Functionalized Exendin-4 Derivatives

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 glucose-dependent insulinotropic polypeptide (GIP) receptor and optionally the glucagon receptor (GCG) 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., 267:7402-05,1992). 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 oxidation in position 14 (Hargrove DM et al., Regul. Pept., 141 : 1 13-9, 2007) as well as deamidation and isomerization of asparagine in position 28 (WO 2004/035623).

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

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

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

HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

Liraglutide is a marketed chemically modified GLP-1 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

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

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

Hypoglycemia is a common side effect of insulin treated patients with hyperglycemia (elevated blood glucose levels) due to diabetes. Thus, glucagon's most predominant role in glucose regulation is to counteract insulin action and maintain blood glucose levels.

Hoist (Hoist, J. J. Physiol. Rev. 2007, 87, 1409) and Meier (Meier, J. J. Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1 , liraglutide and exendin-4, 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 WO1998008871 , WO2008081418 and WO2008023050, the contents of which are herein incorporated by reference.

It has been described that dual activation of the GLP-1 and GIP receptors, e.g. by combining the actions of GLP-1 and GIP in one preparation, leads to a therapeutic principle with significantly better reduction of blood glucose levels, increased insulin secretion and reduced body weight in mice with T2DM and obesity compared to the marketed GLP-1 agonist liraglutide (e.g. VA Gault et al., Clin Sci (Lond), 121 , 107-1 17, 201 1 ). Native GLP-1 and GIP were proven in humans following co-infusion to interact in an additive manner with a significantly increased insulinotropic effect compared to GLP-1 alone (MA Nauck et al., J. Clin. Endocrinol. Metab., 76, 912-917, 1993).

Designing hybrid molecules which combine agonism on the GLP-1 receptor, the GIP receptor and the glucagon receptor offers the therapeutic potential to achieve significantly 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 (e.g. VA Gault et al., Clin Sci (Lond), 121 , 107-1 17, 201 1 ).

Compounds of this invention are exendin-4 derivatives, which show agonistic activity at the GLP-1 and the GIP receptor and optionally the glucagon

receptor and which have - among others - preferably the following modifications: Tyr at position 1 and lie at position 12.

Surprisingly, it was found that the modification of the selective GLP-1 R agonist Exendin-4 by Tyr in position 1 and lie in position 12 results in a peptide with high dual activity at the GLP-1 and GIP receptors. This observation is surprising, since the same modification in other GLP-1 agonists, such as GLP-1 itself, does not result in high activity at the GIP receptor, as shown in Table 2.

Table 2: Potencies of exendin-4 and GLP-1 peptide analogues at GLP-1 and GIP receptors (indicated in pM) at increasing concentrations and measuring the formed cAMP as described in Methods.

Peptides which bind and activate both the GIP and the GLP-1 receptor and optionally the glucagon receptor, and improve glycaemic control, suppress body weight gain and reduce food intake are described in patent applications WO 201 1/1 19657 A1 , WO 2012/138941 A1 , WO 2010/01 1439 A2, WO 2010/148089 A1 , WO 201 1/094337 A1 , WO 2012/0881 16 A2, the contents of which are herein incorporated by reference. These applications disclose that mixed agonists of the GLP-1 receptor, the GIP receptor and optionally the glucagon receptor can be designed as analogues of the native GIP or glucagon sequences.

Compounds of this invention are exendin-4 peptide analogues comprising leucine in position 10 and glutamine in position 13. Krstenansky et al. (Biochemistry, 25, 3833-3839, 1986) show the importance of residues 10 to 13 of glucagon for its receptor interactions and activation of adenylate cyclase. In the exendin-4 peptide analogues of this invention, several of the underlying residues are different from said of glucagon. In particular, residues Tyr10 and Tyr13, are replaced by leucine in position 10 and glutamine, 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 behavior 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 GIP receptor and optionally on the glucagon receptor.

Furthermore, compounds of this invention are exendin-4 derivatives with fatty acid acylated residues in position 14. This fatty acid functionalization in position 14 results in an improved pharmacokinetic profile. Surprisingly, the fatty acid functionalization in position 14 also leads to peptides with a significantly higher GIPR activity, for example those shown in Example 9, Table 8.

BRIEF SUMMARY OF THE INVENTION

Provided herein are exendin-4 analogues which potently activate the GLP-1 and the GIP receptor and optionally the glucagon 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)

R1 - Z - R2 (I)

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

Tyr-Aib-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-X12-Gln-X14-X15-X16- X17-X18-X19-X20-X21 -Phe-lle-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-X40 (II)

X3 represents an amino acid residue selected from Gin, Glu and His, X12 represents an amino acid residue selected from lie and Lys, X14 represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is functional ized by -C(O)-R5, -C(O)O-R5, -C(O)NH-R5, -S(O)2-R5 or R5, preferably by -C(O)-R5, wherein R5 may be a moiety comprising up to 50 or up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S and/or P,

X15 represents an amino acid residue selected from Asp and Glu, X16 represents an amino acid residue selected from Ser, Lys, Glu and Gin,

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

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

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

X20 represents an amino acid residue selected from Gin, Aib, Phe, Leu, Lys, His, Arg, Pip, (S)MeLys, (R)MeLys, (S)MeOrn and (R)MeOrn, X21 represents an amino acid residue selected from Asp, Glu, Leu and Tyr,

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

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

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

R represents NH2,

R2 represents OH or NH2.

or a salt or solvate thereof.

The compounds of the invention are GLP-1 and GIP receptor agonists and optionally glucagon receptor agonists as determined by the observation that they are capable of stimulating intracellular cAMP formation. In vitro potency determination in cellular assays of agonists is quantified by determining the concentrations that cause 50% activation of maximal response (EC50) as described in Methods.

In certain embodiments, the invention therefore provides a peptidic compound having the formula (I):

R1 - Z - R2 (I)

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

Tyr-Aib-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-X12-Gln-X14-X15-X16- X17-X18-X19-X20-X21 -Phe-lle-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-X40 (II)

X3 represents an amino acid residue selected from Gin, Glu and His, X12 represents an amino acid residue selected from lie and Lys,

X14 represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is functional ized by -C(O)-R5, -C(O)O-R5, -C(O)NH-R5, -S(O)2-R5 or R5, preferably by -C(O)-R5, wherein R5 is a moiety comprising up to 50 or up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S and/or P, X15 represents an amino acid residue selected from Asp and Glu, X16 represents an amino acid residue selected from Ser, Lys, Glu and Gin,

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

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

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

X20 represents an amino acid residue selected from Gin, Aib, Phe, Leu, Lys, His, Arg, Pip, (S)MeLys, (R)MeLys, (S)MeOrn and (R)MeOrn, X21 represents an amino acid residue selected from Asp, Glu, Leu and Tyr,

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

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

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

R1 represents NH2,

R2 represents OH or NH2.

or a salt or solvate thereof, wherein the peptidic compound has a relative activity of at least 0.04%, preferably at least 0.08%, more preferably at least 0.2% compared to that of natural GIP at the GIP 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 0.07%, preferably at least 0.1 %, more preferably at least 0.14%, more preferably at least 0.35% and even more preferably at least 0.4% compared to that of GLP-1 (7-36) 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 0.04% (i.e. EC50 < 000 pM), more preferably 0.08% (i.e. ECso < 500 pM) and even more preferably 0.2% (i.e. EC50 < 200 pM) compared to that of natural GIP at the GIP receptor (EC5o = 0.4 pM).

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 0.1 %, preferably at least 0.2%, more preferably at least 0.3%, more preferably at least 0.4% and even more preferably at least 0.5% compared to that of natural glucagon at the glucagon receptor.

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

According to one embodiment, the compounds of the invention have an EC50 for hGLP-1 receptor of 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.

According to one embodiment, the compounds of the invention have an EC50 for hGIP 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.

According to another embodiment, the compounds of the invention have optionally an EC5o for hGlucagon 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.

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 EC5o for hGIP 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 optionally an EC5o for hGlucagon 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.

