GIP agonist compounds and methods

1. A GIP analogue represented by the general Formula I:

R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R 2   (I) (SEQ ID NO: 42)

wherein

R 1 is H—, Ac or pGlu;

X2 is Aib or D-Ala;

X10 is Tyr;

X11 is Ser;

X12 is Ψ or Ile;

X15 is Asp or Glu;

X16 is Lys or Ψ;

X17 is Ile or Ψ;

X18 is His or Ala;

X19 is Gln or Ala;

X20 is Gln, Lys, or Arg;

X21 is Ala, Asp or Glu;

X23 is Val or Ile;

X24 is Asn or Glu;

X25 is Tyr or Trp;

X27 is Leu;

X28 is Ala;

X29 is Ala, Gln, Thr, Ser or Lys or is absent;

Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 43), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 46), or absent;

Y2 is Ψ or is absent;

R 2 is —NH 2 or —OH;

wherein Ψ is a Lys residue and wherein the side chain of said Lys residue is conjugated to a lipophilic substituent;

wherein the GIP analogue contains one and only one residue Ψ;

and wherein the GIP analogue has agonist activity at the GIP receptor;

or a pharmaceutically acceptable salt thereof.

2. A GIP analogue according to claim 1 comprising one of the following residues or combinations of residues:

Aib2, Asp15, Lys20;

Aib2, Asp15, Arg20;

Aib2, Asp15, Arg20, Ile23;

Aib2, Ile12, Asp15, Arg20, Ile23, Glu24;

Ile12, Asp15, Ile23;

Ile12, Asp15, Ile23 Glu24;

Ile12, Asp15, Ala21, Ile23;

Aib2, Ala21, Ile23, Glu24;

Aib2, Asp15, Ile23;

Aib2, Asp15, Arg20, Ile23, Gln29;

DAla2, Asp15, Ile23;

Aib2, Asp15, Ile17, Lys20, Ala28;

Asp15, Ile23, Glu24.

3. A GIP analogue according to claim 1 represented by the general Formula III:

R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Y1-Y2-R 2   (III) (SEQ ID NO: 50)

wherein

R 1 is H—, Ac or pGlu;

X15 is Asp or Glu;

X16 is Lys or Ψ;

X17 is Ile or Ψ;

X18 is His or Ala X19 is Gln or Ala;

X20 is Gln, Lys or Arg;

X21 is Ala, Asp or Glu;

X24 is Asn or Glu;

X25 is Tyr or Trp

X29 is Gln or is absent;

Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 43), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 46), or absent;

Y2 is Ψ or is absent;

R 2 is —NH 2 or —OH;

wherein Ψ is a Lys residue and wherein the side chain of said Lys residue is conjugated to a lipophilic substituent;

and wherein the GIP analogue contains one and only one residue Ψ;

and wherein the GIP analogue has agonist activity at the GIP receptor;

or a pharmaceutically acceptable salt thereof.

4. A GIP analogue according to claim 3 comprising one of the following residues or combinations of residues:

Asp15, Lys20;

Asp15, Arg20;

Asp15, Arg20, Glu24;

Asp15, Lys16;

Asp15, Lys16, Glu24;

Asp15, Ψ16, Ala21;

Ala21, Glu24;

Asp15, Arg20, Gln29;

Asp15, Arg20, Gly29;

Asp15, Ile17, Arg20, Gly29;

Asp15, Ile17, Lys20, Gly29;

Asp15, Ala28;

Asp15, Ile17, Lys20, Ala28;

Asp15, Ile23, Glu24;

Asp15, Ψ17, Lys20;

Asp15, Ψ17, Arg20;

Asp15 , Ψ17, Arg20

Asp15, Ψ17, Arg20, Glu24;

Asp15, Lys 16, Ψ17;

Asp15, Lys 16, Ψ17, Glu24;

Asp15 , Ψ17, Ala21;

Ala21, Ψ17, Glu24;

Asp15, Asp15 , Ψ17, Arg20, Gln29;

Asp15 , Ψ17, Arg20, Gly29;

Asp15, Ile17, Arg20, Gly29;

Asp15, Ile17, Lys20, Gly29;

Asp15; Ψ17;

Asp15, Ψ17, Ala28;

Asp15, Ile17, Lys20, Ala28;

Asp15 , Ψ17, Ile23, Glu24.

5. A GIP analogue according to claim 1 , wherein Ψ is a Lys in which the side chain is conjugated to a substituent having the formula —Z 1 or —Z 2 —Z 1 .

