Dual GLP-1 / Glucagon Receptor Agonists derived from Exendin-4

Description

FIELD OF THE INVENTION

The present invention relates to dual GLP-1 / glucagon receptor agonists 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. These dual GLP-1 / glucagon receptor agonists show reduced activity on the GIP receptor to reduce the risk of hypoglycemia and are structurally derived from exendin-4, a pure GLP-1 receptor agonist.

BACKGROUND OF THE INVENTION

Pocai et al (Obesity 2012;20:1566-1571 ; Diabetes 2009, 58, 2258) and Day et al. (Nat Chem Biol 2009;5:749) describe dual agonists of the glucagon-like peptide-1 (GLP-1 ) and glucagon receptors, e.g. by combining the actions of GLP-1 and glucagon in one molecule, which lead to a therapeutic principle with anti-diabetic action and a pronounced weight lowering effect superior to pure GLP-1 agonists, among others due to glucagon-receptor mediated increased satiety and energy expenditure.

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, 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.

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: 4.

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: 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. 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: 5.

YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-OH

Peptides which are based on the structures of GLP-1 or glucagon, and 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 2011/075393, WO 2008/152403, WO

2010/070251 , WO 2010/070252, WO 2010/070253, WO 2010/070255, WO

2011/160630, WO 2011 /006497, WO 2011 /087671 , WO 2011 /087672,

WO2011/117415 ,WO2011/117416, WO 2012/177443 WO 2012/177444, WO

2012/150503, WO 2013/004983, WO 2013/092703, WO 2014/041195 and WO 2014/041375, the contents of which are herein incorporated by reference. The body weight reduction was shown to be superior to pure GLP-1 agonists.

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 2012/088116 and by VA Gault et al (Biochem Pharmacol, 85, 16655-16662, 2013; Diabetologia, 56, 1417-1424, 2013).

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 GLP-1 receptor, whereas it shows 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.

SEQ ID EC50 hGLP-1 R EC50 hGIP R EC50 hGlucagon

NO: peptide [pM] [pM] R [pM]

1 exendin-4 0.4 12500.0 > 10000000

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

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

Exendin-4 shares many of the glucoregulatory actions observed with GLP-1 . Clinical and nonclinical 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.,11 :544-56 , 2009; Norris SL et al, Diabet Med., 26:837-46, 2009; Bunck MC et al, Diabetes Care., 34:2041 -7, 2011 ).

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).

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 : 113-9, 2007) as well as deamidation and isomerization of asparagine in position 28 (WO 2004/035623).

Compounds of this invention are exendin-4 derivatives, which in addition to the agonistic activity at the GLP-1 receptor of native exendin-4 show agonistic activity at the glucagon receptor and which have - among others - the following modification: at position 14 an amino acid carrying an -NH2 group in the side-chain, which is further substituted with a lipophilic residue (e.g. a fatty acid combined with a linker) and at position 27 an Aib.

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.

Furthermore, we surprisingly found that compounds carrying an Aib amino acid in position 27 show reduced activity on the GIP receptor compared to the corresponding derivatives with Lys at position 27 as in native exendin-4, as shown in Example 5, Table 8. A reduced activation of the GIP receptor is potentially beneficial as there are reports in the literature that high levels of GIP in diabetics might in some cases lead to more frequent episodes of hypoglycemia (T McLaughlin et al., J Clin Endocrinol Metab, 95, 1851-1855, 2010; A Hadji-Georgopoulos, J Clin Endocrinol Metab, 56, 648-652, 1983).

Furthermore, compounds of this invention are exendin-4 derivatives with fatty acid acylated residues in position 14. This fatty acid functionalization in position 14 resulted 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, for example those shown in Example 5, Table 7. In addition, this modification results in an improved pharmacokinetic profile.

It is described in the literature (Murage EN et al., Bioorg. Med. Chem. 16 (2008), 10106-10112), that a GLP-1 analogue with an acetylated lysine at position 14 showed significantly reduced potency on the GLP-1 receptor compared to natural GLP-1 .

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

Native exendin-4 is a pure GLP-1 receptor agonist without activity on the glucagon receptor and low activity on the GIP receptor. Provided herein are exendin-4 derivatives based on the structure of native exendin-4 but differing at ten or more positions as compared to SEQ ID NO: 1 wherein the differences contribute to the enhancement of the agonistic activity at the glucagon receptor. 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 by a lipophilic residue (e.g. a fatty acid combined with a linker). Furthermore, we surprisingly found that a replacement of the lysine at position 27 by Aib leads to reduced GIP receptor activity compared to the GLP-1 receptor activity. A reduced activation of the GIP receptor is potentially beneficial as there are reports in the literature that high levels of GIP in diabetics might in some cases lead to more frequent episodes of hypoglycemia (T McLaughlin et al., J Clin Endocrinol Metab, 95, 1851-1855, 2010; A Hadji-Georgopoulos, J Clin Endocrinol Metab, 56, 648-652, 1983).

