Description

FIELD OF THE INVENTION

The present invention relates to exendin-4 peptide analogues which activate the glucagon-like peptide 1 (GLP-1 ) and the glucagon (GCG) receptor and optionally the glucose-dependent insulinotropic polypeptide (GIP) receptor and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as 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., 1992, 267, 7402-05). Exendin-4 is an activator of the glucagon-like peptide-1 (GLP-1 ) receptor, whereas it shows only very low activation of the GIP receptor and does not activate the glucagon receptor (see Table 1 ).

Table 1 : Potencies of exendin-4 at human GLP-1 , GIP and Glucagon receptors (indicated in pM) at increasing concentrations and measuring the formed cAMP as described in Methods.

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 and GIP, exendin-4 is more 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; Deacon CF, Horm Metab Res, 36: 761 -5, 2004).

Exendin-4 was also shown to be much more stable towards degradation by neutral endopeptidase (NEP), when compared to GLP-1 , glucagon or oxyntomodulin (Druce MR et al., Endocrinology, 150(4), 1712-1721 , 2009).

Nevertheless, exendin-4 is chemically labile due to methionine oxdiation 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 analogue 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, JB et al., Lancet, 374:39-47, 2009).

The amino acid sequence of Liraglutide is shown as SEQ ID NO: 3:

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 as SEQ ID NO: 5:

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. Recent publications suggest that glucagon has in addition beneficial effects on reduction of body fat mass, reduction of food intake, and increase of energy expenditure (KM Heppner, Physiology & Behavior 2010, 100, 545-548).

GIP (glucose-dependent insulinotropic polypeptide) is a 42 amino acid peptide that is released from intestinal K-cells following food intake. GIP and GLP-1 are the two gut enteroendocrine cell-derived hormones accounting for the incretin effect, which accounts for over 70% of the insulin response to an oral glucose challenge (Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-2157).

GIP's amino acid sequence is shown as SEQ ID NO: 4:

YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-OH

Hoist (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1 , liraglutide and exendin-4, improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (FPG and PPG). Peptides which bind and activate the GLP-1 receptor are described in patent applications

WO 98/08871 A1 , WO2008/081418 A1 and WO2008/023050 A1 , the contents of which are herein incorporated by reference.

Designing hybrid molecules which combine agonism on the GLP-1 receptor, the glucagon receptor and optionally the GIP receptor offers the therapeutic potential to achieve better reduction of blood glucose levels, increased insulin secretion and an even more pronounced significant effect on body weight reduction compared to the marketed GLP-1 agonist Liraglutide (Hjort et al. Journal of Biological Chemistry, 269, 30121 -30124,1994; Day JW et al, Nature Chem Biol, 5: 749-757, 2009).

Peptides which bind and activate both the GLP-1 and the glucagon receptor and optionally the GIP receptor, and improve glycaemic control, 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 /087671 , WO 201 1 /087672, WO201 1/1 17415 ,WO201 1/1 17416, WO 2012/177443 WO 2012/177444, WO 2012/150503, WO 2013/004983, WO 2013/092703, WO 2014/041 195 and WO

2014/041375, the contents of which are herein incorporated by reference.

These applications disclose that mixed agonists of the GLP-1 receptor, the glucagon receptor and optionally the GIP receptor can be designed as analogues of the native GLP-1 or glucagon sequences.

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-4. Such peptides comprise glucagon's amino acid motif YSKY in position 10-13. Krstenansky et al (Biochemistry, 25, 3833-3839, 1986) show the importance of these 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 and the peptides described in WO 2006/134340. 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. This replacement, especially in combination with isoleucine in position 23 and glutamate in position 24, leads to exendin-4 derivatives with potentially improved biophysical properties as solubility or aggregation behaviour in solution. The non-conservative replacement of an aromatic amino acid with a polar amino acid in position 13 of an exendin-4 analogue surprisingly leads to peptides with high activity on the glucagon receptor, keeping their activity on the GLP-1 receptor (see also WO2013/186240 .