In still another embodiment, the EC50 for both receptors, i.e. for the hGLP-1 receptor and for the hGIP receptor, is 500 pM or less, more preferably 200 pM or less, more preferably 150 pM or less, more preferably 100 pM or less, more preferably 90 pM or less, more preferably 80 pM or less, more preferably 70 pM or less, more preferably 60 pM or less, more preferably 50 pM or less, more preferably 40 pM or less, more preferably 30 pM or less, more preferably 20 pM or less.

In still another embodiment, the EC50 for all three receptors, i.e. for the hGLP-1 receptor, for the hGIP receptor and for the hGlucagon receptor, is 500 pM or less, more preferably 200 pM or less, more preferably 150 pM or less, more preferably 100 pM or less, more preferably 90 pM or less, more preferably 80 pM or less, more preferably 70 pM or less, more preferably 60 pM or less, more preferably 50 pM or less, more preferably 40 pM or less, more preferably 30 pM or less, more preferably 20 pM or less.

The EC50 for hGLP-1 receptor, hGIP receptor and hGlucagon receptor may be determined as described in the Methods herein and as used to generate the results described in Example 9.

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

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

The compounds of the invention have the ability to reduce blood glucose level, and/or to reduce HbA1 c levels of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods. The results of such experiments are described in Examples 13, 14, 16 and 17.

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

The compounds of the invention also have the ability to reduce body weight of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods and in Examples 13 and 15.

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 and GIP receptor activation; additionally in combination with amino acids like Gin in position 3 also very potent glucagon receptor activation can be provided.

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 Pos.14 showed significantly reduced potency 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 25°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 25°C in solution at pH 4.5 or pH 7.4, the remaining peptide amount is at least 80%, more preferably at least 85%, even more preferably at least 90% and even more preferably at least 95%.

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

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

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

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

More preferred groups R5 may comprise a lipophilic moiety, e.g. an acyclic linear or branched (C12-C22) saturated or unsaturated hydrocarbon group. The lipophilic moiety may be attached to the -NH2 side chain group by a linker in all stereoisomeric forms, e.g. a linker comprising one or more, e.g. 2, 3 or 4, amino acid linker groups such as γ-aminobutyric acid (GABA), ε-aminohexanoic acid (ε-Ahx), γ-Glu and/or β-Ala. In one embodiment the lipophilic moiety is attached to the -NH2 side chain group by a linker. In another embodiment the lipophilic moiety is directly attached to the -NH2 side chain group. Specific examples of amino acid linker groups are (β-Ala)-!-4, (Y-GI U)I-4, (£-Ahx) -4, or (GABA) -4. Preferred amino acid linker groups are β-Ala, Y-Glu, B-Ala-B-Ala and γ-Glu-Y-Glu.

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

2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tndecyl)-chroman-6-yloxy-carbonyl]-propionylamino}-butyryl-, (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-, (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylannino)-hexanoylannino]-butyryl-, (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylannino)-butyryl-, (S)-4-Carboxy-4-tetradecanoylamino-butyryl-, (S)-4-(1 1 -Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl-, (S)-4-Carboxy-4-[1 1 -((2S,3R,4R,5R)-2, 3,4,5, 6-pentahydroxy-hexylcarbamoyl)-undecanoyl-amino]-butyryl-, (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-henicosa-noylamino-butyryl-, (S)-4-Carboxy-4-docosanoylamino-butyryl-, (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-, (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-Carboxy-4-icosanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylannino)-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylannino)-butyryl-, 3-(3-Octadecanoyl-amino-propionylamino)-propionyl-, 3-(3-Hexadecanoyl-amino-propionyl-amino)-propionyl-, 3-Hexadecanoylamino-propionyl-, (S)-4-Carboxy-4-[(R)-4-((3R,5S,7R,8R,9R,10S,12S,13R,14R,17R)-3,7,12-trihydroxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]-phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-[(R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylamino)-butyryl-, Tetradecanoyl-, 1 1 -Carboxy-undecanoyl-, 1 1 -Benzyloxycarbonyl-undecanoyl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-tetra-decanoylamino-butyrylannino)-butyryl-, 6-[Hydroxy-(naphthalene-2-yloxy)-phosphoryloxy]-hexanoyl-, 6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-, 4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-, 4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylannino]-butyrylannino}- butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-hepta-decanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl-, (S)-4-Carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-hepta-decanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyryl-amino]-ethoxy}-ethoxy)-acetyl, (S)-4-Carboxy-4-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylannino]-butyrylamino}-butyrylamino)-butyryl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-1 H-tetrazol-5-yl-hexadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-carboxy-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)-decanoylamino]-butyrylannino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylannino}-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(7-carboxy-heptanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylaminoj-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2- [(S)-4-carboxy-4-(1 1 -carboxy-undecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,

(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(13-carboxy-tridecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoyl-amino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl-, and (S)-4-Carboxy-4-{(S)-4-carboxy-4- [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-.

Further preferred are stereoisomers, particularly enantiomers of these groups, either S- or R-enantiomers. The term "R" in Table 3 is intended to mean the attachment site of -C(O)-R5 at the peptide back bone, i.e. particularly the ε-amino group of Lys.

ĭ33

ln some embodiments, the invention relates to peptidic compounds of Formula (I) as defined above, wherein X14 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group is functionalized by -C(O)-R5, X40 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group can be functionalized by -C(O)-R5, and R5 is a lipophilic moiety selected from an acyclic linear or branched (C4-C3o) saturated or unsaturated hydrocarbon group, and/or a cyclic saturated, unsaturated or aromatic group, wherein the lipophilic moiety may be attached to the -NH2 side chain group by a linker selected from ( -Ala)i-4, (Y-GI U)I-4, (£-Ahx)1-4, or (GABA)1-4 in all stereoisomeric forms.

In certain embodiments, X14 represents an amino acid residue with a functionalized -NH2 side chain group, such as functionalized Lys, Orn, Dab or Dap, wherein at least one H atom of the -NH2 side chain group is replaced by -C(O)-R5, which is selected from the group consisting of the substituents according to Table 3 above.

In some embodiments, X14 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group is functionalized by -C(O)-R5, X40 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the -NH2 side chain group can be functionalized by -C(O)-R5, and -C(O)-R5 is selected from the group consisting of the substituents according to Table 3 above.

In some embodiments of the invention, position X14 and/or X40 in formula (II) represents Lysine (Lys). According to some embodiments, Lys at position 14 and optionally at position 40 is functionalized, e.g. with a group -C(O)R5 as described above. In other embodiments, X40 is absent and X14 is Lys functionalized with -C(O)-R5, -C(O)O-R5, -C(O)NH-R5, -S(O)2-R5 or R5, preferably by -C(O)-R5, wherein R5 is as defined above. In particular, X14 is Lys functionalized with C(O)-R5, wherein R5 is selected from the group

consisting of (S)-4-carboxy-4-hexadecanoylamino-butyryl (γΕ-χ53), (S)-4-carboxy-4-octadecanoylamino-butyryl (γΕ-χ70), 4-hexadecanoylamino-butyryl (GABA-x53), 4-{3-[(Ρ)-2,5,7,8-ίθίΓ3ηηθίήγΙ-2-((4Ρ,8Ρ)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-(GABA-x60), 4-octadecanoylamino-butyryl (GABA-x70), 4-((Z)-octadec-9-enoylamino)-butyryl (GABA-x74), 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl (Phosphol ), Hexadecanoyl (x53), (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl (x52), (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylannino)-propionylamino]-propionylannino}-butyryl (γΕ-χ59), (S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tndecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl (γΕ-χ60), (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl (γΕ-χ61 ), (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylannino)-hexanoylamino]-butyryl (γΕ-χ64), (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylannino)-butyryl (γΕ-χ65), (S)-4-carboxy-4-tetradecanoylamino-butyryl (γΕ-χ69), (S)-4-(1 1 - Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl (γΕ-χ72), (S)-4-carboxy-4-[1 1 -((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl (γΕ-χ73), (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl (γΕ-χ74), (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl (γΕ-χ75), (S)-4-Carboxy-4-henicosanoylamino-butyryl (γΕ-χ76), (S)-4-Carboxy-4-docosanoylamino-butyryl (γΕ-χ77), (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl (γΕ-χ79), (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl (γΕ-χ80), (S)-4-Carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl (γΕ-χ81 ), (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl (γΕ-χ82), (S)-4-Carboxy-4-icosanoylamino-butyryl (γΕ-χ95), (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl (γΕ-γΕ-χ53), (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylannino)-butyryl (γΕ-γΕ-χ70), and 3-(3-Octadecanoylamino-propionylannino)-propionyl ( -Ala- -Ala-x70).