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-X19-Arg-Leu-Phe-lle-Glu-Trp-Leu-Aib-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala- Pro-Pro-Pro-Ser-R1 (I)

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

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 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,

X19 represents an amino acid residue selected from Ala and Val,

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

X29 represents an amino acid residue selected from Thr, D-Ala and Gly, R1 is NH2 or OH,

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 in the assay system described in Methods.

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 % (i.e. EC5o < 700 pM), more preferably of 1 % (i.e. EC5o < 70 pM), more preferably of 5% (i.e. EC5o < 14 pM) and even more preferably of

10% (i.e. ECso < 7 pM) compared to that of GLP-1 (7-36)amide at the GLP-1 receptor. Furthermore, the compounds exhibit at least a relative activity of 0.1 % (i.e. EC5o < 1000 pM), more preferably of 0.5% (i.e. EC5o < 200 pM) and even more preferably of 1 % (i.e. EC5o < 100 pM) 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 Example 4.

The compounds of the invention preferably 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 75 pmol or less, more preferably of 50 pmol or less, more preferably of 25 pmol or less, more preferably of 15 pmol or less, more preferably of 10 pmol and more preferably of 5 pmol or less and/or 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 75 pmol or less and/or an EC50 for hGIP receptor of 250 pmol or more, preferably of 500 pmol or more; more preferably of 1000 pmol or more. It is particularly preferred that the EC50 for both hGLP-1 and hGlucagon receptors is 250 pm or less, more preferably of 200 pmol or less, more preferably of 150 pmol or less, more preferably of 100 pmol or less, more preferably of 60 pmol or less.The EC50 for the hGLP-1 receptor, the hGlucagon receptor and the 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, 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 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 7 and 8.

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) or leucine at position 14 (see Table 7). Furthermore, oxidation (in vitro or in vivo) of methionine is not possible anymore.

It was also found that compounds carrying an Aib amino acid in position 27 show reduced activity on the GIP receptor compared to the corresponding derivatives with Lys at position 27 as in native exendin-4, as shown in Example 5, Table 8. A reduced activation of the GIP receptor is potentially beneficial as there are reports in the literature that high levels of GIP in diabetics might in some cases lead to more frequent episodes of hypoglycemia (T McLaughlin et al., J Clin Endocrinol Metab, 95, 1851-1855, 2010; A Hadji-Georgopoulos, J Clin Endocrinol Metab, 56, 648-652, 1983).

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 mg/ml.

Furthermore, 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 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 the Examples. Preferably, after 7 days at 40°C in solution at pH 4.5 or pH 7.4 the remaining peptide is at least 70%, more preferably at least 75%, even more preferably at least 80%.

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

5- 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

Structure / lUPAC name

γΕ-χ70

HO ^O

(S)-4-Carboxy-4-octadecanoylamino-butyryl-

AEEAc- AEEAc- γΕ -x99

O

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

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 AEEAc- AEEAc-AEEAc 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 AEEAc- AEEAc-AEEAc and

R5 represents a group selected from pentadecanyl or heptadecanyl.

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-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,

X19 represents an amino acid residue selected from Ala and Val,

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

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

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-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,

X19 represents an amino acid residue selected from Ala and Val,

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

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

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 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 an amino acid residue selected from Glu and Asp, X19 represents Ala,

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

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

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 Ser,

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-, (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,

X19 represents an amino acid residue selected from Ala and Val,

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

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

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-, (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,

X19 represents an amino acid residue selected from Ala and Val,

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

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

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

X19 represents an amino acid residue selected from Ala and Val,

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 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 (S)- 4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, X15 represents an amino acid residue selected from Glu and Asp,

X19 represents an amino acid residue selected from Ala and Val,

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

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

X15 represents Glu,

X19 represents an amino acid residue selected from Ala and Val,

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

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

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 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-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 Asp,

X19 represents an amino acid residue selected from Ala and Val,

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

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

X19 represents an amino acid residue selected from Ala and Val,

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

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

X19 represents Ala,

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

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

X19 represents Ala,

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

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

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 an amino acid residue selected from Glu and Asp,

X19 represents Val,

X28 represents Ala,

X29 represents Gly,

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 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-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,

X19 represents an amino acid residue selected from Ala and Val,

X28 represents Ala,

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

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 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-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,

X19 represents an amino acid residue selected from Ala and Val,

X28 represents Ala,

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

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 Gin,

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

X15 represents Asp,

X19 represents Ala,

X28 represents Ser,

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

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 (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,

X19 represents Ala,

X28 represents Lys,

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

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

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

X19 represents an amino acid residue selected from Ala and Val,

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

X29 represents Gly,

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 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-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,

X19 represents an amino acid residue selected from Ala and Val,

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

X29 represents Gly,

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

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

X19 represents Ala,

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

X29 represents D-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 Gin,

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 Asp,

X19 represents Ala,

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

X29 represents an amino acid residue selected from Gly and D-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 and/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: 6-27, as well as salts or solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 6-22 and 24-27, as well as salts or solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 9, 12 and 15 as well as salts 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).