Compounds of this invention are exendin-4 derivatives, which not only show agonistic activity at the GLP-1 receptor but also at the glucagon receptor and optionally the GIP receptor and which have only 4 or 5 amino acid exchanges compared to native exendin-4 including - amongst others - in

position 14 an amino acid substituted with a lipophilic side-chain (e.g. a fatty acid combined with a linker).

Surprisingly, it was found that the modification of the amino acids in position 2 and 3 of native exendin-4 in combination with a fatty acid acylated residue in position 14 leads to peptides with a significantly higher glucagon receptor activity than the corresponding peptides with otherwise identical amino acid sequence with methionine (as in exendin-4) or leucine in position 14 (see Table 7). Additionally, this fatty acid functionalization in position 14 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 native GLP-1 and glucagon.

Compounds of this invention preferably are 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 analogues with only 4 or 5 amino acid modifications (compared to native exendin-4) which potently activate not only the GLP-1 receptor but also the glucagon receptor and optionally the GIP receptor. In these exendin-4 analogues - 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 a lipophilic side-chain (e.g. a fatty acid optionally combined with a linker).

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

H2N-His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15- Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro- Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R1 (I)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib, X3 represents an amino acid residue selected from Gin and His, X14 represents an amino acid residue with a functionalized -NH2 side chain group, selected from the group consisting of Lys, Orn, Dab, or Dap, wherein the -NH2 side chain group is functionalized by -Z- C(O)-R5, wherein

Z represents a linker in all stereoisomeric forms and

R5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from N and O,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 is NH2 or OH,

or a salt or solvate thereof.

The compounds of the invention are GLP-1 and glucagon receptor agonists and optionally GIP receptor agonists as determined by the observation that they are capable of stimulating intracellular cAMP formation in the assay system described in Methods.

In addition, the peptidic compound, particularly with a lysine at position 14 which is further substituted with a lipophilic residue, exhibits a relative activity of at least 0.1 % (i.e. EC50 < 700 pM), preferably at least 1 % (i.e. EC50 < 70 pM) and more preferably at least 5% (i.e. EC5o < 14 pM) compared to that of GLP-1 (7-36)-amide at the GLP-1 receptor.

In addition, the peptidic compound, particularly with a lysine at position 14 which is further substituted with a lipophilic residue, exhibits a relative activity of at least 0.1 % (i.e. EC50 < 1000 pM), more preferably 0.3% (i.e. EC5o < 333 pM) and even more preferably 1 % (i.e. EC5o < 100 pM) compared to that of natural glucagon at the glucagon receptor.

Optionally, in some embodiments, the peptidic compound, particularly with a lysine at position 14 which is further substituted with a lipophilic residue, exhibits a relative activity of at least 0.01 % (i.e. EC5o < 4000 pM), preferably at least 0.02% (i.e. EC50 < 2000 pM), more preferably at least 0.04% (i.e. EC50 < 1000 pM), more preferably at least 0.1 % (i.e. EC50 < 400 pM), and even more preferably at least 0.2% (i.e. EC5o < 200 pM) compared to that of natural GIP at the GIP receptor.

The term "activity" as used herein preferably refers to the capability of a compound to activate the human GLP-1 receptor, the human glucagon receptor and optionally the human GIP 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 Example 4.

According to one embodiment, the compounds of the invention have an EC50 for hGLP-1 receptor of 500 pM or less, preferably of 200 pM or less, more more preferably of 100 pM or less, more preferably of 75 pM or less, more preferably of 50 pM or less, more preferably of 40 pM or less, more preferably of 30 pM or less, and more preferably of 20 pM or less.

According to one embodiment, the compounds of the invention have an EC50 for hGlucagon receptor of 500 pM or less, more preferably of 300 pM or less, more preferably of 200 pM or less, more preferably of 150 pM or less, more

preferably of 100 pM or less.

According to another embodiment, the compounds of the invention have optionally an EC5o for hGIP receptor of 2000 pM or less, preferably of 500 pM or less, more preferably of 200 pM or less, more preferably of 150 pM or less, more preferably of 100 pM or less.

