Novel analogues of glucose-dependent insulinotropic polypeptide

1 . A novel GIP analogue which codes an amino acid sequence shown by formula 1:

(SEQ ID NO: 49)

Tyr-A-B-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-

(1)

Ala-Met

wherein A and B are amino acid residues including D-amino acid residues, N-methylated amino acid residues and any other non-proteinogenic amino acid residues or a pharmaceutically acceptable salt thereof, excluding the sequence of native GIP (1-14).

2 . A novel GIP analogue according to claim 1 , wherein the N-terminus of the tyrosine residue in position 1 can be modified by alkylation, sulphonylation, glycation, homoserine formation, pyroglutamic acid formation, disulphide bond formation, deamidation of asparagine or glutamine residues, methylation, t-butylation, t-butyloxycarbonylation, 4-methylbenzylation, thioanysilation, thiocresylation, bencyloxymethylation, 4-nitrophenylation, bencyloxycarbonylation, 2-nitrobencoylation, 2-nitrosulphenylation, 4-toluenesulphonylation, pentafluorophenylation, diphenylmethylation, 2-chlorobenzyloxycarbonylation, 2,4,5-trichlorophenylation, 2-bromobenzyloxycarbonylation, 9-fluorenylmethyloxycarbonylation, triphenylmethylation, 2,2,5,7,8,-pentamethylchroman-6-sulphonylation, hydroxylation, oxidation of methionine, formylation, acetylation, anisylation, bencylation, bencoylation, trifluoroacetylation, carboxylation of aspartic acid or glutamic acid, phosphorylation, sulphation, cysteinylation, glycolysation with pentoses, deoxyhexoses, hexosamines, hexoses or N-acetylhexosamines, farnesylation, myristolysation, biotinylation, palmitoylation, stearoylation, geranylgeranylation, glutathionylation, 5′-adenosylation, ADP-ribosylation, modification with N-glycolylneuraminic acid, N-acetylneuraminic acid, pyridoxal phosphate, lipoic acid, 4′-phosphopantetheine, and N-hydroxysuccinimide.

3 . A novel GIP analogue according to claim 1 , wherein the peptide is modified by the introduction of at least one 6-amino fatty acid acylated lysine in any amino acid position.

4 . A compound according to claim 1 having the amino acid sequence:

(SEQ ID NO: 21)

Tyr-(D-Ala)-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-

Ile-Ala-Met.

5 . A compound according to claim 1 having the amino acid sequence:

(SEQ ID NO: 20)

Tyr-Ala-Pro-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-

Ala-Met.

6 . GIP analogues having the amino acid sequences and comprising a reduced peptide bond:

(SEQ ID NO: 19)

Tyr-Ala-Ψ(CH 2 NH 2 )-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-

Ser-Ile-Ala-Met;

(SEQ ID NO: 11)

Tyr-Ala-Ψ(CH 2 NH)-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-

Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-

Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys;

and

pharmaceutically acceptable salts thereof.

7 . A GIP analogue having the amino acid sequence:

(SEQ ID NO: 51)

Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-

Tyr-Met

or a pharmaceutically acceptable salt thereof.

8 . GIP analogues having the amino acid sequences:

(SEQ ID NO: 52)

Ala-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-

Ala-Met,

(SEQ ID NO: 53)

Tyr-Ala-Ala-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-

Ala-Met;

(SEQ ID NO: 54)

Tyr-Ala-Glu-Ala-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-

Ala-Met;

(SEQ ID NO: 55)

Tyr-Ala-Glu-Gly-Ala-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-

Ala-Met;

(SEQ ID NO: 56)

Tyr-Ala-Glu-Gly-Thr-Ala-Ile-Ser-Asp-Tyr-Ser-Ile-

Ala-Met;

(SEQ ID NO: 57)

Tyr-Ala-Glu-Gly-Thr-Phe-Ala-Ser-Asp-Tyr-Ser-Ile-

Ala-Met;

(SEQ ID NO: 58)

Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ala-Asp-Tyr-Ser-Ile-

Ala-Met;

(SEQ ID NO: 59)

Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Ala-Tyr-Ser-Ile-

Ala-Met;

(SEQ ID NO: 60)

Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Ala-Ser-Ile-

Ala-Met;

(SEQ ID NO: 61)

Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ala-Ile-

Ala-Met;

(SEQ ID NO: 62)

Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ala-

Ala-Met;

(SEQ ID NO: 63)

Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-

Ala-Ala;

and

or a pharmaceutically acceptable salt thereof.

9 . GIP analogues having the amino acid sequence and comprising linker peptides:

(SEQ ID NO: 64)

Tyr-A-B-Gly-Thr-Phe-C-Gln-Gln-Asp-Phe-Val-Asn-Trp-

Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Trp-Lys-

His-Asn-Ile-Thr-Gln;

wherein C is

a) not used,

b) a linker peptide comprising 4 amino acid residues selected from the group consisting of amino acid residues, D-amino acids and non-proteinogenic amino acids, is allowed and within the scope of the present invention,

c)

Glu-Lys-Glu-Lys,

(SEQ ID NO: 65)

d)

Ala-Ala-Ala-Ala,

(SEQ ID NO: 66)

e) a linker peptide comprising 12 amino acid residues selected from the group consisting of amino acid residues, D-amino acids and non-proteinogenic amino acids,

f) Glu-Lys-Glu-Glu-Lys-Glu-Lys-Glu-Glu-Lys-Glu-Lys, (SEQ ID NO: 67)

g) 6-Ahx n (6-aminohexanoic acid) with n=1-3, or

h) Omega-amino fatty acids (saturated and unsaturated) of ω-NH 2 —(CHx)n-COOH with n=10-34; and

wherein A and B are amino acid residues, D-amino acid residues, N-methylated amino acid residues or any other non-proteinogenic amino acid residues; and

pharmaceutically acceptable salts thereof.

10 . A GIP analogue according to claim 9 , wherein the N-terminus of the tyrosine residue in position 1 can be modified by alkylation, sulphonylation, glycation, homoserine formation, pyroglutamic acid formation, disulphide bond formation, deamidation of asparagine or glutamine residues, methylation, t-butylation, t-butyloxycarbonylation, 4-methylbenzylation, thioanysilation, thiocresylation, bencyloxymethylation, 4-nitrophenylation, bencyloxycarbonylation, 2-nitrobencoylation, 2-nitrosulphenylation, 4-toluenesulphonylation, pentafluorophenylation, diphenylmethylation, 2-chlorobenzyloxycarbonylation, 2,4,5-trichlorophenylation, 2-bromobenzyloxycarbonylation, 9-fluorenylmethyloxycarbonylation, triphenylmethylation, 2,2,5,7,8,-pentamethylchroman-6-sulphonylation, hydroxylation, oxidation of methionine, formylation, acetylation, anisylation, bencylation, bencoylation, trifluoroacetylation, carboxylation of aspartic acid or glutamic acid, phosphorylation, sulphation, cysteinylation, glycolysation with pentoses, deoxyhexoses, hexosamines, hexoses or N-acetylhexosamines, farnesylation, myristolysation, biotinylation, palmitoylation, stearoylation, geranylgeranylation, glutathionylation, 5′-adenosylation, ADP-ribosylation, modification with N-glycolylneuraminic acid, N-acetylneuraminic acid, pyridoxal phosphate, lipoic acid, 4′-phosphopantetheine, and N-hydroxysuccinimide.

11 . A GIP analogue according to claim 10 , wherein the peptide is modified by the introduction of at least one ε-amino fatty acid acylated lysine in any amino acid position.

12 . A novel GIP analogue according to claim 10 , wherein the peptide is modified by introduction of a reduced peptide bond or any other modification of the peptide bond between A and B.

13 . Novel GIP analogues having the amino acid sequence and comprising linker peptides:

(SEQ ID NO: 68)

Tyr-A-B-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-

Met-D-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-

Lys-Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-

Gln

wherein D is

a) unused,

b) a linker peptide comprising 4 amino acid residues selected from the group consisting of amino acid residues, D-amino acids and non-proteinogenic amino acids,

c) Ala-Ala-Ala-Ala, (SEQ ID NO: 66)

d) Glu-Lys-Glu-Lys, (SEQ ID NO: 65)

e) 6-Ahx n (6-aminohexanoic acid) with n=1-3, or

f) an omega-amino fatty acid (saturated and unsaturated) of ω-NH 2 —(CHx)n-COOH with n=10-34; and

wherein A and B are amino acid residues, D-amino acid residues, N-methylated amino acid residues or any other non-proteinogenic amino acid residues; and

pharmaceutically acceptable salts thereof.

14 . A GIP analogue according to claim 13 , wherein the N-terminus of the tyrosine residue in position 1 can be modified by alkylation, acetylation or glycation.

15 . A GIP analogue according to claim 13 , wherein the peptide is modified by the introduction of at least one ε-amino fatty acid acylated lysine in any amino acid position.

16 . A GIP analogue according to claim 13 , wherein the peptide is modified by introduction of a reduced peptide bond or other modification of the peptide bond between A and B.

17 . GIP analogues having the amino acid sequences and comprising a phosphorylated seryl residue:

(SEQ ID NO: 69)

Tyr-[Ser(P)]-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-

Ile-Ala-Met,

(SEQ ID NO: 70)

Tyr-[Ser(P)]-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-

Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-

Asn-Trp-Leu-Leu-Ala-Gln-Lys,

(SEQ ID NO: 71)

Tyr-[Ser(P)]-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-

Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-

Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-

Trp-Lys-His-Asn-Ile-Thr-Gln;

and

pharmaceutically acceptable salts thereof.

18 . A compound having the amino acid sequence:

a pharmaceutically acceptable salt thereof.

19 . A compound according to claim 1 in free carboxylic acid form or a pharmaceutically acceptable salt thereof.

20 . A compound according to claim 1 in amid form or a pharmaceutically acceptable salt thereof.

21 . A compound according to claim 1 characterized in that the compound is resistant to the degradation by dipeptidyl peptidase IV or dipeptidyl peptidase IV-like enzyme activity.

22 . A compound according to claim 1 characterized in that the compound is a GIP-receptor agonist.

23 . A compound according to claim 1 characterized in that the compound is a GIP-receptor antagonist.

24 . A compound according to claim 1 characterized in that the compound potentiates cyclic AMP production.

25 . A compound according to claim 1 characterized in that the compound blocks the activation of caspase-3.

26 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable acid addition salt thereof.

27 . Use of a compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for GIP-receptor binding for the prevention or treatment of diseases or conditions related to impaired binding of GIP-receptor analogues.

28 . Use according to claim 27 for the manufacture of a medicament for the prevention or treatment of β-cell apoptosis.

29 . Use according to claim 27 for the manufacture of a medicament for the potentiation of glucose dependent proliferation of pancreatic β-cells

30 . Use according to claim 27 for the manufacture of a medicament for the treatment of non-insulin-dependent diabetes mellitus and obesity.

31 . A method for treating conditions mediated by GIP-receptor binding comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1 .

32 . A method for lowering elevated blood glucose levels in mammals resulting from food intake comprising administering a therapeutically effective amount of at least one compound according to claim 1.