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).

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 39 amino 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 1 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 functionalized 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-C30) 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 of γ-Glutamate (γΕ) and AEEAc. Preferred groups R5 comprise a lipophilic moiety, e.g. an acyclic linear or branched (C12-C20) 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 AEEAc-AEEAc-AEEAc. 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

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-X19-Arg-Leu-Phe-lle-Glu-Trp-Leu-Aib-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala- Pro-Pro-Pro-Ser-R1 (I)

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

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 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,

X19 represents an amino acid residue selected from Ala and Val,

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

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

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

6. 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 AEEAc- AEEAc-AEEAc and

R5 represents a group selected from pentadecanyl or heptadecanyl.

7. 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-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,

X19 represents an amino acid residue selected from Ala and Val,

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

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

R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents D-Ser,

X3 represents 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 an amino acid residue selected from Glu and Asp,

X19 represents Ala,

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

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

R1 represents NH2,

or a salt or solvate thereof.

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

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

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-, (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,

X19 represents an amino acid residue selected from Ala and Val,

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

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

R1 represents NH2,

or a salt or solvate thereof.

10. A compound of any one of claims 1 - 7, 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-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-,

X15 represents Glu,

X19 represents an amino acid residue selected from Ala and Val,

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

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

R1 represents NH2,

or a salt or solvate thereof.

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

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

X19 represents an amino acid residue selected from Ala and Val,

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

X29 represents an amino acid residue selected from Thr, D-Ala and Gly, R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents an amino acid residue selected from D-Ser and 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-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylannino]- ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4- Carboxy-4-octadecanoylamino-butyrylannino]-ethoxy}-ethoxy)-acetylannino]- 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,

X19 represents Ala,

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

X29 represents an amino acid residue selected from Thr, D-Ala and Gly, R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents D-Ser,

X3 represents Gin,

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 an amino acid residue selected from Glu and Asp,

X19 represents Val,

X28 represents Ala,

X29 represents Gly,

R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents an amino acid residue selected from D-Ser and 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-butyrylamino)- butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylannino]- 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,

X19 represents an amino acid residue selected from Ala and Val,

X28 represents Ala,

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

R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents D-Ser,

X3 represents Gin,

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

X15 represents Asp,

X19 represents Ala,

X28 represents Ser,

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

R1 represents NH2,

or a salt or solvate thereof.

16. A compound of any one of claims 1 - 7, 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 (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,

X19 represents Ala,

X28 represents Lys,

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

R1 represents NH2,

or a salt or solvate thereof.

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

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

X19 represents an amino acid residue selected from Ala and Val,

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

X29 represents Gly,

R1 represents NH2,

or a salt or solvate thereof.

18. A compound of any one of claims 1 - 7, 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-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4- hexadecanoylamino-butyrylamino)-butyryl-,

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

X19 represents Ala,

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

X29 represents D-Ala,

R1 represents NH2,

or a salt or solvate thereof.

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

X2 represents D-Ser,

X3 represents Gin,

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 Asp,

X19 represents Ala,

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

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

R1 represents NH2,

or a salt or solvate thereof.

20. The compound of any one of claims 1 - 19, selected from the compounds of SEQ ID NO: 6-27, as well as salts or solvates thereof.

21 .The compound of any one of claims 1 - 19, selected from the compounds of SEQ ID NO: 6-22 and 24-27, as well as salts or solvates thereof.

22. The compound of any one of claims 1 - 21 for use in medicine, particularly in human medicine.

23. The compound for use according to claim 22 which is present as an active agent in a pharmaceutical composition together with at least one

pharmaceutically acceptable carrier.

24. The compound for use according to claim 22 or 23 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, GPR119 agonists, GPR40 agonists, GPR120 agonists, GPR142 agonists, systemic or low-absorbable TGR5 agonists, Cycloset, inhibitors of 11 -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.

25. The compound for use according to any one of claims 22 - 24 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.

26. The compound for use according to any one of claims 22-24 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.

27. The compound for use according to any one of claims 22 - 26 for the

treatment or prevention of hyperglycemia, type 2 diabetes, obesity.

28. The compound for use according to any one of claims 22 - 27 for the

simultaneous treatment of diabetes and obesity.

29. A pharmaceutical composition comprising at least one compound according to any one of claims 1 - 21 or a physiologically acceptable salt or a solvent of any of them.