According to another embodiment, the compounds of the invention have an EC5o for hGLP-1 receptor of 500 pM or less, preferably of 200 pM or less, more preferably of 150 pM or less, more preferably of 100 pM or less, more preferably of 90 pM or less, more preferably of 80 pM or less, more preferably of 70 pM or less, more preferably of 60 pM or less, more preferably of 50 pM or less, more preferably of 40 pM or less, more preferably of 30 pM or less, and more preferably of 20 pM or less, and/or an EC50 for hGlucagon receptor of 500 pM or less, preferably of 400 pM or less, more preferably of 350 pM or less, more preferably of 200 pM or less, more preferably of 150 pM or less, more preferably of 100 pM or less, and/or optionally an EC5o for hGIP receptor of 2000 pM or less, preferably of 500 pM or less, more preferably of 200 pM or less, more preferably of 150 pM or less, more preferably of 100 pM or less.

In still another embodiment, the EC50 for both receptors, i.e. for the hGLP-1 receptor and for the hGlucagon receptor, is 500 pM or less, more preferably 200 pM or less, more preferably 100 pM or less, more preferably 75 pM or less, more preferably 50 pM or less, more preferably 25 pM or less.

In still another embodiment, the EC50 for all three receptors, i.e. for the hGLP-1 receptor, for the hGlucagon receptor and for the hGIP receptor, is 500 pM or less, more preferably 200 pM or less, more preferably 100 pM or less, more preferably 75 pM or less, more preferably 50 pM or less, more preferably 25 pM or less.

The EC5o for hGLP-1 receptor, hGlucagon receptor and hGIP receptor may be determined as described in the Methods herein and as used to generate the results described in Example 4.

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 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 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.

Surprisingly, it was found that peptidic compounds of the formula (I), particularly those with a lysine (or close analogues) at position 14 which is further substituted with a lipophilic residue, showed very potent GLP-1 receptor and glucagon receptor and optionally GIP receptor activation.

It is described in the literature (Murage EN et al., Bioorg. Med. Chem. 16 (2008), 10106-101 12), that a GLP-1 analogue with an acetylated lysine at position14 showed significantly reduced potency on the GLP-1 receptor compared to natural GLP-1 .

Furthermore, oxidation (in vitro or in vivo) of methionine, present in the core structure of exendin-4, is not possible anymore for peptidic compounds of the formula (I).

Further, compounds of the invention preferably 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, 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 40°C in solution at pH 4.5 or pH 7.4. The remaining amount of peptide is determined by chromatographic analyses as described in Methods and Examples.

Preferably, after 7 days at 40°C in solution at pH 4.5 or pH 7.4, the remaining peptide 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 which is a linear sequence of 39 amino carboxylic acids, particularly a-amino carboxylic acids linked by peptide, i.e. carboxamide, bonds.

In a further embodiment, R1 is NH2 and in a further embodiment R1 is OH.

Specific preferred examples for -Z-C(O)-R5 groups are listed in the following Table 2, which are 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-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy- 4-(17-carboxy-heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl.

Further preferred are stereoisomers, particularly enantiomers of these groups, either S- or R-enantiomers. The term "R" in Table 2 is intended to mean the attachment site of -Z-C(O)-R5 at the peptide back bone, i.e. particularly the ε-amino group of Lys.

Table 2

A further embodiment relates to a group of compounds, wherein

X14 represents Lys wherein the -NH2 side chain group is functionalized with a group -Z-C(O)R5 , wherein

Z represents a group selected from γΕ, γΕ-γΕ, AEEAc-AEEAc-γΕ and AE EAc-AE EAc-AE EAc and

R5 represents a group selected from pentadecanyl, heptadecanyl or 16-carboxy-hexadecanyl .

A further embodiment relates to a group of compounds, wherein

X14 represents Lys wherein the -NH2 side chain group is functionalized with a group -Z-C(O)R5 , wherein

Z represents a group selected from γΕ, γΕ-γΕ, AEEAc-AEEAc-γΕ and AE EAc-AE EAc-AE EAc and

R5 represents a group selected from pentadecanyl or heptadecanyl.

