embodiment relates to a group of compounds of formula (I), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin, His and Na-methylated Gin [Gin (a-NHCH3)],

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-;

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser and Lys,

X17 represents Arg,

X18 represents an amino acid residue selected from Arg and Ala,

X20 represents an amino acid residue selected from Gin and Aib,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents an amino acid residue selected from Ala and Asn,

X29 represents Gly,

X35 represents Ala,

X39 is Ser,

X40 is absent.

A further embodiment relates to a group of compounds of formula (I), wherein

X2 represents an amino acid residue selected from D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl-, (S)-4-carboxy-4-((S)-4- carboxy hexadecanoylamino-butyrylamino)-butyryl-, or (S)-4-carboxy-4- octadecanoylamino-butyryl-;

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents Glu,

X17 represents Glu,

X18 represents Ala,

X20 represents an amino acid residue selected from Arg and Lys,

X21 represents Leu,

X28 represents Ala,

X29 represents Gly,

X35 represents Ala,

X39 is Ser,

X40 is absent.

A still further preferred embodiment relates to a group of compounds wherein

X40 is absent.

A still further preferred embodiment relates to a group of compounds, wherein

the functionalized Lys in position 14 is functionalized at its ε-amino group with -C(O)-R5, and-C(O)-R5 is (S)-4-carboxy-4-hexadecanoyl-amino-butyryl, (S)-4-carboxy-4-octadecanoylamino-butyryl, hexadecanoyl or octadecanoyl.

A still further preferred embodiment relates to a group of compounds wherein

X2 represents an amino acid residue selected from Aib and D-Ser;

X3 represents an amino acid residue selected from Gin and His;

X14 represents Lys, wherein the -NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4- Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- octadecanoylamino-butyrylamino)-butyryl-, 3-(3-Octadecanoylamino- propionylamino)-propionyl-, 3-(3-Hexadecanoylamino-propionylamino)- propionyl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, 4- Hexadecanoylamino-butyryl- and 4-octadecanoylamino-butyryl-,

X15 represents an amino acid residue selected from Asp and Glu;

X16 represents an amino acid residue selected from Ser and Glu;

X17 represents an amino acid residue selected from Arg, Gin, Lys, Aib and Leu; X18 represents an amino acid residue selected from Arg and Ala;

X20 represents an amino acid residue selected from Gin, Aib and Lys;

X21 represents an amino acid residue selected from Asp, Glu and Lys;

X28 represents an amino acid residue selected from Asn, Ser, Aib, Ala and Arg; X29 represents an amino acid residue selected from Gly, Thr, Ala and D-Ala;

X35 represents Ala;

X39 represents Ser and

X40 is absent.

A still further preferred embodiment relates to a group of compounds wherein

X2 represents an amino acid residue selected from Aib and D-Ser;

X3 represents Gin;

X14 represents Lys, wherein the -NH2 side chain group is functionalized by one of the groups selected from (S)-4-carboxy-4-hexadecanoyl-amino-butyryl, (S)-4- carboxy-4-octadecanoylamino-butyryl, hexadecanoyl and octadecanoyl;

X15 represents Glu;

X16 represents Ser;

X17 represents an amino acid residue selected from Arg, Gin and Lys;

X18 represents Ala;

X20 represents Gin;

X21 represents Asp;

X28 represents Ala;

X29 represents Gly;

X35 represents Ala;

X39 represents Ser and

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X2 represents Aib,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-Carboxy-4-henicosanoylamino-butyryl- and (S)-4-Carboxy-4- octadecanoylamino-butyryl-;

X15 represents Asp,

X16 represents an amino acid residue selected from Lys and Glu,

X17 represents an amino acid residue selected from Arg and Glu,

X18 represents an amino acid residue selected from Ala and Arg,

X20 represents an amino acid residue selected from Gin and Lys,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents Ala,

X29 represents an amino acid residue selected from Gly and D-Ala,

X35 represents Ala,

X39 is Ser,

X40 is absent.