In some embodiments, X14 is Lys functionalized with C(O)-R5, wherein R5 is selected from the group consisting of (S)-4-carboxy-4-hexadecanoylamino-butyryl (yE-x53), (S)-4-carboxy-4-octadecanoylamino-butyryl (yE-x70), (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl (yE-γΕ-χ70), 4-octadecanoylamino-butyryl (GABA-x70), (S)-4-Carboxy-4-henicosanoylamino-butyryl (yE-x76), and 3-(3-Octadecanoylamino-propionylamino)-propionyl ( -Ala- -Ala-x70).

A further embodiment relates to a group of compounds, wherein

R1 is NH2,

R2 is NH2 or

R1 and R2 are NH2.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin, Glu and His, X12 represents an amino acid residue selected from lie and Lys, X14 represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is functionalized by - C(O)- R5, wherein R5 is as described above,

X15 represents an amino acid residue selected from Asp and Glu, X16 represents an amino acid residue selected from Ser, Lys, Glu and Gin,

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

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

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

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

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

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

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

X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin, Glu and His, X12 represents an amino acid residue selected from lie and Lys, X14 represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is functionalized by - C(O)- R5, wherein R5 is as described above,

X15 represents an amino acid residue selected from Asp and Glu, X16 represents an amino acid residue selected from Ser, Lys, Glu and Gin,

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

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

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

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

Leu, Lys, His, Pip, (S)MeLys, (R)MeLys and (S)MeOrn,

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

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

Ser,

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

X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin, Glu and His, X12 represents lie,

X14 represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is functional ized by - C(O)- R5, wherein R5 is as described above,

X15 represents an amino acid residue selected from Asp and Glu, X16 represents an amino acid residue selected from Ser, Lys, Glu and Gin,

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

X18 represents an amino acid residue selected from Ala and Arg, X19 represents an amino acid residue selected from Ala and Val, X20 represents an amino acid residue selected from Gin, Aib, Lys, Pip, (S)MeLys, (R)MeLys and (S)MeOrn and His,

X21 represents an amino acid residue selected from Asp, Glu and Leu, X28 represents an amino acid residue selected from Asn and Ala, X29 represents an amino acid residue selected from Gly, Thr and D- Ala,

X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin, Glu and His, X12 represents an amino acid residue selected from lie and Lys, X14 represents an amino acid residue having a side chain with an -NH2 group, wherein the -NH2 side chain group is functionalized by - C(O)- R5, wherein R5 is as described above,

X15 represents an amino acid residue selected from Asp and Glu, X16 represents an amino acid residue selected from Ser, Lys, Glu and Gin,

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

X18 represents an amino acid residue selected from Ala and Arg, X19 represents an amino acid residue selected from Ala and Val,

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

X21 represents an amino acid residue selected from Asp, Glu and Leu, X28 represents an amino acid residue selected from Asn and Ala, X29 represents an amino acid residue selected from Gly, Thr and D- Ala,

X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin and Glu, X12 represents lie,

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

X15 represents an amino acid residue selected from Glu and Asp, X16 represents an amino acid residue selected from Ser and Lys, X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

X20 represents an amino acid residue selected from Gin and Aib, X21 represents an amino acid residue selected from Asp and Glu, X28 represents an amino acid residue selected from Asn and Ala, X29 represents an amino acid residue selected from Gly and Thr, X40 is absent.

A further embodiment relates to a group of compounds, wherein

X3 represents Glu,

X12 represents lie,

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

X15 represents an amino acid residue selected from Glu and Asp, X16 represents an amino acid residue selected from Ser and Lys, X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

X20 represents an amino acid residue selected from Gin and Aib, X21 represents an amino acid residue selected from Asp and Glu, X28 represents an amino acid residue selected from Asn and Ala, X29 represents an amino acid residue selected from Gly and Thr, X40 is absent.

A further embodiment relates to a group of compounds, wherein

X3 represents Gin,

X12 represents lie,

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

X15 represents an amino acid residue selected from Glu and Asp, X16 represents an amino acid residue selected from Ser and Lys,

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

X20 represents an amino acid residue selected from Gin and Aib, X21 represents an amino acid residue selected from Asp and Glu, X28 represents an amino acid residue selected from Asn and Ala, X29 represents an amino acid residue selected from Gly and Thr, X40 is absent.

A further embodiment relates to a group of compounds, wherein

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

A further embodiment relates to a group of compounds, wherein

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

A further embodiment relates to a group of compounds, wherein

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

A further embodiment relates to a group of compounds, wherein

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

X12 represents lie,

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

X15 represents an amino acid residue selected from Glu and Asp, X16 represents an amino acid residue selected from Ser and Lys, X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

X20 represents an amino acid residue selected from Gin and Aib, X21 represents an amino acid residue selected from Asp and Glu, X28 represents an amino acid residue selected from Asn and Ala, X29 represents an amino acid residue selected from Gly and Thr, X40 is absent.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin, His and Glu, X12 represents lie,

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

X15 represents Glu,

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

X17 represents Glu,

X18 represents Ala,

X19 represents Val,

X20 represents Arg,

X21 represents Leu,

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

X29 represents an amino acid residue selected from Gly and Thr, X40 is absent.

A further embodiment relates to a group of compounds, wherein

X3 represents Glu,

X12 represents lie,

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

X15 represents Glu,

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

X17 represents Glu,

X18 represents Ala,

X19 represents Val,

X20 represents Arg,

X21 represents Leu,

X28 represents an amino acid residue selected from Asn, Aib and Ala, X29 represents Gly,

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin, His and Glu, X12 represents an amino acid residue selected from lie and Lys, X14 represents Lys, wherein the -NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4- hexadecanoylamino-butyryl- and (S)-4-Carboxy-4-octadecanoylamino- butyryl-,

X15 represents an amino acid residue selected from Glu and Asp, X16 represents Glu,

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

X18 represents an amino acid residue selected from Ala and Arg, X19 represents Ala,

X20 represents an amino acid residue selected from Pip, (S)MeLys, (R)MeLys and (S)MeOrn,

X21 represents Glu,

X28 represents an amino acid residue selected from Asn, Ser and Ala, X29 represents an amino acid residue selected from Gly and Thr,

X40 is absent.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin, His and Glu, X12 represents an amino acid residue selected from lie and Lys, X14 represents Lys, wherein the -NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4- hexadecanoylamino-butyryl-, hexadecanoyl- and (S)-4-Carboxy-4- octadecanoylamino-butyryl-,

X15 represents an amino acid residue selected from Glu and Asp, X16 represents an amino acid residue selected from Ser, Lys, Glu and Gin,

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

X18 represents an amino acid residue selected from Ala, Aib, Leu and Tyr,

X19 represents an amino acid residue selected from Ala, Val and Aib, X20 represents Aib,

X21 represents an amino acid residue selected from Glu, Leu and Tyr, X28 represents an amino acid residue selected from Asn, Arg and Ala, X29 represents an amino acid residue selected from Gly, Ala, D-Ala and Thr,

X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin, His and Glu, X12 represents an amino acid residue selected from lie and Lys,

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

X15 represents an amino acid residue selected from Glu and Asp, X16 represents an amino acid residue selected from Ser, Lys and Glu, X17 represents an amino acid residue selected from Arg, Lys, lie, Glu and Gin,

X18 represents an amino acid residue selected from Ala, Arg and Lys, X19 represents an amino acid residue selected from Ala, Val and Gin, X20 represents an amino acid residue selected from Gin, Phe, Leu, Lys, His and Arg,

X21 represents an amino acid residue selected from Glu, Asp and Leu, X28 represents an amino acid residue selected from Asn, Arg, Lys and Ala,

X29 represents an amino acid residue selected from Gly, Aib and Thr, X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

X12 represents lie.

A further embodiment relates to a group of compounds, wherein

X19 represents Ala.

A further embodiment relates to a group of compounds, wherein

X16 represents Glu,

X20 represents an amino acid residue selected from Pip, (S)MeLys, (R)MeLys and (S)MeOrn.

A further embodiment relates to a group of compounds, wherein

X28 represents Ala,

X29 represents Gly.

A further embodiment relates to a group of compounds, wherein

X28 represents Asn,

X29 represents Thr.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin and Glu, X12 represents lie,

X14 represents Lys, wherein the -NH2 side chain group is functionalized by -C(O)-R5, wherein R5 is selected from (S)-4-Carboxy- 4-hexadecanoylamino-butyryl- (γΕ-χ53), (S)-4-Carboxy-4- octadecanoylamino-butyryl- (γΕ-χ70), (S)-4-Carboxy-4-((S)-4-carboxy- 4-octadecanoylamino-butyrylamino)-butyryl- (γΕ-γΕ-χ70), 3-(3- Octadecanoylamino-propionylamino)-propionyl- (βΑ-βΑ-χ70), 4- octadecanoylamino-butyryl- (GABA-x70), and (S)-4-Carboxy-4- henicosanoylamino-butyryl- (γΕ-χ76),

X15 represents an amino acid residue selected from Asp and Glu, X16 represents an amino acid residue selected from Ser and Lys, X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

X20 represents an amino acid residue selected from Gin and Aib, X21 represents an amino acid residue selected from Asp and Glu, X28 represents an amino acid residue selected from Asn and Ala, X29 represents an amino acid residue selected from Gly and Thr, X40 is absent.

A further embodiment relates to a group of compounds, wherein

X3 represents an amino acid residue selected from Gin and Glu, X12 represents lie,

X14 represents Lys, wherein the -NH2 side chain group is functionalized by - C(O)-R5, wherein R5 is (S)-4-Carboxy-4- hexadecanoylamino-butyryl- (γΕ-χ53),

X15 represents an amino acid residue selected from Asp and Glu, X16 represents an amino acid residue selected from Ser and Lys,

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

X20 represents an amino acid residue selected from Gin and Aib, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Asn and Ala, X29 represents an amino acid residue selected from Gly and Thr, X40 is absent.

A further embodiment relates to a group of compounds, wherein

X3 represents Glu,

X12 represents lie,

X14 represents Lys, wherein the -NH2 side chain group is functionalized by - C(O)-R5, wherein R5 is selected from (S)-4-Carboxy- 4-octadecanoylamino-butyryl- (γΕ-χ70), (S)-4-Carboxy-4-((S)-4- carboxy-4-octadecanoylamino-butyrylamino)-butyryl- (γΕ-γΕ-χ70), 3-(3- Octadecanoylamino-propionylamino)-propionyl- (βΑ-βΑ-χ70), 4- octadecanoylamino-butyryl- (GABA-x70), and (S)-4-Carboxy-4- henicosanoylamino-butyryl- (γΕ-χ76),

X15 represents Glu,

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

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

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

X21 represents Glu,

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

X29 represents an amino acid residue selected from Gly and Thr, X40 is absent.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 8-39 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 8-10 and 12-38 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 8-13 and 39 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 8-10 and 12-13 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 14-21 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compounds of SEQ ID NO: 22-38 as well as salts and 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 additionally therapeutically effective agent. In other embodiments, however, the compounds are used together with at least one additional therapeutically active agent, as described in "combination therapy".

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

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

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

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

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

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

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), Dap (2,3-diamino propionic acid), NIe (norleucine), GABA (γ-aminobutyric acid) or Ahx (ε-aminohexanoic acid).

Furthermore, the following codes were used for the amino acids shown in Table 4:

Table 4:

structure name code

(S)MeLys (S)-a-met yl-lysine (S)MeLys

H .N o

N H

(R)MeLys (R)-a-met yl-lysine (R)MeLys

□

(S)MeOrn (S)-a-met yl-ornithin (S) eOrn

NH,

Pip 4-amino-piperidine-4-carboxylic acid Pip

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 39-40 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 (II) differs from native exendin-4 at least at one of those positions which are stated to allow variation. Amino acids within the peptide moiety (II) can be considered to be numbered consecutively from 0 to 40 in the conventional N-terminal to C-terminal direction. Reference to a ..position" within peptidic moiety (II) 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.

The amino acid residues at position 14 and optionally at position 40, having a side chain with an - NH2 group, e.g. Lys, Orn, Dab or Dap are conjugated to a functional group, e.g. acyl groups. Thus, one or more selected amino acids of the peptides in the present invention may carry a covalent attachment at their side chains. In some cases those attachments may be lipophilic. These lipophilic side chain attachments have the potential to reduce in vivo clearance of the peptides thus increasing their in vivo half-lives.

The lipophilic attachment may consist of a lipophilic moiety which can be a branched or unbranched, aliphatic or unsaturated acyclic moiety and/or a cyclic moiety selected from one or several aliphatic or unsaturated homocycles or heterocycles, aromatic condensed or non-condensed homocycles or heterocycles, ether linkages, unsaturated bonds and substituents, e.g. hydroxy and/or carboxy groups. The lipophilic moiety may be attached to the peptide either by alkylation, reductive amination or by an amide bond, a carbamate or a sulfonamide bond in case of amino acids carrying an amino group at their side chain.

Nonlimiting examples of lipophilic moieties that can be attached to amino acid side chains include fatty acids, e.g. C8-3o fatty acids such as palmitic acid, myristic acid, stearic acid and oleic acid, and/or cyclic groups as described above or derivatives thereof.

There might be one or several linkers between the amino acid of the peptide and the lipophilic attachment. Nonlimiting examples of those linkers are β-alanine, γ-glutamic acid, a-glutamic acid, γ-aminobutyric acid and/or ε-aminohexanoic acid or dipeptides, such as -Ala- -Ala (also abbreviated A-βΑ herein) and/or γ-Glu-y-Glu (also abbreviated γΕ-γΕ herein) in all their stereo-isomer forms (S and R enantiomers).

Thus, one nonlimiting example of a side chain attachment is palmitic acid which is covalently linked to the a-amino group of glutamic acid forming an amide bond. The γ-carboxy group of this substituted glutamic acid can form an amide bond with the side chain amino group of a lysine within the peptide.

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 solid phase synthesis was carried out on Rink-resin with a loading of 0.38 mmol/g, 75-150 μιτι from the company Agilent Technologies. The Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in the solid phase synthesis protocol. The ivDde-group was cleaved from the peptide on resin according to literature (S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603). Hereafter Fmoc- -Ala-OH was coupled to the liberated amino-group employing the coupling reagents HBTU/DIPEA followed by Fmoc-deprotection with 20% piperidine in DMF. Again Fmoc-β-Ala-OH was coupled followed by Fmoc-deprotection and the final coupling of stearic acid using HBTU/DIPEA. The peptide was cleaved from the resin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified via preparative HPLC on a Waters column (XBridge, BEH130, Prep C18 5μΜ) using an acetonitrile/water gradient (both buffers with 0.05% TFA). The purified peptide was analysed by LCMS (Method C). Deconvolution of the mass signals found under the peak with retention time 28.97 min revealed the peptide mass 4618.6 which is in line with the expected value of 4618.32.