A further embodiment relates to a group of compounds, wherein

X2 represents Ser,

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

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

X15 represents Glu,

X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

X2 represents 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 (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-

hexadecanoylamino-butyrylannino)-butyryl,

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

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

R1 represents NH2,

or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

X2 represents Aib,

X3 represents an amino acid residue selected from Gin and His, X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)- ethoxy]-acetyl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy- heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl ,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 represents NH2,

or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

X2 represents Aib,

X3 represents an amino acid residue selected from Gin and His, X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-

hexadecanoylamino-butyrylannino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylannino}-ethoxy)- ethoxy]-acetyl-,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 represents NH2,

or a salt or solvate thereof.

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 Gin,

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

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

X28 represents an amino acid residue selected from Ala and Lys, R1 represents NH2,

or a salt or solvate thereof.

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 His,

X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-

acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylannino}-ethoxy)- ethoxy]-acetyl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy- heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl ,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 represents NH2,

or a salt or solvate thereof.

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 His,

X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)- ethoxy]-acetyl-,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 represents NH2,

or a salt or solvate thereof.

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

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys,

R1 represents NH2,

or a salt or solvate thereof.

A further embodiment relates to a group of compounds, 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 by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,

X15 represents Glu,

X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

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 and His,

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

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

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

R1 represents NH2,

or a salt or solvate thereof.

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 and His,

X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylannino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylannino}-ethoxy)- ethoxy]-acetyl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy- heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl ,

X15 represents Glu,

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

R1 represents NH2,

or a salt or solvate thereof.

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 and His, X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)- ethoxy]-acetyl-,

X15 represents Glu,

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

R1 represents NH2,

or a salt or solvate thereof.

A further embodiment relates to a group of compounds, 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 by (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)- 4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,

X15 represents Asp,

X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

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 and His, X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)- ethoxy]-acetyl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy- heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl ,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

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 and His,

X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)- ethoxy]-acetyl-,

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

X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

A further embodiment relates to a group of compounds, 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 by (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)- 4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,

X15 represents Glu,

X28 represents Lys,

R1 represents NH2,

or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

X2 represents Aib,

X3 represents His,

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

X15 represents an amino acid residue selected from Glu and Asp, X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

X14 represents Lys, wherein the -NH2 side chain group is

functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4- Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4- carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- or a salt or solvate thereof.

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

X14 represents Lys, wherein the -NH2 side chain group is

functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-.

or a salt or solvate thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 6-31 as well as salts and/or solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 6-29 and 31 as well as salts and/or solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 8, 1 1 and 12 as well as salts and/or solvates thereof.

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 additional 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.

Further preferred medical uses include treatment or prevention of

degenerative disorders, particularly neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ataxia, e.g spinocerebellar ataxia, Kennedy disease, myotonic dystrophy, Lewy body dementia, multi-systemic atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, prion-associated diseases, e.g. Creutzfeldt-Jacob disease, multiple sclerosis, telangiectasia, Batten disease, corticobasal degeneration, subacute combined degeneration of spinal cord, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, infantile Refsum disease, Refsum disease, neuroacanthocytosis, Niemann-Pick disease, Lyme disease, Machado-Joseph disease, Sandhoff disease, Shy-Drager syndrome, wobbly hedgehog syndrome, proteopathy, cerebral β-amyloid angiopathy, retinal ganglion cell degeneration in glaucoma,

synucleinopathies, tauopathies, frontotemporal lobar degeneration (FTLD), dementia, cadasil syndrome, hereditary cerebral hemorrhage with

amyloidosis, Alexander disease, seipinopathies, familial amyloidotic neuropathy, senile systemic amyloidosis, serpinopathies, AL (light chain) amyloidosis (primary systemic amyloidosis), AH (heavy chain) amyloidosis, AA (secondary) amyloidosis, aortic medial amyloidosis, ApoAI amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, familial amyloidosis of the Finnish type (FAF), Lysozyme amyloidosis, Fibrinogen amyloidosis, Dialysis amyloidosis, Inclusion body myositis/myopathy, Cataracts, Retinitis pigmentosa with rhodopsin mutations, medullary thyroid carcinoma, cardiac atrial amyloidosis, pituitary prolactinoma, Hereditary lattice corneal dystrophy, Cutaneous lichen amyloidosis, Mallory bodies, corneal lactoferrin amyloidosis, pulmonary alveolar proteinosis, odontogenic (Pindborg) tumor amyloid, cystic fibrosis, sickle cell disease or critical illness myopathy (CIM).

Further medical uses include treatment of bone related disorders, such as osteoporosis or osteoarthritis, etc., where increased bone formation and decreased bone resorption might be beneficial.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The amino acid sequences of the present invention contain the conventional one letter and three letter codes for naturally occuring amino acids, as well as generally accepted three letter codes for other amino acids, such as Aib (a-aminoisobutyric acid), Orn (ornithin), Dab (2,4-diamino butyric acid) or Dap (2,3-diamino propionic acid).

The term„native exendin-4" refers to native exendin-4 having the sequence HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO: 1 ).

The invention provides peptidic compounds as defined above.

The peptidic compounds of the present invention comprise a linear backbone of amino carboxylic acids linked by peptide, i.e. carboxamide bonds. Preferably, the amino carboxylic acids are a-amino carboxylic acids and more preferably L-a-amino carboxylic acids, unless indicated otherwise. The peptidic compounds preferably comprise a backbone sequence of 39amino carboxylic acids.

The peptidic compounds of the present invention may have unmodified side-

chains, but carry at least one modification at one of the side chains.

For the avoidance of doubt, in the definitions provided herein, it is generally intended that the sequence of the peptidic moiety (I) differs from native exendin-4 at least at one of those positions which are stated to allow variation. Amino acids within the peptide moiety (I) can be considered to be numbered consecutively from 0 to 39 in the conventional N-terminal to C-terminal direction. Reference to a ..position" within peptidic moiety (I) should be constructed accordingly, as should reference to positions within native exendin-4 and other molecules, e.g., in exendin-4, His is at position 1 , Gly at position 2, Met at position 14, ... and Ser at position 39.

An amino acid residue with an -NH2 side chain group, e.g. Lys, Orn, Dab or Dap, is functional ized in that at least one H atom of the -NH2 side chain group is replaced by -Z-C(O)-R5, wherein R5 comprises a lipophilic moiety, e.g. an acyclic linear or branched (C8-C3o) saturated or unsaturated hydrocarbon group, which is unsubstituted or substituted e.g. by halogen, -OH and/or CO2H and Z comprises a linker in all stereoisomeric forms, e.g. a linker comprising one or more, e.g. 1 to 5, preferably 1 , 2 or 3 amino acid linker groups selected from the group γ-Glutamate (γΕ) and AEEAc.

Preferred groups R5 comprise a lipophilic moiety, e.g. an acyclic linear or branched (Ci2-C2o) saturated or unsaturated hydrocarbon group, e.g.

pentadecanyl, hexadecanyl or heptadecanyl, which is unsubstituted or substituted by CO2H, more preferably pentadecanyl, heptadecanyl or 16-carboxy-hexadecanyl. In one embodiment amino acid linker groups are selected from γΕ, γΕ-γΕ, AEEAc-AEEAc-γΕ and AE E Ac-AE EAc-AE EAc . In another embodiment the amino acid linker group is γΕ. In another

embodiment the amino acid linker group is γΕ-γΕ. In another embodiment the amino acid linker group is AEEAc-AEEAc-γΕ. In another embodiment the amino acid linker group is AEEAc-AEEAc-AEEAc.

In a further aspect, the present invention provides a composition comprising a compound of the invention as described herein, or a salt or solvate thereof, in admixture with a carrier.