In one embodiment, the invention provides a peptidic compound having the formula (I): R1 - Z - R2 (I),

wherein Z is a peptide moiety having the formula (I la)

H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K(YE-x53)-D-S-K-A-Aib-Q-D-F-l-E-W-L-K-A-G-G-P-S-S-

G-A-P-P-P-S-NH2 (Ila).

In another embodiment, the invention provides a peptidic compound having the formula (I):

R1 - Z - R2 (I),

wherein Z is a peptide moiety having the formula (Mb)

H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K(YE-x53)-D-S-K-A-S-Q-D-F-l-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 (Mb).

In another embodiment, the invention provides a peptidic compound having the formula (I):

R1 - Z - R2 (I),

wherein Z is a peptide moiety having the formula (lie)

H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K(YE-x53)-D-S-K-A-L-Q-D-F-l-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 (lie).

In another embodiment, the invention provides a peptidic compound having the formula (I):

R1 - Z - R2 (I),

wherein Z is a peptide moiety having the formula (lid)

H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K(YE-x53)-D-S-K-A-A-Q-D-F-l-E-W-K-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 (lid).

Specific examples of peptidic compounds of the invention are the compounds of SEQ ID NO: 4-181 , as well as salts and solvates thereof.

Further specific examples of peptidic compounds of the invention are the compounds of SEQ ID NO: 4-181 and 196-223 as well as salts and solvates thereof.

Further specific examples of peptidic compounds of the invention are the compounds of SEQ ID NO: 7, 1 1 -13, 22, 24-31 , 34-39, 44-48, 86, 97, 123-124, 130-159, 164, 166, 173-176, as well as salts and solvates thereof.

Further specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 7, 1 1 -13, 22, 24-31 , 34-39, 44-48, 86, 97, 123-124, 130-159, 164, 166, 173-176, 196-223, 226-229 as well as salts and solvates thereof.

In some embodiments, the compound of the invention is selected from the group consisting of SEQ ID NOs.: 25, 31 , 133, 148, 153, 155 and 158. In other embodiments, the compound of the invention is selected from the group consisting of SEQ ID NOs.: 209, 210, 21 1 , 212 and 213.

According to one particular embodiment, the compound of the invention is represented by SEQ ID NO.: 97 (see Table 10). In another particular embodiment, the compound of formula (I) is represented by SEQ ID NO.: 24 (see Table 10).

In certain embodiments, i.e. when the compound of formula (I) comprises genetically encoded amino acid residues, the invention further provides a nucleic acid (which may be DNA or RNA) encoding said compound, an expression vector comprising such a nucleic acid, and a host cell containing such a nucleic acid or expression vector.

In a further aspect, the present invention provides a composition comprising a compound of the invention in admixture with a carrier. In preferred embodiments, the composition is a pharmaceutically acceptable composition and the carrier is a pharmaceutically acceptable carrier. The compound of the invention may be in the form of a salt, e.g. a pharmaceutically acceptable salt or a solvate, e.g. a hydrate. In still a further aspect, the present invention provides a composition for use in a method of medical treatment, particularly in human medicine.

In certain embodiments, the nucleic acid or the expression vector may be used as therapeutic agents, e.g. in gene therapy.

The compounds of formula (I) are suitable for therapeutic application without an additionally therapeutically effective agent. In other embodiments, however, the compounds are used together with at least one additional therapeutically active agent, as described in "combination therapy".

The compounds of formula (I) are particularly suitable for the treatment or prevention of diseases or disorders caused by, associated with and/or accompanied by disturbances in carbohydrate and/or lipid metabolism, e.g. for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity and metabolic syndrome. Further, the compounds of the invention are particularly suitable for the treatment or prevention of degenerative diseases, particularly neurodegenerative diseases.

The compounds described find use, inter alia, in preventing weight gain or promoting weight loss. By "preventing" is meant inhibiting or reducing when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of a disorder.

The compounds of the invention may cause a decrease in food intake and/or increase in energy expenditure, resulting in the observed effect on body weight.

Independently of their effect on body weight, the compounds of the invention may have a beneficial effect on circulating cholesterol levels, being capable of improving lipid levels, particularly LDL, as well as HDL levels (e.g. increasing HDL/LDL ratio).

Thus, the compounds of the invention can be used for direct or indirect therapy of any condition caused or characterised by excess body weight, such as the treatment and/or prevention of obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea. They may also be used for treatment and prevention of the metabolic syndrome, diabetes, hypertension, atherogenic dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, or stroke. Their effects in these conditions may be as a result of or associated with their effect on body weight, or may be independent thereof.

Preferred medical uses include delaying or preventing disease progression in type 2 diabetes, treating metabolic syndrome, treating obesity or preventing overweight, for decreasing food intake, increase energy expenditure, reducing body weight, delaying the progression from impaired glucose tolerance (IGT) to type 2 diabetes; delaying the progression from type 2 diabetes to insulin-requiring diabetes; regulating appetite; inducing satiety; preventing weight regain after successful weight loss; treating a disease or state related to overweight or obesity; treating bulimia; treating binge eating; treating atherosclerosis, hypertension, type 2 diabetes, IGT, dyslipidemia, coronary heart disease, hepatic steatosis, treatment of beta-blocker poisoning, use for inhibition of the motility of the gastrointestinal tract, useful in connection with investigations of the gastrointestinal tract using techniques such as X-ray, CT- and NMR-scanning.

Claims

1 . A peptidic compound having the formula (I):

R1 - Z - R2 (I)

wherein Z is a peptide moiety having the formula (II)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-X16-X17-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-X35-Pro-Pro-Pro- X39-X40 (II)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin, His and a-amino- functionalized Gin, wherein Gin may be functionalized in that an H of the a-NH2 group is substituted by (Ci-C4)-alkyl,

X14 represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is functionalized by -C(O)-R5, -C(O)O-R5, - C(O)NH-R5, -S(O)2-R5 or R5, preferably by -C(O)-R5, wherein R5 may be a moiety comprising up to 50 or up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S and/or P,

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser, Glu and Lys,

X17 represents an amino acid residue selected from Arg, Glu, Gin, Leu, Aib and Lys,

X18 represents an amino acid residue selected from Arg, Ala and Lys,

X20 represents an amino acid residue selected from Gin, Arg, Lys, His, Glu and Aib,

X21 represents an amino acid residue selected from Asp, Leu and Glu,

X28 represents an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Ala and Asp,

X29 represents an amino acid residue selected from Gly, Ala, D-Ala and Thr,

X35 represents an amino acid residue selected from Ala, Glu, Arg and Lys,

X39 represents Ser or is absent and

X40 is absent or represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is optionally functionalized by -C(O)-R5, - C(O)O-R5, -C(O)NH-R5, -S(O)2-R5 or R5, preferably by -C(O)-R5, wherein R5 may be a moiety comprising up to 50 or up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S and/or P,

R1 represents the N-terminal group of the peptidic compound and is selected from NH2 and mono- or bisfunctionalized NH2,

R2 represents the C-terminal group of the peptidic compound and is selected from

(i) OH or functionalized OH and

(ii) NH2 or mono- or bisfunctionalized NH2,

or a salt or solvate thereof.

The compound of claim 1 , wherein

X14 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group is functional ized by -C(O)-R5,

X40 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group can be functional ized by -C(O)-R5, and

R5 is a lipophilic moiety selected from an acyclic linear or branched (C4-C30) saturated or unsaturated hydrocarbon group, and/or a cyclic saturated, unsaturated or aromatic group, wherein the lipophilic moiety may be attached to the -NH2 side chain group by a linker selected from ( -Ala)i-4, (Y-GI U)I-4, (£-Ahx) -4, or (GABA) -4 in all stereoisomeric forms.

A compound of any one of claims 1 - 2, wherein

X14 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group is functionalized by -C(O)-R5,

X40 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group can be functionalized by -C(O)-R5, and

-C(O)-R5 is selected from

(S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-,4-Hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-, Hexadecanoyl-, (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl-, (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-

carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-propionylamino]-propionylamino}-butyryl, (S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylannino}-butyryl-, (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-, (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylannino)-hexanoylannino]-butyryl, (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylannino)-butyryl, (S)-4-Carboxy-4-tetradecanoylamino-butyryl-, (S)-4-(1 1 -Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl, (S)-4-Carboxy-4-[1 1 -((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylannino]-butyryl-, (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, (S)-4-Carboxy-4-docosanoylamino-butyryl-, (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-, (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-Carboxy-4-icosanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylannino)-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylannino)-butyryl-, 3-(3-Octadecanoylamino-propionylamino)-propionyl-, 3-(3-Hexadecanoylamino-propionylannino)-propionyl-, 3-Hexadecanoylamino-propionyl-, (S)-4-Carboxy-4-[(R)-4-((3R,5S,7R,8R,9R,10S.12S.13R.14R.17R)-3,7,12-trihydroxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-[(R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylamino)-butyryl-,

Tetradecanoyl-, 1 1 -Carboxy-undecanoyl-, 1 1 -Benzyloxycarbonyl-undecanoyl, (S)-4-Carboxy-4-((S)-4-carboxy-4-tetradecanoylamino-butyrylannino)-butyryl-, 6-[Hydroxy-(naphthalen-2-yloxy)-phosphoryloxy]-hexanoyl-, 6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-, 4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-, 4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4- carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylannino]-butyrylannino}-butyryl, (S)-4-Carboxy-2 [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylannino]-butyryl, (S)-4-Carboxy-4 {(S)-4-carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylannino]-butyrylannino}-butyryl, (S)-4-Carboxy-4 [2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyryl,(S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl, (S)-4-Carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17 carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, 2 (2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[(S)-4-Carboxy-4-(17 carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetyl, (S)-4-Carboxy 4-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-butyrylamino}-butyrylamino)-butyryl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-1 H-tetrazol-5-yl-hexadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy 4-(16-carboxy-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(17 carboxy-heptadecanoylamino)-butyrylannino]-butyrylannino}-butyryl, (S)-4-Carboxy-4-((S)-4-carboxy-4-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)-decanoylamino]-butyrylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylaminoj-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4 carboxy-4-(7-carboxy-heptanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy 4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(1 1 -carboxy-undecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(13-carboxy-tridecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2 {2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylannino]-butyrylannino}-butyryl, and (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy-

nonadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl.

A compound of any one of claims 1 - 3,

wherein

R1 is NH2,

R2 is NH2 or

R1 and R2 are NH2.

The compound of any one of claims 1 - 4

wherein

X14 is Lys, which is functionalized with a group -C(O)R5, wherein R5 is as described in any one of claims 1 -3.

The compound of any one of claims 1 - 5, wherein

X14 is Lys, which is functionalized with a group -C(O)R5, wherein R5 comprises a lipophilic moiety, an acyclic linear or branched (Ci2-C22) saturated hydrocarbon group attached directly to the -NH2 side chain group or attached to the -NH2 side chain group by a linker selected form the group of β-Ala, γ-Glu, β-Αΐ3-β-Αΐ8 and γ-Glu-y-Glu in all stereoisomeric forms.

A compound of any one of claims 1 - 6, wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin, His and a-amino-functionalized Gin, wherein Gin may be functionalized in that an H of the a-NH2 group is substituted by (Ci -C4)-alkyl,

X14 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group is functionalized by -C(O)-R5,

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser, Lys and Glu,

X17 represents an amino acid residue selected from Arg, Glu, Gin, Leu and Lys,

X18 represents an amino acid residue selected from Arg and Ala,

X20 represents an amino acid residue selected from Gin, Arg, Lys and Aib,

X21 represents an amino acid residue selected from Asp, Leu and Glu,

X28 represents an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Asp and Ala,

X29 represents an amino acid residue selected from Gly, Ala, D-Ala and Thr,

X35 represents an amino acid residue selected from Ala or Glu,

X39 is Ser or is absent,

X40 is either absent or represents Lys, wherein the -NH2 side chain group can be functionalized by -C(O)-R5 and

-C(O)-R5 is as defined in claim 2.

A compound of any one of claims 1 - 7, wherein

X2 represents an amino acid residue selected from D-Ser and Aib,

X3 represents Gin,

X14 represents an amino acid residue selected from Lys and Orn, wherein the -NH2 side chain group is functionalized by -C(O)-R5,

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser and Glu,

X17 represents an amino acid residue selected from Arg, Gin and Lys,

X18 represents an amino acid residue selected from Arg and Ala,

X20 represents an amino acid residue selected from Gin, Arg, Lys and Aib,

X21 represents an amino acid residue selected from Asp, Leu and Glu,

X28 represents an amino acid residue selected from Asn, Arg, Lys, Aib, Ser and Ala,

X29 represents an amino acid residue selected from Gly, Ala or Thr,

X35 represents Ala,

X39 is Ser or is absent,

X40 is either absent or represents Lys, wherein the -NH2 side chain group can be functionalized by -C(O)-R5 and

-C(O)-R5 is as defined in claim 2.

The compound of any one of claims 1 - 8, wherein

X20 represents an amino acid residue selected from Gin, Lys and Aib.

A compound of any one of claims 1 - 9, wherein

X2 represents an amino acid residue selected from D-Ser and Aib,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized by one of the groups selected from 3-(3-octadecanoylamino-propionyl-amino)-propionyl-, 4- hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12- trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4- octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, hexadecanoyl-, (S)-4-carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-carboxy-4-(4-dodecyloxy- benzoylamino)-butyryl-, (S)-4-carboxy-4-henicosanoylamino-butyryl-, (S)-4-carboxy- 4-docosanoylamino-butyryl-, (S)-4-carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-carboxy-4-[(4'-octyloxy- biphenyl-4-carbonyl)-amino]-butyryl-, (S)-4-carboxy-4-(12-phenyl-dodecanoylamino)- butyryl-, (S)-4-carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)- butyryl-, (S)-4-carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl- (S)-4-carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)- chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4-carboxy-4-((9Z,12Z)- octadeca-9,12-dienoylamino)-butyryl-, (S)-4-carboxy-4-octadecanoylamino-butyryl- and (S)-4-carboxy-4-hexadecanoylamino-butyryl-,

X15 represents Glu,

X16 represents Ser,

X17 represents an amino acid residue selected from Arg, Gin and Lys,

X18 represents Ala,

X20 represents Gin,

X21 represents Asp,

X28 represents Ala,

X29 represents Gly,

X35 represents Ala,

X39 is Ser

X40 is absent.

The compound of any one of claims 1 - 10, wherein

X2 represents Aib,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-Carboxy-4-hexadecanoylamino-butyryl- and (S)-4-Carboxy-4- octadecanoylamino-butyryl-;

X15 represents an amino acid residue selected from Asp and Glu,

X16 represents an amino acid residue selected from Ser and Glu,

X17 represents an amino acid residue selected from Gin and Lys,

X18 represents Ala,

X20 represents an amino acid residue selected from Gin and Lys,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents Ala,

X29 represents an amino acid residue selected from Gly and D-Ala,

X35 represents Ala,

X39 is Ser,

X40 is absent.

12. A compound of any one of claims 1 - 1 1 , wherein

X2 represents D-Ser,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-;

X15 represents an amino acid residue selected from Glu and Asp,

X16 represents an amino acid residue selected from Ser and Glu,

X17 represents an amino acid residue selected from Arg, Glu, Lys and Aib,

X18 represents an amino acid residue selected from Arg, Lys and Ala,

X20 represents an amino acid residue selected from Gin, Lys and Aib,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents an amino acid residue selected from Ala and Asn,

X29 represents Gly,

X35 represents Ala,

X39 is Ser,

X40 is absent.

13. A compound of any one of claims 1 - 12, wherein

X2 represents an amino acid residue selected from Aib and D-Ser;

X3 represents an amino acid residue selected from Gin and His;

X14 represents Lys, wherein the -NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-

Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylannino)-butyryl-, 3-(3-Octadecanoylamino-propionyla-mino)-propionyl-, 3-(3-Hexadecanoylamino-propionyla-nnino)-propionyl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, 4-Hexadecanoylamino-butyryl- and 4-octadecanoylamino-butyryl-,

X15 represents an amino acid residue selected from Asp and Glu;

X16 represents an amino acid residue selected from Ser and Glu;

X17 represents an amino acid residue selected from Arg, Gin, Lys, Aib and Leu;

X18 represents an amino acid residue selected from Arg and Ala;

X20 represents an amino acid residue selected from Gin, Aib and Lys;

X21 represents an amino acid residue selected from Asp, Glu and Lys;

X28 represents an amino acid residue selected from Asn, Ser, Aib, Ala and Arg;

X29 represents an amino acid residue selected from Gly, Thr, Ala and D-Ala;

X35 represents Ala;

X39 represents Ser and

X40 is absent.

A compound of any one of claims 1 - 13, wherein

the functionalized Lys in position 14 is functionalized at its ε-amino group with -C(O)-R5, and-C(O)-R5 is (S)-4-carboxy-4-hexadecanoyl-amino-butyryl, (S)-4-carboxy-4-octadecanoylamino-butyryl, hexadecanoyl or octadecanoyl.

A compound of claim 14, wherein

X2 represents an amino acid residue selected from Aib and D-Ser;

X3 represents Gin;

X14 represents Lys, wherein the -NH2 side chain group is functionalized by one of the groups selected from (S)-4-carboxy-4-hexadecanoyl-amino-butyryl, (S)-4-carboxy-4-octadecanoylamino-butyryl, hexadecanoyl and octadecanoyl;

X15 represents Glu;

X16 represents Ser;

X17 represents an amino acid residue selected from Arg, Gin and Lys;

X18 represents Ala;

X20 represents Gin;

X21 represents Asp;

X28 represents Ala;

X29 represents Gly;

X35 represents Ala;

X39 represents Ser and

X40 is absent.

The compound of any one of claims 1 - 15, wherein

X2 represents Aib,

X3 represents Gin,

X14 represents Lys, wherein the -NH2 side chain group is functionalized, particularly by (S)-4-Carboxy-4-henicosanoylamino-butyryl- and (S)-4-Carboxy-4- octadecanoylamino-butyryl-;

X15 represents Asp,

X16 represents an amino acid residue selected from Lys and Glu,

X17 represents an amino acid residue selected from Arg and Glu,

X18 represents an amino acid residue selected from Ala and Arg,

X20 represents an amino acid residue selected from Gin and Lys,

X21 represents an amino acid residue selected from Asp and Leu,

X28 represents Ala,

X29 represents an amino acid residue selected from Gly and D-Ala

X35 represents Ala,

X39 is Ser,

X40 is absent.

17. The compound of any one of claims 1 -16, selected from the compounds of SEQ ID NO. 4-181 , or a salt or solvate thereof.

18. The compound of any one of claims 1 -16, selected from the compounds of SEQ ID NO. 4-181 , 196-223, 226-229 or a salt or solvate thereof.

19. Compound according to any one of claims 1 -18, which has a high solubility at acidic pH values, e.g. at pH 4.5 at 25°C, and/or at physiological pH values, e.g., at pH 7.4 at 25°C, wherein the solubility at said pH value and/or pH values is particularly at least 0.5 mg/ml, or at least 1 .0 mg/ml.

The compound of any one of claims 1 -19 for use in medicine, particularly in human medicine.

The compound for use according to claim 20 which is present as an active agent in a pharmaceutical composition together with at least one pharmaceutically acceptable carrier.

The compound for use according to claim 20 or 21 together with at least one additional therapeutically active agent, wherein the additional therapeutically active agent is selected from the series of Insulin and Insulin derivatives, GLP-1 , GLP-1 analogues and GLP-1 receptor agonists, polymer bound GLP-1 and GLP-1 analogues, dual GLP1/GIP agonists, PYY3-36 or analogues thereof, pancreatic polypeptide or analogues thereof, Glucagon receptor agonists, GIP receptor agonists or antagonists, ghrelin antagonists or inverse agonists, Xenin and analogues thereof, DDP-IV inhibitors, SGLT2 inhibitors, dual SGLT2 / SGLT1 inhibitors, Biguanides Thiazolidinediones, dual PPAR agonists, Sulfonylureas, Meglitinides, alpha-glucosidase inhibitors, Amylin and Amylin analogues, GPR1 19 agonists, GPR40 agonists, GPR120 agonists, GPR142 agonists, systemic or low-absorbable TGR5 agonists, Cycloset, inhibitors of 1 1 -beta-HSD, activators of glucokinase, inhibitors of DGAT, inhibitors of protein tyrosinephosphatase 1 , inhibitors of glucose-6-phosphatase, inhibitors of fructose-1 ,6-bisphosphatase, inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrogenase kinase, alpha2-antagonists, CCR-2 antagonists, modulators of glucose transporter-4, Somatostatin receptor 3 agonists, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the derivatives thereof, nicotinic acid receptor 1 agonists, PPAR-alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors, cholesterol absorption inhibitors, bile acid-binding substances, IBAT inhibitors, MTP inhibitors, modulators of PCSK9, LDL receptor up-regulators by liver selective thyroid hormone receptor β agonists, HDL-raising compounds, lipid metabolism modulators, PLA2 inhibitors , ApoA-l enhancers,

thyroid hormone receptor agonists, cholesterol synthesis inhibitors, omega-3 fatty acids and derivatives thereof, active substances for the treatment of obesity, such as Sibutramine, Tesofensine, Orlistat, CB-1 receptor antagonists, MCH-1 antagonists, MC4 receptor agonists and partial agonists, NPY5 or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor, or the combinations of bupropione/naltrexone (CONTRAVE), bupropione/zonisamide (EMPATIC), bupropione/phentermine or pramlintide/metreleptin, QNEXA (Phentermine+ topiramate), lipase inhibitors, angiogenesis inhibitors, H3 antagonists, AgRP inhibitors, triple monoamine uptake inhibitors (norepinephrine and acetylcholine), MetAP2 inhibitors, nasal formulation of the calcium channel blocker diltiazem, antisense against production of fibroblast growth factor receptor 4, prohibitin targeting peptide-1 , drugs for influencing high blood pressure, chronic heart failure or atherosclerosis, such as angiotensin II receptor antagonists, ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors.

The compound for use according to claim 20 or 21 together with at least one additional therapeutically active agent, wherein the additional therapeutically active agent particularly is a GLP-1 compound and/or an insulinic compound and/or a gastrointestinal peptide.

The compound for use according to claim 20 or 21 together with at least one additional therapeutically active agent, wherein the additional therapeutically active agent particularly is insulin or an insulin derivative.

The compound for use according to claim 20 or 21 , wherein the pharmaceutical composition is for parenteral administration, preferably in a single dose injectable form, particularly in the form of a pen.

The compound for use according to any one of claims 20 - 25 for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, metabolic syndrome and neurodegenerative disorders, particularly for delaying or preventing disease progression in type 2 diabetes, treating metabolic syndrome, treating obesity or preventing overweight, for decreasing food intake, increase energy expenditure, reducing body weight, delaying the progression from impaired glucose tolerance (IGT) to type 2 diabetes; delaying the progression from type 2 diabetes to insulin-requiring diabetes; regulating appetite; inducing satiety; preventing weight regain after successful weight loss; treating a disease or state related to overweight or obesity; treating bulimia; treating binge eating; treating atherosclerosis, hypertension, IGT, dyslipidemia, coronary heart disease, hepatic steatosis, treatment of beta-blocker poisoning, use for inhibition of the motility of the gastro-intestinal tract, useful in connection with investigations of the gastro-intestinal tract using techniques such as X-ray, CT- and NMR-scanning.

The compound for use according to any one of claims 20 - 26 for the treatment or prevention of hyperglycemia, type 2 diabetes, obesity and metabolic syndrome or reducing body weight.

The compound for use according to any one of claims 20 - 26 for simultaneous treatment of obesity and diabetes.