Example 5:

Synthesis of SEQ ID NO: 9

The solid phase synthesis was carried out on Novabiochem Rink-Amide resin (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.34 mmol/g. The Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in the solid phase synthesis protocol. The ivDde-group was cleaved from the peptide on resin according to a modified literature procedure (S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603), using 4% hydrazine hydrate in DMF. Hereafter Palm-Glu(YOSu)-OtBu was coupled to the liberated amino-group. The peptide was cleaved from the resin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified via preparative HPLC on a Waters column (Sunfire, Prep C18) using an acetonitrile/water gradient (both buffers with 0.1 % TFA). The purified peptide was analysed by LCMS (Method B). Deconvolution of the mass signals found under the peak with retention time 12.7 min revealed the peptide mass 4577.3 which is in line with the expected value of 4577.22.

Example 6:

Synthesis of SEQ ID NO: 36

The solid phase synthesis was carried out on Novabiochem Rink-Amide resin (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.34 mmol/g. The Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in the solid phase synthesis protocol. The ivDde-group was cleaved from the peptide on resin according to a modified literature procedure (S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603), using 4% hydrazine hydrate in DMF. Hereafter Palm-Glu(YOSu)-OtBu was coupled to the liberated amino-group. The peptide was cleaved from the resin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified via preparative HPLC on a Waters column (Sunfire, Prep C18) using an acetonitrile/water gradient (both buffers with 0.05% TFA). The purified peptide was analysed by LCMS (Method B). Deconvolution of the mass signals found under the peak with retention time 12.53 min revealed the peptide mass 4489.57 which is in line with the expected value of 4490.13.

Example 7:

Synthesis of SEQ ID NO: 39

The solid phase synthesis was carried out on Novabiochem Rink-Amide resin (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.34 mmol/g. The Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in the solid phase synthesis protocol. The ivDde-group was cleaved from the peptide on resin according to a modified literature procedure (S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603), using 4% hydrazine hydrate in DMF. Hereafter Palm-Glu(YOSu)-OtBu was coupled to the liberated amino-group. The peptide was cleaved from the resin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified via preparative HPLC on a Waters column (Sunfire, Prep C18) using an acetonitrile/water gradient (both buffers with 0.05% TFA). The purified peptide was analysed by LCMS (Method B). Deconvolution of the mass signals found under the peak with retention time 13.5 min revealed the peptide mass 4491 .3 which is in line with the expected value of 4492.1 .

In an analogous way, the following peptides SEQ ID NO: 8 - 41 were synthesized and characterized (Method A-E), see Table 5.

Table 5: list of synthesized peptides and comparison of calculated vs. found molecular weight.

SEQ ID NO: calc. Mass found mass

8 4576.2 4575.6

9 4577.2 4577.3

10 4478.0 4477.5

1 1 4462.1 4462.5

12 4548.1 4547.7

13 4506.1 4505.3

14 4561 .2 4560.9

15 4605.3 4605.7

16 4734.4 4733.6

17 4561 .3 4561 .4

18 4618.3 4618.6

19 4648.3 4647.6

20 4647.4 4647.4

21 4520.1 4518.9

22 4464.0 4463.4

23 4565.1 4564.5

24 4522.1 4521 .4

25 4579.1 4578.7

26 4620.2 4619.6

27 4563.2 4562.4

28 4504.1 4504.5

29 4477.0 4477.2

30 4420.0 4419.2

31 4505.1 4505.1

32 4477.1 4476.5

33 4519.1 4518.0

34 4533.2 4532.1

35 4449.0 4448.4

36 4490.1 4489.6

37 4491 .1 4491 .0

38 4590.3 4590.2

39 4492.1 4491 .3

O 4094.5 4092.3

*41 4194.6 4194.0

-acylated comparison compound

Example 8: Chemical stability and solubility

Solubility and chemical stability of peptidic compounds were assessed as described in Methods. The results are given in Table 6.

Table 6: Chemical stability and solubility

Example 9: In vitro data on GLP-1 , GIP and glucagon receptor

Potencies of peptidic compounds at the GLP-1 , GIP and glucagon receptors were determined by exposing cells expressing human glucagon receptor (hGLUC R), human GIP (hGIP R) and human GLP-1 receptor (hGLP-1 R) to the listed compounds at increasing concentrations and measuring the formed cAMP as described in Methods.

The results for Exendin-4 derivatives with activity at the human GIP (hGIP R), human GLP-1 receptor (hGLP-1 R) and human glucagon receptor (hGLUC R) are shown in Table 7.

Table 7. EC5o values of exendin-4 peptide analogues at GLP-1 , GIP and Glucagon receptors (indicated in pM)

SEQ ID NO: EC50 hGIP R EC50 hGLP-1 R EC50 hGLUC R

[pM] [pM] [pM]

8 9.8 5.3 18.3

9 5.7 3.6 7710.0

10 15.1 13.2 40000.0

11 3.2 11 .5 7220.0

12 8.9 12.7 1890.0

13 71 .0 7.3 31 .3

14 4.4 4.3 3760.0

15 8.2 8.1 5810.0

16 5.1 4.0 2890.0

17 9.6 8.7 9740.0

18 8.1 7.6 4950.0

19 13.8 4.0 707.5

20 24.5 23.2 3310.0

21 6.4 4.8 10100.0

22 16.6 32.0 11600.0

23 79.5 11 .8 19100.0

24 23.5 13.5 38900.0

25 73.6 9.5 20500.0

26 19.7 4.9 8510.0

27 6.7 4.0 6390.0

28 10.9 3.2 9.9

29 127.0 7.0 46.8

30 22.1 12.0 226.0

31 6.5 6.0 3080.0

32 7.1 8.4 82.6

33 9.1 6.4 12900.0

34 22.2 4.6 11600.0

35 7.3 6.9 39100.0

36 6.4 3.4 5785.0

37 21 .2 8.9 32.0

38 11 .2 6.7 11 .4

39 8.5 4.3 19300.0

Comparison Testing

A selection of inventive exendin-4 derivatives comprising a functionalized amino acid in position 14 has been tested versus corresponding compounds having in this position 14 a 'non-functionalized' amino acid. The reference pair compounds and the corresponding EC50 values at GLP-1 and GIP receptors (indicated in pM) are given in Table 8. As shown, the inventive exendin-4 derivatives show a superior activity in comparison to the compounds with a 'non-functionalized' amino acid in position 14.

Table 8. Comparison of exendin-4 derivatives comprising a non-functionalized amino acid in position 14 vs. exendin-4 derivatives comprising a functionalized amino acid in position 14. EC50 values at GLP-1 and GIP receptors are indicated in pM. (K=lysine, Nle=norleucine, L=leucine, γΕ-x53=(S)-4-Carboxy-4-hexadecanoylamino-butyryl-)

EC50 hGIP R EC50 hGLP-1 R residue in

SEQ ID NO:

[pM] [pM] position 14

32 7.1 8.4 Κ(γΕ-χ53)

40 858 3.2 L

9 5.7 3.6 Κ(γΕ-χ53)

41 449 11 .2 Nle

Example 10: Pharmacokinetic testing

Pharmacokinetic profiles were determined as described in Methods. Calculated T /2 and cmax values are shown in Table 9.

Table 9. Pharmacokinetic profiles of exendin-4 derivatives.

Example 1 1 : Effect of SEQ ID NO: 9 and SEQ ID NO: 13 on gastric emptying and intestinal passage in female NMRI-mice

Female NMRI-mice, weighing on average 25 - 30 g, received 1 , 3 and 10 pg/kg of SEQ ID NO: 9, or 10 pg/kg of SEQ ID NO: 13 or phosphate buffered saline (vehicle control) subcutaneously, 60 min prior to the administration of the coloured bolus. 30 min later, the assessment of stomach contents and intestinal passage was done (Fig. 1 and 2).

In these studies, SEQ ID NO: 9 reduced intestinal passage by 49, 62 and 64 % (p<0.0001 ) and increased remaining gastric contents by 32, 79 and 1 1 1 % (p<0.0001 ), respectively. SEQ ID NO: 13 reduced intestinal passage by 60 % (p<0.0001 ) and increased remaining gastric contents by 40 % (p<0.0001 ), respectively. (p<0.0001 versus vehicle control, 1 -W-ANOVA, followed by Dunnett's post-hoc test).

