FIELD OF THE INVENTION

The present invention relates to long acting glucagon-like peptide-1 (GLP-1) and human glucose-dependent insulinotropic polypeptide/ Gastro Intestinal Peptide (GIP) dual agonist polypeptides which may be useful for treating type 2 diabetes mellitus (T2D), diabetes with obesity, obesity and hyperlipidemia.

BACKGROUND OF THE INVENTION

Treatment of type 2 diabetes mellitus (T2DM) with glucagon-like peptide-1 receptor agonists (GLP-1RAs) leads to improved glycaemic control, reduced body weight, and improvement in several cardiovascular risk factors. These benefits are mediated by the glucagon-like peptide-1 receptor (GLP-1R), a member of the class B family of G protein-coupled receptors, that is expressed in pancreatic beta-cells, various cell types of the gastrointestinal tract and neurons throughout both the central (CNS) and the peripheral nervous systems. Activation of GLP-1R signaling by GLP-1RAs improves glucose homeostasis by enhancing glucose-stimulated insulin secretion, delaying gastric emptying and decreasing plasma glucagon levels, and reduces body weight by activating anorexigenic pathways in the brain. Due to the glucose-dependence of beta-cell activation, GLP-1RAs are not associated with increased risk of hypoglycaemia. While the broad metabolic benefits of GLP-1RAs have established this class in the T2DM treatment paradigm, many patients do not reach their HbA1c/glycaemic targets and weight loss achieved with these agents, thus, requiring a higher dose, which also increases GI adverse events, and remains well below what can be attained with bariatric surgery, the most potent clinical intervention for obesity. Thus, there are significant opportunities to improve upon the existing GLP-1RA class.

One emerging approach is to combine foundational GLP-1RA therapy with pharmacological strategies targeting additional pathways implicated in nutrient and energy metabolism, such as the glucose-dependent insulinotropic polypeptide (GIP) pathway. GIP is an incretin that is secreted from K cells in the upper small intestine, duodenum, in response to food. Postprandial GIP levels are approximately 4-fold higher compared to GLP-1 under normal physiological conditions. GIP is responsible for the majority of the insulinotropic incretin effect in man, and has important additional functions that are distinct

from GLP-1. Unlike GLP-1, GIP is both glucagonotropic and insulinotropic in a glycaemic- dependent manner, dose-dependently stimulating glucagon secretion under hypoglycaemic conditions and insulin under hyperglycaemic conditions, glucagon released does facilitate insulin secretion. Although both GIP-receptor (GIPR) and GLP-1R are present in beta-cells, GIPR expression is distributed differently in extra-pancreatic tissues as GIPR is abundant in adipose tissue and is found in many non-overlapping areas of the CNS. GIP is implicated in adipose tissue carbohydrate and lipid metabolism by its actions to regulate glucose uptake, lipolysis and lipoprotein lipase activity. The findings suggest that pharmacological activation of GIPR may have a therapeutic benefit on peripheral energy metabolism. Recently, uni-molecular, multi-functional peptides that combine GLP-1RA activity with GIP activity have been suggested as new therapeutic agents for glycaemic and weight control.

United States Patent No. 9474780 discloses dual GLP-1 and GIP receptor agonists including tirzepatide.

Tirzepatide is under Phase-III clinical studies for T2DM and obesity.

WIPO publication numbers WO2017/74714A1, WO2020/23386A1, WO2020/023388A1, WO2015/067715A2, WO2016/111971A1 and WO2013/164483A1 disclose GLP-1 R and GIP R dual agonist compounds.

SUMMARY OF THE INVENTION

The present invention provides a polypeptide or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence:

Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-Xaa15-K-I-A-Xaa19-X3-Xaa21-F-V-Xaa24-W-L-X4- A-G-G-P-S-S-G-A-P-P-P-S-X5-X6-X7-X8-X9-X10-X11 (Seq. ID 1)

wherein X1 is Aib, (L)-norvaline or (D)-norvaline;

X2 is selected from Aib, Leu, (D)-Leu, Val , (D)-Val, Ile, (D)-Ile, and L or D isomer of an amino acid of Formula

, wherein represents the point of attachment to Leu and R is selected from

C2-5alkyl, C3-7cycloalkyl, C3-7cyclolalkyl-C1-3alkyl-, C3-5alkenyl, C3-5alkynyl, C5- 7cycloalkenyl-CH2-, and C1-3haloalkyl-; or R along with the carbon to which it is attached, forms a C3-6cycloalkyl ring;