6. A GIP analogue according to claim 5 , wherein —Z 1 is a fatty chain having at a terminus a connection —X— to Ψ or to Z 2 ;

wherein —X— is a bond, —CO—, —SO—, or —SO 2 —;

and, optionally, Z 1 has a polar group at the end of the chain distal from connection —X—; said polar group comprising a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group.

7. A GIP analogue according to claim 6 wherein Z 1 is a group of formula:

A-B-Alk-X— wherein A is hydrogen or a carboxylic acid, a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; B is a bond or a linker; X is a bond, acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO 2 —);

and Alk is a fatty chain that may be optionally substituted with one or more substituents.

8. A GIP analogue according to claim 7 , wherein Z 1 is:

A-B—C 16-20 alkylene-(CO)— wherein A is H or —COOH and B is

17-carboxy-heptadecanoyl HOOC—(CH 2 ) 16 —(CO)—;

19-carboxy-nonadecanoyl HOOC—(CH 2 ) 18 —(CO)—;

Octadecanoyl H 3 C—(CH 2 ) 16 —(CO)—; or

Eicosanoyl H 3 C—(CH 2 ) 18 —(CO)—.

9. A GIP analogue according to claim 5 , wherein Z 2 is a spacer bound at one terminus by Y, which is a nitrogen, oxygen or sulfur atom, and at the other terminus by X, which is a bond or an acyl (—CO—), sulfinyl (—SO—), sulfonyl (—SO 2 —) or absent.

10. A GIP analogue according to claim 5 , wherein —Z 1 -Z 2 is:

11. A GIP analogue according to claim 1 having the sequence

(SEQ ID NO: 51)

Y-Aib-EGTFISDYSIELDKΨHQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 52)

Y-Aib-EGTFISDYSIELDΨIHQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 53)

Y-Aib-EGTFISDYSIELEKΨHQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 54)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPSΨ;

(SEQ ID NO: 55)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQΨ;

(SEQ ID NO: 56)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKGΨ;

(SEQ ID NO: 57)

Y-Aib-EGTFISDYSIELDKΨHQQDFVNYLLAQGPSSGAPPPS;

(SEQ ID NO: 58)

Y-Aib-EGTFISDYSIELDKΨHQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 69)

Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 60)

Y-Aib-EGTFISDYSIELEKΨAAKEFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 61)

Y-Aib-EGTFISDYSIELEKΨAQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 62)

Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPSΨ;

(SEQ ID NO: 63)

Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQΨ;

(SEQ ID NO: 64)

Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAGPSSGAPPPS;

(SEQ ID NO: 65)

Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPSΨ;

(SEQ ID NO: 66)

Y-Aib-EGTFISDYSIELDKKΨAQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 67)

Y-Aib-EGTFISDYSIELDKKΨAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 68)

Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 69)

Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 70)

Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 71)

Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 72)

Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPSKΨ;

(SEQ ID NO: 73)

Y-Aib-EGTFISDYSIELDKKΨAAQAFVNWLLAGPSSGAPPPS;

(SEQ ID NO: 74)

Y-Aib-EGTFISDYSIELDKKΨAAQDFVNWLLAAGPSSGAPPPS,

(SEQ ID NO: 75)

Y-Aib-EGTFISDYSIELDKKΨAAQDFINWLLAGPSSGAPPPS,

(SEQ ID NO: 76)

Y-Aib-EGTFISDYSIELDKKΨAAQDFIEWLLAGPSSGAPPPS,

(SEQ ID NO: 77)

Y-Aib-EGTFISDYSIELDKKΨAAQDFIEWLLAGPSSGAPPPS,

(SEQ ID NO: 78)

Y-Aib-EGTFISDYSIELDKΨIAQRAFIEWLLAQGPSSGAPPPS,

(SEQ ID NO: 79)

Y-Aib-EGTFISDYSKΨELDKIAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 80)

Y-DAla-EGTFISDYSIELDKKΨAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 81)

Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 82)

Y-Aib-EGTFISDYSIELDKKΨAAQDFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 83)

Y-Aib-EGTFISDYSIELDKKΨAAQDFINWLLAQGPSSGAPPPS, 

or

(SEQ ID NO: 84)

Y-Aib-EGTFISDYSIELDKKΨAAQAFIEWLLAQGPSSGAPPPS.

12. A GIP analogue according to claim 1 having the sequence

Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)-HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 1);

Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)-IHQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 2);

Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)-HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 3);

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3) (SEQ ID NO: 4);

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K(Hexadecanoyl-isoGlu) (SEQ ID NO: 5);

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQ-K(Hexadecanoyl-isoGlu) (SEQ ID NO: 6);

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-K(Hexadecanoyl-isoGlu) (SEQ ID NO: 7);

Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

HQQDFVNYLLAQGPSSGAPPPS (SEQ ID NO: 8);

Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 9);

Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 10);

Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAKEFVNWLLAQGPSSGAPPPS (SEQ ID NO: 11);

Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 12);

Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPS-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3) (SEQ ID NO: 13);

Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-

Peg3) (SEQ ID NO: 14);

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAGPSSGAPPPS (SEQ ID NO: 15);

Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPS-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3) (SEQ ID NO: 16);

Y-A1b-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 17);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 18);

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 19);

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 20);

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AQKEFVEWLLAAGPSSGAPPPS (SEQ ID NO: 21);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQKEFVEWLLAAGPSSGAPPPS (SEQ ID NO: 22);

Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3) (SEQ ID NO: 23);

Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3) (SEQ ID NO: 24);

Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3) (SEQ ID NO: 25);

Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy-nonadecanoyl)-

[(Piperazine-1-yl)-acetyl]-Peg3-Peg3) (SEQ ID NO: 26);

Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3) (SEQ ID NO: 27);

Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3) (SEQ ID NO: 28);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyn-isoGlu-Peg3-Peg3)-

AAQAFVNWLLAGPSSGAPPPS (SEQ ID NO: 29);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAAGPSSGAPPPS (SEQ ID NO: 30);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFINWLLAGPSSGAPPPS (SEQ ID NO: 31);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFIEWLLAGPSSGAPPPS (SEQ ID NO: 32);

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AAQDFIEWLLAGPSSGAPPPS (SEQ ID NO: 33);

Y-Aib-EGTFISDYSIELD-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

IAQRAFIEWLLAQGPSSGAPPPS; (SEQ ID NO: 34)

Y-Aib-EGTFISDYS-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

ELDKIAQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 35);

Y-DAla-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 36);

Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy-nonadecanoyl)-

[(Piperazine-1-yl)-acetyl]-Peg3-Peg3) (SEQ ID NO: 37);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFIEWLLAQGPSSGAPPPS (SEQ ID NO: 38);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFINWLLAQGPSSGAPPPS (SEQ ID NO: 39);

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 40);

or

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AAQAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 41).

13. A GIP analogue according to claim 1 which is:

(SEQ ID NO: 1)

H-Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)-HQQDFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 2)

H-Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)-IHQQDFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 3)

H-Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)-HQQDFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 4)

H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 5)

H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K(Hexadecanoyl-isoGlu)-NH 2 ;

(SEQ ID NO: 6)

H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQ-K(Hexadecanoyl-isoGlu)-NH 2 ;

(SEQ ID NO: 7)

H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-K(Hexadecanoyl-isoGlu)-NH 2 ;

(SEQ ID NO: 8)

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

HQQDFVNYLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 9)

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

HQQDFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 10)

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 11)

H-Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAKEFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 12)

H-Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 13)

H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPS-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 14)

H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-

Peg3)-NH 2 ;

(SEQ ID NO: 15)

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 16)

H-Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPS-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 17)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 18)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 19)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AQRAF1EWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 20)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AQRAFVEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 21)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AQKEFVEWLLAAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 22)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQKEFVEWLLAAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 23)

H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 24)

H-Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 25)

H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 26)

H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy-nonadecanoyI)-

[(Piperazine-1-yl)-acetyl]-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 27)

H-Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 28)

H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 29)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQAFVNWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 30)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 31)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFINWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 32)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFIEWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 33)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AAQDFIEWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 34)

H-Y-Aib-EGTFISDYSIELD-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

IAQRAFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 35)

H-Y-Aib-EGTFISDYS-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

ELDKIAQRAFIEWLLAQGPSSGAPPPS-NH 2;; ;

(SEQ ID NO: 36)

H-Y-DAla-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 37)

H-Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy-nonadecanoyl)-

[(Piperazine-1-yl)-acetyl]-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 38)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 39)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFINWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 40)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQAFIEWLLAQGPSSGAPPPS-NH 2 ; 

and or

(SEQ ID NO: 41)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2;.

14. A pharmaceutical composition comprising a GIP analogue according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a carrier.

15. A method of treating a metabolic disorder in an individual in need thereof, comprising administering to said individual a GIP analogue according to claim 1 , or a pharmaceutically acceptable salt thereof.

16. The method according to claim 15 wherein the metabolic disorder is diabetes, a diabetes related disorder, obesity, or an obesity related disorder.

17. The method according to claim 16 wherein the diabetes related disorder is selected from the group consisting of insulin resistance, glucose intolerance, increased fasting glucose, hypoglycemia (for example induced by insulin treatment), pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension and dyslipidemia.

18. The method according to claim 16 wherein the obesity related disorder is selected from the group consisting of obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, a proinflammatory state, and combinations thereof.