Example 12:

Effect of SEQ ID NO: 12, SEQ ID NO: 13 and liraglutide on 22-hours food intake in female NMRI-mice

Fed female NMRI-mice, weighing on average 25-30 g, were administered 0.1 mg/kg of SEQ ID NO: 12, SEQ ID NO: 13, liraglutide or phosphate buffered saline (vehicle control) subcutaneously, directly prior to start of feeding monitoring. Lights-off phase (dark phase) started 4 hours later.

All tested compounds induced a pronounced reduction of feed intake, reaching after 22 hours for liraglutide 47% (p=0.006), for SEQ ID NO: 12 71 % (p<0.0001 ) and SEQ ID NO: 13 93% (p=0.0003, 2-W-ANOVA-RM on ranks, post hoc Dunnett's Test) at the end of the study, respectively (Fig. 3a).

Effect of SEQ ID NO: 9 on 22-hours food intake in female NMRI-mice

Fed female NMRI-mice, weighing on average 25-30 g, were administered 3 g/kg or 10 pg/kg of SEQ ID NO: 9 or phosphate buffered saline (vehicle control) subcutaneously, directly prior to start of feeding monitoring. Lights-off phase (dark phase) started 4 hours later.

SEQ ID NO: 9 induced a pronounced reduction of feed intake, reaching after 22 hours for 3 pg/kg 1 1 % (not significant, p=0.78), and for 10 pg/kg 62% (p= 0.0005, 2-W-ANOVA-RM on ranks, post hoc Dunnett's Test) at the end of the study, respectively (Fig. 3b).

Example 13:

Subchronic effects of SEQ ID NO: 9 after subcutaneous treatment on blood glucose and body weight in female diet-induced obese (DIO) C57BL/6NCrl mice (18 weeks on high-fat diet, method 1 )

1 ) Glucose profile

Diet-induced obese female C57BL/6NCrl mice were administered daily in the afternoon, at the end of the light phase (12 h lights on) with 10, 30 and 100 g/kg of SEQ ID NO: 9 or phosphate buffered solution (vehicle control on standard or high-fat diet) subcutaneously. On day 6 of treatment and at predefined time points, more blood samples were taken to measure blood glucose and generate the blood glucose profile over 24 h.

Already at the beginning of blood sampling on day 6 of treatment the basal blood glucose levels were dose-dependently decreased compared to DIO control mice (Fig. 4).

2) Body weight

Female obese C57BL/6NCrl mice were treated for 4 weeks once daily subcutaneously in the afternoon, at the end of the light phase (12 h lights on) with 10, 30 or 100 pg/kg SEQ ID NO: 9 or vehicle. Body weight was recorded daily, and body fat content was determined before the start of treatment and after 4 weeks of treatment.

Comparable data can be obtained for both female and male mice.

Treatment with SEQ ID NO: 9 reduced body weight, whereas in the high-fat diet control group maintained body weight (Fig. 5 and Table 10). Calculating the relative body weight change from baseline values revealed a dose-dependent decrease of body weight, varying between 13.3-16.4% at 10 pg/kg, 17.6-20.9% at 30 pg/kg and 21 .7-22.7% at 100 pg/kg (Fig. 6). These changes resulted from a decrease in body fat, as shown by the absolute changes in body fat content (Fig. 7 and Table 10).

Table 10. Weight change in DIO mice over a 4-week treatment period (mean ± SEM)

Example 14: Acute and subchronic effects of SEQ ID NO: 13, SEQ ID NO: 12, SEQ ID NO: 10 and SEQ ID NO: 9 after subcutaneous treatment on blood glucose and HbA1 c in female leptin-receptor deficient diabetic db/db mice (method 3)

1 ) Glucose profile

After blood sampling to determine the blood glucose baseline level, fed diabetic female db/db mice were administered 100 pg/kg of of SEQ ID NO: 13, SEQ ID NO: 12, SEQ ID NO: 10 and SEQ ID NO: 9 or phosphate buffered solution (vehicle-treated db/db control) subcutaneously in the morning, at the beginning of the light phase (12 h lights on). At predefined time points, more blood samples were taken to measure blood glucose and generate the blood glucose profile over 24 h.

Comparable data can be obtained for both female and male mice.

At the tested dose, of SEQ ID NO: 13, SEQ ID NO: 12, SEQ ID NO: 10 and SEQ ID NO: 9 demonstrated a significant decrease in blood glucose compared to db/db control mice, lasting longer than 24 h in the SEQ ID NO: 10 and SEQ ID NO: 9 dose group (Fig. 8).

2) Blood glucose & HbA1 c

Female diabetic mice were treated for 4 weeks once daily subcutaneously with 10, 30 or 100 pg/kg SEQ ID NO: 9 or vehicle in the morning, at the beginning of the light phase (12 h lights on). Blood glucose and HbA1 c were determined before start of treatment and at the end of the study after 4 weeks of treatment. A strong and dose-dependent decrease in blood glucose, superior to liraglutide in the medium and highest dose could be observed (Fig. 9). Before treatment started, no significant differences in blood glucose levels could be detected between db/db groups, only the lean control animals had significant lower glucose levels. During the 4 weeks of treatment, glucose levels increased in the vehicle-treated db/db control group, indicating a worsening of the diabetic situation. All SEQ ID NO: 9-treated animals displayed a significant lower blood glucose level than the db control mice at the end of the study.

Comparable data can be obtained for both female and male mice.

Corresponding to blood glucose, at start of the study, no significant differences in HbA1 c levels could be detected between db/db groups, only the lean control animals had significant lower levels. During the 4 weeks of treatment, HbA1 c increased in the vehicle-treated db/db control group, corresponding to the increasing blood glucose levels. Animals treated with SEQ ID NO: 9 displayed a lower HbA1 c level than the db/db control mice at the end of the study in all three doses (Fig. 10).

Example 15: Subchronic effects of SEQ ID NO: 9 and SEQ ID NO: 21 after subcutaneous treatment on body weight in female diet-induced obese (DIO) C57BL/6NCrl mice (14 weeks of prefeeding with high-fat diet, method 2)

Female obese C57BL/6NCrl mice were treated for 3 weeks once daily subcutaneously in the late afternoon, prior the end of the light phase (12 h lights on) with 10 pg/kg SEQ ID NO: 9 and SEQ ID NO: 21 or vehicle. Body weight was recorded daily.

Treatment with SEQ ID NO: 9 and SEQ ID NO: 21 reduced body weight, whereas the high-fat diet control group even gained body weight (Fig. 1 1 and Table 1 1 ). Calculating the relative body weight change from baseline values revealed a decrease of body weight up to 15.1 % at 10 pg/kg SEQ ID NO: 9 and 18.0% at 10 pg/kg SEQ ID NO: 21 (Fig. 12).

Table 1 1 . Weight change in DIO mice over a 3-week treatment period (mean

± SEM)

Example 16: Effects of 4 weeks of treatment with SEQ ID NO: 16, and SEQ ID NO: 21 on glucose, HbA1 c and oral glucose tolerance in female diabetic dbdb-mice (method 4)

Female dbdb-mice, received 3 and 10 pg/kg of SEQ ID NO: 16 and 10 pg/kg of SEQ ID NO: 21 or phosphate buffered saline (vehicle control) once daily, subcutaneously over four weeks.

Both compounds reached a statistical significant reduction of non-fasted glucose compared to vehicle control at the 10 pg/kg dose (Fig. 13); p<0.05, 1 -way-ANOVA, followed by Dunnett's post-hoc test.

Furthermore, both compounds prevented an increase of HbA1 c in a statistical significant manner compared to vehicle control at the 10 pg/kg dose (Fig. 14); (p<0.05, 1 -way-ANOVA, followed by Dunnett's post-hoc test). Treatment with SEQ ID NO: 16, and SEQ ID NO: 21 lead to improved oral glucose tolerance (Fig. 15; represented as normalized to 0 mmol/l at 0 min), and reduction of AUC under the glucose curve reached statistical significance compared to vehicle control (Fig. 16); (p<0.05, 1 -way-ANOVA, followed by Dunnett's post-hoc test).

Example 17: SEQ ID NO: 14 and SEQ ID NO: 21 on glucose lowering in non-fasted female diabetic dbdb-mice

Female dbdb-mice, received 3 pg/kg of SEQ ID NO: 14, SEQ ID NO: 21 or phosphate buffered saline (vehicle control) subcutaneously, at time 0 min. Both compounds immediately lowered glucose values (baseline at 20-22 mmol/l), with SEQ ID NO: 14 reaching the maximal effect of ~8 mmol/l (Fig. 18) and SEQ ID NO: 21 of 10 - 12 mmol/l glucose reduction (Fig. 17), respectively, at 240 min and keeping it to the end of observation at 480 min.

Both compounds reached a statistical significant reduction of glucose compared to vehicle control from t = 60 min until end of observation (p<0.05, 2-way-ANOVA on repeated measures, followed by Dunnett's post-hoc test).

Table 12: Sequences

SEQ I D sequence

NO:

1 H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-l-E-W-L- K-N-G-G-P-S-S-G-A-P-P-P-S-NH2

2 H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-l-A-W-L- V-K-G-R-NH2

3 H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K(YE-X53)-E-F-I- A-W-L-V-R-G-R-G

4 Y-A-E-G-T-F-l-S-D-Y-S-l-A-M-D-K-l-H-Q-Q-D-F-V-N-W-L-L- A-Q-K-G-K-K-N-D-W-K-H-N-l-T-Q

5 H-S-Q-G-T-F-T-S-D-Y-S-K-Y-L-D-S-R-R-A-Q-D-F-V-Q-W-L- M-N-T

6 Y-G-E-G-T-F-T-S-D-L-S-l-Q-M-E-E-E-A-V-R-L-F-l-E-W-L-K- N-G-G-P-S-S-G-A-P-P-P-S-NH2

7 Y-A-E-G-T-F-T-S-D-V-S-l-Y-L-E-G-Q-A-A-K-E-F-l-A-W-L-V- K-G-R-NH2

8 Y-Aib-Q-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-K-R-A-A-Aib-E- F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

9 Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-K-R-A-A-Aib-E- F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

10 Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-S-R-A-A-Q-D-F- I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

1 1 Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-K-R-A-A-Aib-D- F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

12 Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-K-R-A-A-Q-D-F- I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2

13 Y-Aib-Q-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-S-R-A-A-Q-D-F- I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2

14 Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x70)-E-K-R-A-A-Q-E-F-l- E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

15 Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x70)-E-K-R-A-A-Aib-E- F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-YE-x70)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(GABA-x70)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K( A- A-x70)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x70)-E-K-R-A-A-Q-E-F-l-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x76)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x70)-E-S-R-A-A-Q-E-F-l-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-S-R-A-A-Q-D-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-S-R-A-A-Aib-D-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-S-R-A-A-Q-E-F-l-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-K-R-A-A-Q-E-F-l-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-K-R-A-A-Aib-D-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-Q-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-K-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-Q-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-S-R-A-A-Q-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-Q-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-S-R-A-A-Aib-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-K-R-A-A-Q-D-F- I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-Q-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-K-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-K-R-A-A-Q-E-F-l-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-S-R-A-A-Aib-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-Q-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-Q-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-D-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-l-Q-K(YE-x53)-E-S-R-A-A-Q-E-F-l-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-L-E-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-Nle-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2
Claims

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

R1 - Z - R2 (I)

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

Tyr-Aib-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-X12-Gln-X14-X15-X16-X17-X18-X19-X20-X21 -Phe-lle-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly- Ala-Pro-Pro-Pro-Ser-X40 (II)

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

X12 represents an amino acid residue selected from lie and Lys,

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

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

X16 represents an amino acid residue selected from Ser, Lys, Glu and Gin, X17 represents an amino acid residue selected from Arg, Lys, Glu, Gin, Leu, Aib, Tyr and Ala,

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

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

X20 represents an amino acid residue selected from Gin, Aib, Lys and His, X21 represents an amino acid residue selected from Asp, Glu and Leu, X28 represents an amino acid residue selected from Asn and Ala,

X29 represents an amino acid residue selected from Gly, Thr and D-Ala, X40 is either absent or represents Lys,

R1 represents NH2,

R2 represents the C-terminal group of the peptidic compound and is selected from OH and NH2,

or a salt or solvate thereof.

2. A compound of claim 1 , wherein

X14 represents an amino acid residue with a functionalized -NH2 side chain group, such as functionalized Lys, Orn, Dab or Dap, wherein at least one H atom of the -NH2 side chain group is replaced by -C(O)-R5, which is selected from

(S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, 4-Hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-, Hexadecanoyl-, (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl-, (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-propionylamino]-propionylamino}-butyryl, (S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-, (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl-, (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-butyryl-, (S)-4-Carboxy-4-tetradecanoylamino-butyryl-, (S)-4-(1 1 -Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl-, (S)-4-Carboxy-4-[1 1 -((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl-, (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, (S)-4-Carboxy-4-docosanoylamino-butyryl-, (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-[(4'-

octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-, (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-Carboxy-4-icosanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylannino)-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylannino)-butyryl-, 3-(3-Octadecanoylamino-propionylannino)-propionyl-, 3-(3-Hexadecanoylamino-propionylannino)-propionyl-, 3-Hexadecanoylamino-propionyl-, (S)-4-Carboxy-4-[(R)-4-((3R,5S,7R,8R,9R,10S,12S,13R,14R,17R)-3,7,12-trihydroxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (SH-Carboxy-^KRH-iiSR.SR.eR.QS.10S.13R.14S.17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylamino)-butyryl-, tetradecanoyl-, 1 1 -Carboxy-undecanoyl-, 1 1 -Benzyloxycarbonyl-undecanoyl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-tetradecanoylamino-butyrylannino)-butyryl-, 6-[Hydroxy-(naphthalen-2-yloxy)-phosphoryloxy]-hexanoyl-, 6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-, 4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-, 4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,(S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[(S)-4- carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-butyryl-, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetyl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-butyrylamino}-butyrylamino)-butyryl-, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-1 H-tetrazol-5-yl-hexadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-carboxy-hexadecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)-decanoylamino]-butyrylannino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylannino}-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(7-carboxy-heptanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylaminoj-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(1 1 -carboxy-undecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylannino]-butyrylannino}-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(13-carboxy-tridecanoylamino)-butyrylannino]-ethoxy}-ethoxy)-acetylannino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl-, and (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylannino}-butyryl-,

X40 is absent or represents Lys.

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

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

4. A compound according to any one of claims 1 -3,

wherein X14 is Lys functionalized with C(O)-R5, wherein R5 is selected from the group consisting of (S)-4-carboxy-4-hexadecanoylamino-butyryl (γΕ-x53), (S)-4-carboxy-4-octadecanoylamino-butyryl (γΕ-χ70), (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl (γΕ-γΕ-χ70), 4-octadecanoylamino-butyryl (GABA-x70), (S)-4-Carboxy-4-henicosanoylamino-butyryl (γΕ-χ76), and 3-(3-Octadecanoylamino-propionylamino)-propionyl ( -Ala- -Ala-x70).

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

wherein R2 is NH2.

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

wherein the peptidic compound has a relative activity of at least 0.04%, preferably at least 0.08%, more preferably at least 0.2% compared to that of natural GIP at the GIP receptor.

7. A compound according to any one of claims 1 -6, wherein the peptidic compound exhibits a relative activity of at least 0.07%, preferably at least 0.1 %, more preferably at least 0.14%, more preferably at least 0.35% and even more preferably at least 0.4% compared to that of

GLP-1 (7-36) at the GLP-1 receptor.