X3 is Gln or Lys; wherein, when X3 is Lys, the side chain amino (Ɛ amino) group of Lys is acylated with a moiety:

{ U W Y Z

wherein U is –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} wherein } is point of attachment with group W;

W is selected from a group consisting of –C(O)-NH-(CH2)p-NH-], –C(O)-C(CH3)2-NH-] and –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], wherein p is 3 or 4 and wherein ] is point of attachment with group Y;

Y is–C(O)-(CH2)2-CH(COOH)NH-- and -- is point of attachment with the group Z;

Z is –C(O)-(CH2)n-COOH or –C(O)-(CH2)n-CH3 wherein n is an integer from 14 to 20; X4 is Leu, Ile or Glu;

X5 is absent, Arg or Lys; wherein when X5 is Lys, the side chain amino (Ɛ amino) group of Lys is acylated with a moiety:

{ U' W' Y' Z'

wherein U’ is –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} wherein } is point of attachment with group W’;

W’ is selected from a group consisting of –C(O)-NH-(CH2)q-NH-], –C(O)-C(CH3)2-NH-] and –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], wherein q is 3 or 4 and wherein ] is point of attachment with group Y’;

Y’ is–C(O)-(CH2)2-CH(COOH)NH-- and -- is point of attachment with the group Z’;

Z’ is –C(O)-(CH2)n-COOH or –C(O)-(CH2)m-CH3 wherein m is an integer from 14 to 20; X6 is absent or Lys;

X7 is absent or Lys;

X8 is absent or Lys;

X9 is absent or Lys;

X10 is absent or Lys;

X11 is absent or Lys;

Xaa15 is Asp or Glu;

Xaa19 is Gln or Ala;

Xaa21 is Ala or Glu;

Xaa24 is Gln or Asn;

wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide and at least one of X3 and X5 is Lys; and with the proviso that when X1 is Aib, X2 is not Aib.

ABBREVIATIONS

Aib: 2-Aminoisobutyric acid

’ i-isopropylethylamine

HOBt: 1-Hydroxybenztriazole

DIPC: N,N’-Di-isopropylcarbodiimide

THF: Tetrahydrofuran

DCM: Dichloromethane

DETAILED DESCRIPTION OF THE INVENTION “Pharmaceutically acceptable salt” according to the invention include acid addition salts formed with either organic or inorganic acids. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may be salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and the like or of organic acids such as, for example, acetic acid, benzenesulfonic acid, methanesulfonic

acid, benzoic acid, citric acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, amino acids such as glutamic acid or aspartic acid, and the like. The pharmaceutically acceptable acid addition salt of the compounds of the present invention includes salts formed with the addition of one or more equivalents of acids, for example, monohydrochloride, dihydrochloride salts, etc. Salts can be prepared by any process under the purview of an ordinary person skilled in the art. (See Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley-VCH and VHCA: Zurich, Switzerland, 2002.).

The term “alkyl” as used herein refers to a saturated hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, either linear or branched, having from 1 to 6 carbon atoms, both inclusive unless defined otherwise and which is attached to the rest of the molecule by a single bond. Suitable non-limiting examples of alkyl groups include, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-pentyl, n-hexyl, etc.

The term “haloalkyl” as used herein refers to any “alkyl” having one or more hydrogen atom(s) replaced by a halogen atom, wherein halogen atom may be selected from fluorine, chlorine, bromine or iodine.

The numerical in phrases like “C2-5”, refers to the number of carbon atoms in the chain. For example, the phrase “C2-5 alkyl” refers to an alkyl chain having 2 to 5 carbon atoms.

The term “alkenyl” as used herein refers to a hydrocarbon chain containing at least one carbon-carbon double bond, and may have (E) or (Z) configuration. An alkenyl group may contain 2 to 8 carbon atoms unless specified otherwise. Unless set forth or recited to the contrary, all alkenyl groups described herein may form part of a straight or branched chain. Suitable non-limiting examples of alkenyl groups include, e.g., ethylene, 2-propenyl (allyl), 2-methyl-2-propenyl and 2-butenyl.

The term “alkynyl” refers to a hydrocarbon chain having at least one carbon-carbon triple bond. An alkynyl group may contain 2 to 8 carbon atoms unless specified otherwise. Unless set forth or recited to the contrary all alkynyl groups described or claimed herein may form part of a straight or branched chains. The non-limiting examples of alkynyl groups include 2-propynyl, 3-butynyl and propargyl.