In a further aspect, the present invention provides a composition comprising a compound of the invention as described herein, or a salt or solvate thereof, in admixture with a carrier.

The invention also provides the use of a compound of the present invention for use as a medicament, particularly for the treatment of a condition as described below.

The invention also provides a composition wherein the composition is a pharmaceutically acceptable composition, and the carrier is a

pharmaceutically acceptable carrier.

Peptide synthesis

The skilled person is aware of a variety of different methods to prepare the peptides that are described in this invention. These methods include but are not limited to synthetic approaches and recombinant gene expression. Thus, one way of preparing these peptides is the synthesis in solution or on a solid support and subsequent isolation and purification. A different way of preparing the peptides is gene expression in a host cell in which a DNA sequence encoding the peptide has been introduced. Alternatively, the gene expression can be achieved without utilizing a cell system. The methods described above may also be combined in any way.

A preferred way to prepare the peptides of the present invention is solid phase synthesis on a suitable resin. Solid phase peptide synthesis is a well-established methodology (see for example: Stewart and Young, Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, III., 1984; E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach, Oxford-IRL Press, New York, 1989). Solid phase synthesis is initiated by

attaching an N-terminally protected amino acid with its carboxy terminus to an inert solid support carrying a cleavable linker. This solid support can be any polymer that allows coupling of the initial amino acid, e.g. a trityl resin, a chlorotrityl resin, a Wang resin or a Rink resin in which the linkage of the carboxy group (or carboxamide for Rink resin) to the resin is sensitive to acid (when Fmoc strategy is used). The polymer support must be stable under the conditions used to deprotect the a-amino group during the peptide synthesis.

After the first amino acid has been coupled to the solid support, the a-amino protecting group of this amino acid is removed. The remaining protected amino acids are then coupled one after the other in the order represented by the peptide sequence using appropriate amide coupling reagents, for example BOP, HBTU, HATU or DIC (Ν,Ν'-diisopropylcarbodiimide) / HOBt (1 -hydroxybenzotriazole), wherein BOP, HBTU and HATU are used with tertiary amine bases. Alternatively, the liberated N-terminus can be functionalized with groups other than amino acids, for example carboxylic acids, etc.

Usually, reactive side-chain groups of the amino acids are protected with suitable blocking groups. These protecting groups are removed after the desired peptides have been assembled. They are removed concomitantly with the cleavage of the desired product from the resin under the same conditions. Protecting groups and the procedures to introduce protecting groups can be found in Protective Groups in Organic Synthesis, 3rd ed., Greene, T. W. and Wuts, P. G. M., Wiley & Sons (New York: 1999).

In some cases it might be desirable to have side-chain protecting groups that can selectively be removed while other side-chain protecting groups remain intact. In this case the liberated functionality can be selectively functionalized. For example, a lysine may be protected with an ivDde ([1 -(4,4-dimethyl-2,6-dioxocyclohex-1 -ylidene)-3-methylbutyl) protecting group

(S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603) which is labile to a very nucleophilic base, for example 4% hydrazine in DMF (dimethyl formamide). Thus, if the N-terminal amino group and all side-chain functionalities are protected with acid labile protecting groups, the ivDde group can be selectively removed using 4% hydrazine in DMF and the corresponding free amino group can then be further modified, e.g. by acylation. The lysine can alternatively be coupled to a protected amino acid and the amino group of this amino acid can then be deprotected resulting in another free amino group which can be acylated or attached to further amino acids.

Claims

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

H2N-His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15- Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro- Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R1 (I)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib, X3 represents an amino acid residue selected from Gin and His, X14 represents an amino acid residue with a functionalized -NH2 side chain group, selected from the group consisting of Lys, Orn, Dab, or Dap, wherein the -NH2 side chain group is functionalized by -Z- C(O)-R5, wherein

Z represents a linker in all stereoisomeric forms and

R5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from N and O,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 is NH2 or OH,

or a salt or solvate thereof.

2. A compound of claim 1 , wherein

R1 is NH2

or a salt or solvate thereof.

3. A compound according to any one of claims 1 - 2, wherein the peptidic compound has a relative activity of at least 0.1 % compared to that of natural glucagon at the glucagon receptor.

4. A compound according to any one of claims 1 - 3, wherein the peptidic compound exhibits a relative activity of at least 0.1 % compared to that of GLP-1 (7-36)-amide at the GLP-1 receptor.

5. A compound of any one of claims 1 - 4, wherein

X14 represents Lys wherein the -NH2 side chain group is functionalized with a group -Z-C(O)R5 , wherein

Z represents a group selected from γΕ, γΕ-γΕ, AEEAc-AEEAc-γΕ and

AE EAc-AE EAc-AE EAc and

R5 represents a group selected from pentadecanyl, heptadecanyl or 16-carboxy-hexadecanyl .

6. A compound of any one of claims 1 - 5, wherein

X14 represents Lys wherein the -NH2 side chain group is functionalized with a group -Z-C(O)R5 , wherein

Z represents a group selected from γΕ, γΕ-γΕ, AEEAc-AEEAc-γΕ and AE EAc-AE EAc-AE EAc and

R5 represents a group selected from pentadecanyl or heptadecanyl.

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

X2 represents Ser,

X3 represents an amino acid residue selected from Gin and His, X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)- 4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,

X15 represents Glu,

X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents 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 (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-

octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylannino)-butyryl,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents Aib,

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

X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)- ethoxy]-acetyl-,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 represents NH2,

or a salt or solvate thereof.

10. 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 Gin,

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

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys, R1 represents NH2,

or a salt or solvate thereof.

1 1 . 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 His,

X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)- ethoxy]-acetyl-,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents an amino acid residue selected from Ala and Lys,

R1 represents NH2,

or a salt or solvate thereof.

12. 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 and His, X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylannino}-ethoxy)- ethoxy]-acetyl-,

X15 represents Glu,

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

R1 represents NH2,

or a salt or solvate thereof.

13. A compound of any one of claims 1 - 6, 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 by (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)- 4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,

X15 represents Asp,

X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

14. 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 and His, X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4- octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4- octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino- ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)- ethoxy]-acetyl-,

X15 represents an amino acid residue selected from Glu and Asp, X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

15. A compound of any one of claims 1 - 6, 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 by (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)- 4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,

X15 represents Glu,

X28 represents Lys,

R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents Aib,

X3 represents His,

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

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

X28 represents Ala,

R1 represents NH2,

or a salt or solvate thereof.

17. The compound of any one of claims 1 - 16, selected from the

compounds of SEQ ID NO: 6-31 , as well as salts and solvates thereof.

18. The compound of any one of claims 1 - 17, selected from the compounds of SEQ ID NO: 6-29 and 31 , as well as salts and solvates thereof.

19. The compound of any one of claims 1 - 18 for use in medicine,

particularly in human medicine.

20. The compound for use according to claim 19 which is present as an active agent in a pharmaceutical composition together with at least one pharmaceutically acceptable carrier.

21 .The compound for use according to claim 19 or 20 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/glucagon agonists, 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, DDP4 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.

22. The compound for use according to any one of claims 19 - 21 for the treatment of glucose intolerance, insulin resistance, pre-diabetes, increased fasting glucose (hyperglycemia), type 2 diabetes, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or any combination of these individual disease components.

23. The compound for use according to any one of claims 19 - 21 for control of appetite, feeding and calory intake, increase of energy expenditure, prevention of weight gain, promotion of weight loss, reduction of excess body weight and altogether treatment of obesity, including morbid obesity.

24. The compound for use according to any one of claims 19 - 23 for the treatment or prevention of hyperglycemia, type 2 diabetes, obesity.

25. The compound for use according to any one of claims 19 - 23 for the simultaneous treatment of diabetes and obesity.

26. A pharmaceutical composition comprising at least one compound according to any one of claims 1 - 18 or a physiologically acceptable salt or a solvent of any of them.