8. A compound according to any one of claims 6 or 7, wherein the peptidic compound further exhibits a relative activity of at least 0.1 %, preferably at least 0.2%, more preferably at least 0.3%, more preferably at least 0.4% and even more preferably at least 0.5% compared to that of natural glucagon at the glucagon receptor.

9. A compound of any one of claims 1 - 8,

wherein

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

X12 represents lie,

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

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

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

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

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

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

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

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

X40 is absent.

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

X3 represents Glu,

X12 represents lie,

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

butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylannino)-butyryl-, 3-(3-Octadecanoylamino-propionylannino)-propionyl- and 4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-,

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

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

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

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

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

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

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

X40 is absent.

1 1 . A compound of any one of claims 1 - 10, wherein

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

12. A compound of any one of claims 1 - 9,

wherein

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

13. A compound of any one of claims 1 - 9, 12,

wherein

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

X12 represents lie,

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

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

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

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

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

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

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

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

X40 is absent.

14. A compound of any one of claims 1 - 13,

wherein X19 represents Ala.

15. A compound of any one of claims 1 - 14,

wherein

X28 represents Ala,

X29 represents Gly.

16. A compound of any one of claims 1 - 14,

wherein

X28 represents Asn,

X29 represents Thr.

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

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

X12 represents lie,

X14 represents Lys, wherein the -NH2 side chain group is functionalized by -C(O)-R5, wherein R5 is selected from (S)-4-Carboxy-4-hexadecanoylamino- butyryl- (γΕ-χ53), (S)-4-Carboxy-4-octadecanoylamino-butyryl- (γΕ-χ70), (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylannino)-butyryl-(γΕ-γΕ-χ70), 3-(3-Octadecanoylamino-propionylannino)-propionyl- (βΑ-βΑ-x70), 4-octadecanoylamino-butyryl- (GABA-x70), and (S)-4-Carboxy-4-henicosanoylamino-butyryl- (γΕ-χ76),

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

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

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

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

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

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

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

X40 is absent.

18. A compound of any one of claims 1 -9,12-17, wherein

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

X12 represents lie,

X14 represents Lys, wherein the -NH2 side chain group is functionalized by -C(O)-R5, wherein R5 is (S)-4-Carboxy-4-hexadecanoylamino-butyryl- (γΕ-x53),

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

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

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

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

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

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

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

X40 is absent.

19. A compound of any one of claims 1 -1 1 , 14-17, wherein

X3 represents Glu,

X12 represents lie,

X14 represents Lys, wherein the -NH2 side chain group is functionalized by -C(O)-R5, wherein R5 is selected from (S)-4-Carboxy-4-octadecanoylamino-butyryl- (γΕ-χ70), (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl- (γΕ-γΕ-χ70), 3-(3-Octadecanoylamino-propionylamino)-propionyl- (βΑ-βΑ-χ70), 4-octadecanoylamino-butyryl-(GABA-x70), and (S)-4-Carboxy-4-henicosanoylamino-butyryl- (γΕ-χ76), X15 represents Glu,

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

X17 represents Arg,

X18 represents Ala,

X19 represents Ala,

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

X21 represents Glu,

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

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

X40 is absent.

20. The compound of any one of claims 1 -19, selected from the compounds of SEQ ID NO: 8-39 or a salt or solvate thereof.

21 . The compound of any one of claims 1 -19, selected from the compounds of SEQ ID NO: 8-10 and 12-38 or a salt or solvate thereof.

22. The compound of claim 20, selected from the compounds of SEQ ID NO: 8-13 and 39 or a salt or solvate thereof.

23. The compound of claim 21 , selected from the compounds of SEQ ID

NO: 8-10 and 12-13 or a salt or solvate thereof.

24. The compound of claim 20, selected from the compounds of SEQ ID NO: 14-21 or a salt or solvate thereof.

25. The compound of claim 20, selected from the compounds of SEQ ID NO: 22-38 or a salt or solvate thereof.

26. The compound of any one of claims 1 -25 for use in medicine, particularly in human medicine.

27. The compound for use according to claim 26 which is present as an active agent in a pharmaceutical composition together with at least one pharmaceutically acceptable carrier.

28. The compound for use according to claim 26 or 27 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, PYY3-36 or analogues thereof, pancreatic polypeptide or analogues thereof, Glucagon receptor agonists, GIP receptor agonists or antagonists, ghrelin antagonists or inverse agonists, Xenin and analogues thereof, DDP-IV inhibitors, SGLT2 inhibitors, dual SGLT2 / SGLT1 inhibitors, Biguanides

Thiazolidinediones, dual PPAR agonists, Sulfonylureas, Meglitinides, alpha-glucosidase inhibitors, Amylin and Amylin analogues, GPR1 19 agonists, GPR40 agonists, GPR120 agonists, GPR142 agonists, systemic or low-absorbable TGR5 agonists, Cycloset, inhibitors of 1 1 - beta-HSD, activators of glucokinase, inhibitors of DGAT, inhibitors of protein tyrosinephosphatase 1 , inhibitors of glucose-6-phosphatase, inhibitors of fructose-1 ,6-bisphosphatase, inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrogenase kinase, alpha2-antagonists, CCR-2 antagonists, modulators of glucose transporter-4, Somatostatin receptor 3 agonists, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the derivatives thereof, nicotinic acid receptor 1 agonists, PPAR-alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors, cholesterol absorption inhibitors, bile acid-binding substances, IBAT inhibitors, MTP inhibitors, modulators of PCSK9, LDL receptor up-regulators by liver selective thyroid hormone receptor β agonists, HDL-raising compounds, lipid metabolism modulators, PLA2 inhibitors , ApoA-l enhancers, thyroid hormone receptor agonists, cholesterol synthesis inhibitors, omega-3 fatty acids and derivatives thereof, active substances for the treatment of obesity, such as Sibutramine, Tesofensine, Orlistat, CB-1 receptor antagonists, MCH-1 antagonists, MC4 receptor agonists and partial agonists, NPY5 or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor, or the combinations of bupropione/naltrexone (CONTRAVE), bupropione/zonisamide (EMPATIC), bupropione/phentermine or pramlintide/metreleptin, QNEXA (Phentermine+ topiramate), lipase inhibitors, angiogenesis inhibitors, H3 antagonists, AgRP inhibitors, triple monoamine uptake inhibitors (norepinephrine and acetylcholine), MetAP2 inhibitors, nasal formulation of the calcium channel blocker diltiazem, antisense against production of fibroblast growth factor receptor 4, prohibitin targeting peptide-1 , drugs for influencing high blood pressure, chronic heart failure or atherosclerosis, such as angiotensin II receptor antagonists, ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting hypertensives, antagonists of the alpha- 2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors.

The compound for use according to claim 26 or 27 together with at least one additional therapeutically active agent, wherein the additional therapeutically active agent particularly is a GLP-1 agonist and/or insulin or an insulin analogue and/or a gastrointestinal peptide.

The compound for use according to any one of claims 26-29 for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, metabolic syndrome and neurodegenerative disorders, particularly for delaying or preventing disease progression in type 2 diabetes, treating metabolic syndrome, treating obesity or preventing overweight, for decreasing food intake, increase energy expenditure, reducing body weight, delaying the progression from impaired glucose tolerance (IGT) to type 2 diabetes; delaying the progression from type 2 diabetes to insulin-requiring diabetes; regulating appetite; inducing satiety; preventing weight regain after successful weight loss; treating a disease or state related to overweight or obesity; treating bulimia; treating binge eating; treating atherosclerosis, hypertension, IGT, dyslipidemia, coronary heart disease, hepatic steatosis, treatment of beta-blocker poisoning, use for inhibition of the motility of the gastro-intestinal tract, useful in connection with investigations of the gastro-intestinal tract using techniques such as X-ray, CT- and NMR-scanning.

The compound for use according to any one of claims 26-30 for the treatment or prevention of hyperglycemia, type 2 diabetes, obesity.