The term “cycloalkyl” as used herein refers to a non-aromatic monocyclic ring system of 3 to 7 carbon atoms unless specified otherwise. Cycloalkyl ring include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “cycloalkenyl” refers to a non-aromatic monocyclic 5 to 7 membered cycloalkyl ring system, with at least one carbon-carbon double bond. The non-limiting examples of cycloalkenylmethyl group includes cyclopentenylmethyl and cyclohexenylmethyl.
Claims:

1. A polypeptide or a pharmaceutically acceptable salt thereof comprising the amino acid sequence:

Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-Xaa15-K-I-A-Xaa19-X3-Xaa21-F-V-Xaa24- W-L-X4-A-G-G-P-S-S-G-A-P-P-P-S-X5-X6-X7-X8-X9-X10-X11 (Seq. ID 1) wherein X1 is Aib, (L)-norvaline or (D)-norvaline;

X2 is selected from Aib, Leu, (D)-Leu, Val, (D)-Val, Ile, (D)-Ile, and L or D isomer of an amino acid of the Formula

, wherein “ ” represents the point of attachment to Leu and R is selected from C2-5alkyl, C3-7cycloalkyl, C3-7cyclolalkyl-C1-3alkyl-, C3-5alkenyl, C3- 5alkynyl, C5-7cycloalkenyl-CH2- and C1-3haloalkyl; or R along with the carbon to which it is attached, forms a C3-6cycloalkyl ring;

X3 is Gln or Lys; wherein, when X3 is Lys, the side chain amino (Ɛ amino) group of Lys is acylated with a moiety:

{ U W Y Z

wherein U is –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} wherein } is point of attachment with group W;

W is selected from a group consisting of –C(O)-NH-(CH2)p-NH-], –C(O)-C(CH3)2- NH-] and –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], wherein p is 3 or 4 and wherein ] is point of attachment with group Y;

Y is–C(O)-(CH2)2-CH(COOH)NH-- and -- is point of attachment with the group Z; Z is –C(O)-(CH2)n-COOH or –C(O)-(CH2)n-CH3 wherein n is an integer from 14 to 20;

X4 is Leu, Ile or Glu;

X5 is absent, Arg or Lys; wherein when X5 is Lys, the side chain amino (Ɛ amino) group of Lys is acylated with a moiety:

{ U' W' Y' Z'

wherein U’ is –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} wherein } is point of attachment with group W’;

W’ is selected from a group consisting of –C(O)-NH-(CH2)q-NH-], –C(O)-C(CH3)2- NH-] and –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], wherein q is 3 or 4 and wherein ] is point of attachment with group Y’;

Y’ is–C(O)-(CH2)2-CH(COOH)NH-- and -- is point of attachment with the group Z’;

Z’ is –C(O)-(CH2)m-COOH or –C(O)-(CH2)m-CH3 wherein m is an integer from 14 to 20;

X6 is absent or Lys;

X7 is absent or Lys;

X8 is absent or Lys;

X9 is absent or Lys;

X10 is absent or Lys;

X11 is absent or Lys;

Xaa15 is Asp or Glu;

Xaa19 is Gln or Ala;

Xaa21 is Ala or Glu;

Xaa24 is Gln or Asn;

wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide and at least one of X3 and X5 is Lys; and

with the proviso that when X1 is Aib, X2 is not Aib.

2. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is Aib.

3. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is (L)-norvaline.

4. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, wherein X2 is Aib, Leu, Ile or L or D isomer of an amino acid of the Formula:

, wherein “
” represents the point of attachment to Leu, and R is selected from C2-5alkyl, C3-7cycloalkyl, C3-7cyclolalkyl-C1-3alkyl-, C3-5alkenyl, C3-5alkynyl, C5-7cycloalkenyl-CH2-, and C1-3haloalkyl; or R along with the Carbon to which it is attached to, forms C3-6cycloalkyl ring.

5. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 4, wherein R is C2-5alkyl.

6. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 5, wherein R is ethyl.

7. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 5, wherein R is n-propyl.

8. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 5, wherein R is n-butyl.

9. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 2, wherein X2 is L or D isomer of an amino acid of the Formula:

, wherein R is n-propyl.

10. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 3, wherein X2 is L or D isomer of an amino acid of the Formula:

, wherein R is n-propyl.

11. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 2, wherein X2 is L or D isomer of an amino acid of the Formula:

, wherein R is n-butyl.

12. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 2, wherein X2 is L or D isomer of an amino acid of the Formula:

, wherein R is ethyl.

13. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 3, wherein X2 is Aib.

14. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 2, wherein X2 is Leu.

15. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 2, wherein X2 is Ile.

16. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-15, wherein X5, X6, X7, X8, X9, X10 and X11 are absent.

17. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 2, wherein X2 is L or D isomer of an amino acid of the Formula:

, wherein R is n-propyl, and X5 is Arg.

18. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, comprising an amino acid sequence:

Y-Aib-E-G-T-F-T-S-D-Y-S-I-X2-L-D-K-I-A-Q-X3-A-F-V-Q-W-L-X4-A-G-G-P- S-S-G-A-P-P-P-S-X5-X6-X7-X8-X9-X10-X11 (Seq. ID 2)

wherein X2 is Leu, Ile, (L)-norvaline, (L)-homoalanine or (L)-norleucine;

X3 is Lys, wherein the side chain amino (Ɛ amino) group of Lys is acylated with a moiety:

{ U W Y Z

wherein U is –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} wherein } is point of attachment with group W;

W is selected from a group consisting of –C(O)-NH-(CH2)p-NH-], –C(O)-C(CH3)2- NH-] and –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], wherein p is 3 or 4 and wherein ] is point of attachment with group Y;

Y is–C(O)-(CH2)2-CH(COOH)NH-- and -- is point of attachment with the group Z; Z is –C(O)-(CH2)n-COOH or –C(O)-(CH2)n-CH3 wherein n is an integer from 14 to 20;

X4 is Ile;

X5 is absent or Arg;

X6 is absent or Lys;

X7 is absent or Lys;

X8 is absent or Lys;

X9 is absent or Lys;

X10 is absent or Lys;

X11 is absent or Lys;

wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide.

19. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 18, wherein X2 is (L)-norvaline.

20. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 18, wherein X2 is (L)-norleucine.

21. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 18, wherein X2 is (L)-homoalanine.

22. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 18, wherein X2 is Leu.

23. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 18, wherein X2 is Ile.

24. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 18-23, wherein X5, X6, X7, X8, X9, X10 and X11 are absent.

25. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 19, wherein X5 is Arg.

26. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 19, wherein X4 is Ile;

X5, X6, X7, X8, X9, X10 and X11 are absent;

W is–C(O)-C(CH3)2-NH-]; and

Z is –C(O)-(CH2)n-COOH, wherein n is 18.

27. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, comprising an amino acid sequence:

Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-D-K-I-A-Q-X3-A-F-V-Q-W-L-X4-A-G-G-P- S-S-G-A-P-P-P-S (Seq. ID 3)

wherein X1 is Aib or (L)-norvaline; X2 is Aib, Leu, Ile, (L)-norvaline, (L)- homoalanine or (L)-norleucine;

X4 is Ile;

X3 is Lys wherein the side chain amino (Ɛ amino) group of Lys is acylated with a moiety:

{ U W Y Z

wherein U is –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} wherein } is point of attachment with group W;

W is selected from a group consisting of –C(O)-NH-(CH2)p-NH-], –C(O)-C(CH3)2- NH-] and –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], wherein p is 3 or 4 and wherein ] is point of attachment with group Y;

Y is–C(O)-(CH2)2-CH(COOH)NH-- and -- is point of attachment with the group Z; Z is –C(O)-(CH2)n-COOH or –C(O)-(CH2)n-CH3 wherein n is an integer from 14 to 20;

and wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide;

with a proviso that when X1 is Aib, X2 is not Aib.

28. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is Aib.

29. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is (L)-norvaline.

30. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X2 is Aib.

31. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X2 is Leu.

32. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X2 is Ile.

33. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X2 is (L)-norvaline.

34. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X2 is (L)-norleucine.

35. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X2 is (L)-homoalanine.

36. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is Aib and X2 is (L)-norvaline.

37. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 and X2 are (L)-norvaline.

38. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is Aib and X2 is (L)-norleucine.

39. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is Aib and X2 is (L)-homoalanine.

40. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is (L)-norvaline and X2 is Aib.

41. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is Aib and X2 is Leu.

42. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is Aib and X2 is Ile.

43. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 27, wherein X1 is Aib;

X2 is (L)-norvaline;

W is–C(O)-C(CH3)2-NH-]; and

Z is –C(O)-(CH2)n-COOH, wherein n is 18.

44. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-43, wherein W and/or W’ is –C(O)-C(CH3)2-NH-] or –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-].

45. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-43, wherein Z and/or Z’ is –C(O)-(CH2)n-COOH and/or –C(O)-(CH2)m-COOH and n or m is 16 or 18.

46. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-43, wherein W and/or W’ is –C(O)-C(CH3)2-NH-], Z and/or Z’ is –C(O)-(CH2)n-COOH and/or –C(O)-(CH2)m-COOH and n or m is 18.

47. The polypeptide or pharmaceutically acceptable salt thereof according to any one of the claims 1-43, wherein W and/or W’ is –C(O)-C(CH3)2-NH-], Z and/or Z’ is –C(O)-(CH2)n-COOH and/or –C(O)-(CH2)m-COOH and n or m is 16.

48. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-25 and 27 to 42, wherein W and/or W’ is –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], Z and/or Z’ is –C(O)-(CH2)n-COOH and/or –C(O)-(CH2)m-COOH and n or m is 16.

49. The polypeptide or pharmaceutically acceptable salt thereof according to any one of the claims 1-25 and 27 to 42, wherein W and/or W’ is –C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], Z and/or Z’ is –C(O)-(CH2)n-COOH and/or –C(O)-(CH2)m-COOH and n or m is 18. 50. The polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, comprising an amino acid sequence selected from the group consisting of:

i.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norvaline Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (Seq ID: 04)

ii.) Tyr L-norvaline Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (Seq ID: 05)

iii.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (Seq ID: 06)

iv.) Tyr L-norvaline Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norvaline Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (Seq ID: 07)

v.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norvaline Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys-NH2 (Seq ID: 08)

vi.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norvaline Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Arg (Seq ID: 09)

vii.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-homoalanine Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (Seq ID: 10)

viii.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norleucine Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (Seq ID: 11)

ix.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ile Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (Seq ID: 12)

51. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-50, wherein -U-W-Y-Z and/or -U’-W’-Y’-Z’ is selected from the group consisting of:

52. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-51, wherein the C terminal amino acid is amidated as a C-terminal primary amide.

53. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-51, wherein the C terminal amino acid is a free carboxylic acid.

54. A polypeptide or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

Compound 1:

Moiety B is

Moiety D is

55. A pharmaceutical composition comprising a polypeptide or a pharmaceutically acceptable salt thereof according to any one of the claims 1-54, and one or more of pharmaceutically acceptable excipient.

56. A pharmaceutical composition according to claim 55 for use as a medicament. 57. A pharmaceutical composition according to claim 55 for use in the treatment or prevention of a disease in a patient.

58. A pharmaceutical composition for use according to claim 57, wherein said disease is selected from the group consisting of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers.

59. A pharmaceutical composition for use according to claims 56-58, wherein said pharmaceutical composition is provided simultaneously, separately, or sequentially in combination with an effective amount of one or more additional therapeutic agents.

60. A method of treating or preventing hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers in a patient, wherein said method comprises administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 55.

61. The method according to claim 60, further comprising administering simultaneously, separately, or sequentially in combination with an effective amount of one or more therapeutic agents.

62. A pharmaceutical composition according to claim 55, for use in the preparation of a medicament for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers.

63. A polypeptide or a pharmaceutically acceptable salt thereof according to any one of claims 1-54 for use as a medicament.

64. A polypeptide or a pharmaceutically acceptable salt thereof according to any one of claims 1-54 for use in the treatment or prevention of a disease in a patient.

65. A polypeptide or a pharmaceutically acceptable salt thereof for use according to claim 64, wherein said disease is selected from the group consisting of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers.

66. The polypeptide or a pharmaceutically acceptable salt thereof according to claims 63-65, wherein said polypeptide or pharmaceutically acceptable salt thereof is provided simultaneously, separately, or sequentially in combination with an effective amount of one or more additional therapeutic agents.

67. A method of treating or preventing hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers in a patient, comprising administering to a patient in need thereof, an effective amount of the polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-54.

68. The method according to any one of claims 67, further comprising administering simultaneously, separately, or sequentially in combination with an effective amount of one or more therapeutic agents.

69. The polypeptide or a pharmaceutically acceptable salt thereof according to any one of claims 1-54, for use in the preparation of a medicament for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers.