GIP-GLP-1 dual agonist compounds and methods
View Patent ↗The present invention relates to acylated GIP analogs which have dual GIP and GLP-1 activity, and their use in the treatment of metabolic disorders.
1. A GIP analogue having the general Formula I:
R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Ile-X13-Leu-X15-X16-Ψ-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-R 2 (SEQ ID NO: 56) (I)
wherein
R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
X2 is selected from Aib and D-Ala;
X10 is selected from Tyr and Leu;
X13 is selected from Ala, Tyr and Aib;
X15 is selected from Asp and Glu;
X16 is selected from Glu and Lys;
X19 is selected from Gln and Ala;
X20 is selected from Lys and Arg;
X21 is selected from Ala and Glu;
X23 is selected from Val and Ile;
X24 is selected from Asn and Glu;
X27 is selected from Leu, Glu and Val;
X28 is selected from Ala, Ser and Arg;
X29 is selected from Aib, Ala, and Gln;
X30 is selected from Lys, Gly and Y1, or is absent;
Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 57), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 58), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 59), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 60) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 61);
Ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —Z 2 -Z 1 , wherein Z 2 -Z 1 is:
and
R 2 is —NH 2 or —OH
or a pharmaceutically acceptable salt thereof.
2. A GIP analogue having the general Formula Ib:
(SEQ ID NO: 56) (Ib)
R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Ile-
X13-Leu-X15-X16-Ψ-Ala-X19-X20-X21-Phe-X23-X24-Trp-
Leu-X27-X28-X29-X30-R 2
wherein
R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
X2 is selected from Aib and D-Ala;
X10 is selected from Tyr and Leu;
X13 is selected from Ala, Tyr and Aib;
X15 is selected from Asp and Glu;
X16 is selected from Glu and Lys;
X19 is selected from Gln and Ala;
X20 is selected from Lys and Arg;
X21 is selected from Ala and Glu;
X23 is selected from Val and Ile;
X24 is selected from Asn and Glu;
X27 is selected from Leu, Glu and Val;
X28 is selected from Ala, Ser and Arg;
X29 is selected from Aib, Ala, Glu and Gln;
X30 is selected from Lys, Gly and Y1, or is absent;
Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 57), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 58), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 59), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 60) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 61);
Ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —Z 2 -Z 1 , wherein Z 2 -Z 1 is:
and
R 2 is —NH 2 or —OH;
or a pharmaceutically acceptable salt thereof.
3. The GIP analogue according to claim 2 , having the general Formula II:
(SEQ ID NO: 62) (II)
R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-
X13-Leu-X15-Glu-Ψ-Ala-Ala-Arg-X21-Phe-X23-X24-Trp-
Leu-Leu-X28-X29-X30-R 2
wherein
R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
X2 is selected from Aib and D-Ala;
X13 is selected from Ala, Tyr;
X15 is selected from Asp and Glu;
X21 is selected from Ala and Glu;
X23 is selected from Val and Ile;
X24 is selected from Asn and Glu;
X28 is selected from Ala, Ser;
X29 is selected from Ala, Glu and Gln; and
X30 is selected from Lys, Gly and Y1, or is absent;
Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 57), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 58), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 59), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 60) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 61);
Ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —Z 2 -Z 1 , wherein Z 2 -Z 1 is:
and
R 2 is —NH 2 or —OH;
or a pharmaceutically acceptable salt thereof.
4. A GIP analogue of claim 1 , comprising one of the following residues or combinations of residues:
Gln19, Arg20, Ala21;
Aib2, Gln19, Arg20, Ala21;
Aib2, Ala13, Gln19, Arg20, Ala21;
Asp15, Gln19, Arg20, Ala21;
Lys16, Gln19, Arg20, Ala21;
Aib2, Ala13, Asp15, Gln19, Arg20, Ala21;
Aib2, Asp15, Gln19, Arg20, Ala21;
Aib2, Lys16, Gln19, Arg20, Ala21;
Aib2, Asp15, Lys16, Gln19, Arg20, Ala21;
Leu27, Ala28, Gln29;
Glu24, Leu27, Ala28, Gln29;
Gln19, Arg20, Ala21; Leu27, Ala28, Gln29;
Gln19, Arg20, Ala21; Glu24, Leu27, Ala28, Gln29;
Asp15, Gln19, Arg20, Ala21;
Glu15, Gln19, Arg20, Ala21;
Aib2, Glu15, Gln19, Arg20, Ala21;
Aib2, Glu15, Lys16, Gln19, Arg20, Ala21;
Glu15, Leu27, Ala28, Gln29;
Glu15, Gln19, Arg20, Ala21; Leu27, Ala28, Gln29;
Glu15, Gln19, Arg20, Ala21, Glu24;
Aib2, Glu15, Gln19, Arg20, Ala21, Glu24;
Aib2, Ala13, Asp15, Gln19, Arg20, Ala21, Glu24;
Aib2, Ala13, Asp15, Gln19, Arg20, Ile23, Glu24;
Aib2, Glu15, Lys16, Gln19, Arg20, Ala21, Glu24;
Aib2, Ala13, Gln19, Arg20, Ala21, Glu24;
Asp15, Ile23, Gln29 Glu15, Glu24, Leu27, Ala28, Gln29;
Glu15, Gln19, Arg20, Ala21; Glu24, Leu27, Ala28, Gln29;
Ala19, Lys20, Glu21;
Ala13, Ala19, Lys20, Glu21;
Ala19, Lys20, Glu21, Ser28;
Ala19, Lys20, Glu21, Ala29;
Ala19, Lys20, Glu21, Ser28, Ala29;
Glu15, Ala19, Lys20, Glu21;
Ala13, Asp15, Ala19, Lys20, Glu21;
Glu15, Ala19, Lys20, Glu21, Ser28;
Glu15, Ala19, Lys20, Glu21, Ala29;
Ala13, Asp15, Ala19, Lys20, Glu21, Ala29;
Glu15, Ala19, Lys20, Glu21, Ser28, Ala29;
Glu16, Ala19, Lys20, Glu21;
Ala13, Asp15, Glu24, Gln29
Glu16, Ala19, Lys20, Glu21, Ser28;
Glu16, Ala19, Lys20, Glu21, Ala29;
Glu16, Ala19, Lys20, Glu21, Ser28, Ala29;
Ala13, Asp15, Ile23;
Glu27, Ser28, Ala29;
Glu16, Glu27, Ser28, Ala29;
Ala19, Lys20, Glu21, Glu27, Ser28, Ala29;
Glu16, Ala19, Lys20, Glu21, Glu27, Ser28, Ala29;
Val27, Aib29;
Asn24, Val27 Aib29;
Asn24, Aib29;
Ala13, Asp15, Glu27;
Glu15, Glu24;
Glu15, Glu24; and
Leu10, or any of the above in combination with Leu10.
5. A GIP analogue according to claim 1 wherein positions 1 to 29 of the GIP analogue have a maximum of 8 changes compared to the sequence:
(SEQ ID NO: 63)
Y-Aib-EGTFTSDYSIYLDKKAQRAFVEWLLAQ.
6. A GIP analogue according to claim 5 wherein:
(a) if positions 1 to 29 of the GIP analogue have 6 or more changes compared to that sequence, the analogue possesses all of Ala20, Lys21 and Glu22 and optionally one or both of Ser28 and Ala29; or
(b) if the analogue does not possess Ala19, Lys20 and Glu21, then positions 1 to 29 have 4 or fewer changes compared to that sequence.
7. A GIP analogue according to claim 1 wherein positions 1 to 29 of the GIP analogue have a maximum of 6 changes compared to the sequence
(SEQ ID NO: 64)
Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA
or
(SEQ ID NO: 65)
Y-Aib-EGTFTSDYSIYLDEKAAKEFIEWLESA.
8. A GIP analogue according to claim 7 wherein the analogue possesses one, two, or all of Ala19, Lys20 and Glu21.
9. A GIP analogue according to claim 8 , wherein the analogue additionally possesses one or more of the following:
Glu15 and/or Glu16;
Ser28 and/or Ala29;
Val27 and/or Aib29;
Asn24, Val27 and/or Aib29;
Asn24 and/or Aib29;
Glu15 and/or Glu27;
Ala13, Glu15 and/or Glu16;
Ala13, Ser28 and/or Ala29;
Ala13, Val27 and/or Aib29;
Ala13, Asn24, Val27 and/or Aib29;
Ala13, Asn24 and/or Aib29;
Ala13, Glu15 and/or Glu27;
Asp15 and/or Glu16;
Asp15, Ser28 and/or Ala29;
Asp15, Val27 and/or Aib29;
Asp15, Asn24, Val27 and/or Aib29;
Asp15, Asn24, Aib29;
Asp15, Glu27;
Glu15 or Glu16 or Ile23;
Ile23, Ser28 and/or Ala29;
Ile23, Val27 and/or, Aib29;
Ile23, Asn24, Val27 and/or Aib29;
Ile23, Asn24 and/or Aib29;
Glu15, Ile23 and/or Glu27;
Aib2 and/or Ala13;
Aib2 and/or Tyr13;
Asp15 and/or Glu16;
Ile23 and/or Glu24;
DAla, Ser28 and/or Ala29;
Asn24 and/or Arg20;
Asn24 and/or Ala29.
10. A GIP analogue according to claim 1 possessing one of the following combinations of residues at the variable positions between 1 and 29:
Aib2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;
D-Ala2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;
Aib2, Tyr10, Tyr13, Glu15, Lys16, Ala19, Lys20, Glu21, Val23, Glu24, Leu27, Ser28, Ala29;
Aib2, Tyr10, Aib13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;
Aib2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Asn24, Leu27, Ala28, Aib29;
Aib2, Tyr10, Tyr13, Asp15, Glu16, Ala19, Lys20, Glu21, Ile23, Glu24, Glu27, Ser28, Ala29;
Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Asn24, Val27, Ala28, Aib29;
Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;
Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;
Aib2, Tyr10, Tyr13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Arg28, Ala29;
Aib2, Leu10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Asn24, Val27, Ala28 Aib29;
Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Val27, Ala28, Aib29;
Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Glu27, Ala28, Gln29;
Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Glu27, Ala28, Gln29;
Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg 20, Ala21, Val23, Glu24, Glu27, Ala28, Gln29;
Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;
D-Ala2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;
Aib2, Tyr10, Ala13, Glu15, Lys16, Ala19, Lys20, Glu21, Val23, Glu24, Leu27, Ser28, Ala29;
Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;
Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Asn24, Leu27, Ala28, Aib29;
Aib2, Tyr10, Ala13, Asp15, Glu16, Ala19, Lys20, Glu21, Ile23, Glu24, Glu27, Ser28, Ala29;
Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Arg28, Ala29;
Aib2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;
D-Ala2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;
Aib2, Tyr10, Tyr13, Glu15, Lys16, Ala19, Lys20, Glu21, Ile23, Glu24, Leu27, Ser28, Ala29;
Aib2, Tyr10, Aib13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;
Aib2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Asn24, Leu27, Ala28, Aib29;
Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Asn24, Val27, Ala28, Aib29;
Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;
Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;
Aib2, Tyr10, Tyr13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Arg28, Ala29;
Aib2, Leu10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Asn24, Val27, Ala28 Aib29;
Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Val27, Ala28, Aib29;
Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Glu27, Ala28, Gln29;
Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Glu27, Ala28, Gln29;
Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg 20, Ala21, Ile23, Glu24, Glu27, Ala28, Gln29.
11. A GIP analogue according to claim 1 residues 1-29 of Formula I have the sequence:
(SEQ ID NO: 66)
Y-Aib-EGTFTSDYSIYLDKΨAQRAFVEWLLAQ;
(SEQ ID NO: 67)
Y-DAla-EGTFTSDYSIYLDKΨAQRAFVEWLLAQ;
(SEQ ID NO: 68)
Y-Aib-EGTFTSDYSIYLEKΨAAKEFVEWLLSA;
(SEQ ID NO: 69)
Y-Aib-EGTFTSDYSI-Aib-LDKΨAQRAFVEWLLAQ;
(SEQ ID NO: 70)
Y-Aib-EGTFTSDYSIYLDKΨAQRAFVNWLLA-Aib;
(SEQ ID NO: 71)
Y-Aib-EGTFTSDYSIYLDEΨAAKEFIEWLESA;
(SEQ ID NO: 72)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVNWLVA-Aib;
(SEQ ID NO: 73)
Y-Aib-EGTFTSDYSIALEKΨAQRAFVEWLLAQ;
(SEQ ID NO: 74)
Y-Aib-EGTFTSDLSIALEKΨAQRAFVEWLLAQ;
(SEQ ID NO: 75)
Y-Aib-EGTFTSDYSIYLEKΨAQRAFVEWLLRA;
(SEQ ID NO: 76)
Y-Aib-EGTFTSDLSIALDKΨAQRAFVNWLVA-Aib;
(SEQ ID NO: 77)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLVA-Aib;
(SEQ ID NO: 78)
Y-Aib-EGTFTSDYSIALEKΨAQRAFVEWLEAQ;
(SEQ ID NO: 79)
Y-Aib-EGTFTSDLSIALEKΨAQRAFVEWLEAQ;
(SEQ ID NO: 80)
Y-DAla-EGTFTSDYSIALEKΨAQRAFVEWLLAQ;
(SEQ ID NO: 81)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAQ;
(SEQ ID NO: 82)
Y-DAla-EGTFTSDYSIALDKΨAQRAFVEWLLAQ;
(SEQ ID NO: 83)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAAP;
(SEQ ID NO: 84)
Y-Aib-EGTFTSDYSIALDKΨAAKEFVEWLLSA;
(SEQ ID NO: 85)
Y-Aib-EGTFTSDYSIALDEΨAQRAFVEWLLAQ;
(SEQ ID NO: 86)
Y-Aib-EGTFTSDYSIALDKΨAQKAFVEWLLAA;
(SEQ ID NO: 87)
Y-Aib-EGTFTSDYSIALDEΨAQRAFVEWLLAA;
(SEQ ID NO: 88)
Y-Aib-EGTFTSDYSIYLDKΨAQREFVEWLLAQ;
(SEQ ID NO: 89)
Y-Aib-EGTFTSDYSIALDKΨAQREFVEWLLAQ;
(SEQ ID NO: 90)
Y-Aib-EGTFTSDYSIALDKΨAQKEFVEWLLAQ;
(SEQ ID NO: 91)
Y-Aib-EGTFTSDYSIALDKΨAQKEFVEWLLAA;
(SEQ ID NO: 92)
Y-Aib-EGTFTSDYSIALDKΨAQRAFIEWLLAQ;
(SEQ ID NO: 93)
Y-Aib-EGTFTSDYSIYLDKΨAQRAFVEWLLAE;
or
(SEQ ID NO: 94)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAE;
or
(b) the peptide backbone (Formula I) has
the sequence:
(SEQ ID NO: 95)
Y-Aib-EGTFTSDYSIYLDKΨAQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 96)
Y-DAla-EGTFTSDYSIYLDKΨAQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 97)
Y-Aib-EGTFTSDYSIYLEKΨAAKEFVEWLLSAGPSSGAPPPS;
(SEQ ID NO: 98)
Y-Aib-EGTFTSDYSI-Aib-LDKΨAQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 99)
Y-Aib-EGTFTSDYSIYLDKΨAQRAFVNWLLA-Aib-K;
(SEQ ID NO: 71)
Y-Aib-EGTFTSDYSIYLDEΨAAKEFIEWLESA;
(SEQ ID NO: 100)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVNWLVA-Aib-KPSSGAPPPS;
(SEQ ID NO: 101)
Y-Aib-EGTFTSDYSIALEKΨAQRAFVEWLLAQK;
(SEQ ID NO: 102)
Y-Aib-EGTFTSDLSIALEKΨAQRAFVEWLLAQK;
(SEQ ID NO: 75)
Y-Aib-EGTFTSDYSIYLEKΨAQRAFVEWLLRA;
(SEQ ID NO: 103)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVNWLVA-Aib-K;
(SEQ ID NO: 104)
Y-Aib-EGTFTSDLSIALDKΨAQRAFVNWLVA-Aib-K;
(SEQ ID NO: 105)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLVA-Aib-K;
(SEQ ID NO: 106)
Y-Aib-EGTFTSDYSIALEKΨAQRAFVEWLEAQGPSSGAPPPS;
(SEQ ID NO: 107)
Y-Aib-EGTFTSDYSIALEKΨAQRAFVEWLEAQK;
(SEQ ID NO: 109)
Y-Aib-EGTFTSDYSIALEKΨAQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 110)
Y-DAla-EGTFTSDYSIALEKΨAQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 111)
Y-Aib-EGTFTSDLSIALEKΨAQRAFVEWLLAQKPSSGAPPPS;
(SEQ ID NO: 112)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAQKPSSGAPPPS;
(SEQ ID NO: 113)
Y-DAla-EGTFTSDYSIALDKΨAQRAFVEWLLAQKPSSGAPPPS;
(SEQ ID NO: 114)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAAPSSGAPPPS;
(SEQ ID NO: 115)
Y-Aib-EGTFTSDYSIALDKΨAAKEFVEWLLSAGPSSGAPPPS
(SEQ ID NO: 116)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 117)
Y-Aib-EGTFTSDYSIALDEΨAQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 118)
Y-Aib-EGTFTSDYSIALDEΨQRAFVEWLLAAGPSSGAPPPS;
(SEQ ID NO: 119)
Y-Aib-EGTFTSDYSIALDKΨAQKAFVEWLLAAGPSSGAPPPS;
(SEQ ID NO: 120)
Y-Aib-EGTFTSDYSIYLDKΨAQREFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 121)
Y-Aib-EGTFTSDYSIALDKΨAQREFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 122)
Y-Aib-EGTFTSDYSIALDKΨAQKEFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 123)
Y-Aib-EGTFTSDYSIALDKΨAQKEFVEWLLAAGPSSGAPPPS;
(SEQ ID NO: 124)
Y-Aib-EGTFTSDYSIALDKΨAQRAFIEWLLAQGPSSGAPPPS;
(SEQ ID NO: 125)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAQGPSSGAPPP;
(SEQ ID NO: 126)
Y-Aib-EGTFTSDLSIALEKΨAQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 127)
Y-Aib-EGTFTSDYSIYLDKΨAQRAFVEWLLAEGPSSGAPPPS;
(SEQ ID NO: 128)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAEGPSSGAPPPS;
or
(SEQ ID NO: 129)
Y-Aib-EGTFTSDYSIALDKΨAQRAFVEWLLAEPSSGAPPPS.
12. A GIP analogue according to claim 1 wherein Ψ is a residue of Lys in which the side chain is conjugated to a substituent having the formula —Z 2 -Z 1 .
13. A GIP analogue according to claim 1 wherein:
(a) residues 1-29 of Formula I have the sequence:
(SEQ ID NO: 130)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 131)
Y-Aib-EGTFTSDYSIYLDK-K([19-Carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 132)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu)-AQRAFVEWLLAQ;
(SEQ ID NO: 133)
H-Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu-GSGSGG)-AQRAFVEWLLAQ;
(SEQ ID NO: 134)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 135)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-heptadec-
anoyl]-isoGlu-Peg3-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 136)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 137)
Y-Aib-EGTFTSDYSIYLDK-K([19-Carboxy-nonadec-
anoyl]-isoGlu-Peg3-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 138)
Y-DAla-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 139)
Y-Aib-EGTFTSDYSIYLEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AAKEFVEWLLSA;
(SEQ ID NO: 140)
Y-Aib-EGTFTSDYSI-Aib-LDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 141)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLLA-Aib;
(SEQ ID NO: 13)
Y-Aib-EGTFTSDYSIYLDE-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AAKEFIEWLESA;
(SEQ ID NO: 142)
Y-Aib-EGTFTSDYSIALDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib;
(SEQ ID NO: 143)
Y-Aib-EGTFTSDYSIALDK-K[19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib;
(SEQ ID NO: 144)
Y-Aib-EGTFTSDYSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 145)
Y-Aib-EGTFTSDLSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 18)
Y-Aib-EGTFTSDYSIYLEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLRA;
(SEQ ID NO: 146)
Y-Aib-EGTFTSDLSIALDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib;
(SEQ ID NO: 147)
Y-Aib-EGTFTSDYSIALDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLVA-Aib;
(SEQ ID NO: 148)
Y-Aib-EGTFTSDYSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLEAQ;
(SEQ ID NO: 149)
Y-Aib-EGTFTSDLSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLEAQ;
(SEQ ID NO: 150)
Y-Aib-EGTFTSDYSIALEK-K[19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 152)
Y-Aib-EGTFTSDLSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 28)
Y-Aib-EGTFTSDYSIYLEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLRA;
(SEQ ID NO: 153)
Y-DAla-EGTFTSDYSIYLDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 154)
Y-Aib-EGTFTSDYSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 155)
Y-DAla-EGTFTSDYSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 152)
Y-Aib-EGTFTSDLSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 24)
Y-Aib-EGTFTSDLSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLEAQK;
(SEQ ID NO: 159)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 160)
Y-DAla-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 161)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAA;
(SEQ ID NO: 162)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AAKEFVEWLLSA;
(SEQ ID NO: 163)
Y-Aib-EGTFTSDYSIALDE-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 164)
Y-Aib-EGTFTSDYSIALDE-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAA;
(SEQ ID NO: 165)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQKAFVEWLLAA;
(SEQ ID NO: 166)
Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQREFVEWLLAQ;
(SEQ ID NO: 167)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQREFVEWLLAQ;
(SEQ ID NO: 168)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQKEFVEWLLAQ;
(SEQ ID NO: 169)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQKEFVEWLLAA;
(SEQ ID NO: 170)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFIEWLLAQ;
(SEQ ID NO: 171)
Y-Aib-EGTFTSDYSIALDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;
(SEQ ID NO: 172)
Y-Aib-EGTFTSDYSIALDK-K((19-Carboxy-
nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-
Peg3)-AQRAFVEWLLAQ;
or
(SEQ ID NO: 173)
Y-Aib-EGTFTSDYSIALDK-K((19-Carboxy-
nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-
Peg3)-AQKEFVEWLLAA;
or
(b) the peptide backbone (Formula I) has
the sequence:
(SEQ ID NO: 1)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 2)
Y-Aib-EGTFTSDYSIYLDK-K([19-Carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 3)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu)-AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 177)
H-Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu-GSGSGG)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 5)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 6)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 7)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-Dapa-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 8)
Y-Aib-EGTFTSDYSIYLDK-K([19-Carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 9)
Y-DAla-EGTFTSDYSIYLDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 10)
Y-Aib-EGTFTSDYSIYLEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-
AAKEFVEWLLSAGPSSGAPPPS;
(SEQ ID NO: 11)
Y-Aib-EGTFTSDYSI-Aib-LDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 12)
Y-Aib-EGTFTSDYSIYLDK-K([17-carboxy-hepta-
decanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLLA-Aib-K;
(SEQ ID NO: 13)
Y-Aib-EGTFTSDYSIYLDE-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AAKEFIEWLESA;
(SEQ ID NO: 14)
Y-Aib-EGTFTSDYSIALDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib-
KPSSGAPPPS;
(SEQ ID NO: 15)
Y-Aib-EGTFTSDYSIALDK-K[19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib-
KPSSGAPPPS;
(SEQ ID NO: 16)
Y-Aib-EGTFTSDYSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK;
(SEQ ID NO: 17)
Y-Aib-EGTFTSDLSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK;
(SEQ ID NO: 18)
Y-Aib-EGTFTSDYSIYLEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLRA;
(SEQ ID NO: 19)
Y-Aib-EGTFTSDYSIALDK-K([17-carboxy-hepta-
decanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib-K;
(SEQ ID NO: 20)
Y-Aib-EGTFTSDLSIALDK-K([17-carboxy-hepta-
decanoyl]-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib-K;
(SEQ ID NO: 21)
Y-Aib-EGTFTSDYSIALDK-K([17-carboxy-hepta-
decanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLVA-Aib-K;
(SEQ ID NO: 22)
Y-Aib-EGTFTSDYSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLEAQGPSSGAPPPS;
(SEQ ID NO: 23)
Y-Aib-EGTFTSDYSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLEAQK;
(SEQ ID NO: 25)
Y-Aib-EGTFTSDYSIALEK-K[19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK;
(SEQ ID NO: 26)
Y-Aib-EGTFTSDLSIALEK-K[19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLEAQK;
(SEQ ID NO: 27)
Y-Aib-EGTFTSDLSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK;
(SEQ ID NO: 28)
Y-Aib-EGTFTSDYSIYLEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLLRA;
(SEQ ID NO: 29)
Y-DAla-EGTFTSDYSIYLDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 30)
Y-Aib-EGTFTSDYSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 31)
Y-DAla-EGTFTSDYSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 33)
Y-Aib-EGTFTSDLSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQKPSSGAPPPS;
(SEQ ID NO: 24)
Y-Aib-EGTFTSDLSIALEK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-AQRAFVEWLEAQK;
(SEQ ID NO: 32)
Y-Aib-EGTFTSDLSIALEK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 37)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQKPSSGAPPPS;
(SEQ ID NO: 38)
Y-DAla-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQKPSSGAPPPS;
(SEQ ID NO: 39)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAAPSSGAPPPS;
(SEQ ID NO: 40)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AAKEFVEWLLSAGPSSGAPPPS;
(SEQ ID NO: 41)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 42)
Y-Aib-EGTFTSDYSIALDE-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 43)
Y-Aib-EGTFTSDYSIALDE-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAAGPSSGAPPPS;
(SEQ ID NO: 44)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQKAFVEWLLAAGPSSGAPPPS;
(SEQ ID NO: 45)
Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQREFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 46)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQREFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 47)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQKEFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 48)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQKEFVEWLLAAGPSSGAPPPS;
(SEQ ID NO: 49)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFIEWLLAQGPSSGAPPPS;
(SEQ ID NO: 50)
Y-Aib-EGTFTSDYSIALDK-K([17-carboxy-
heptadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 51)
Y-Aib-EGTFTSDYSIALDK-K((19-Carboxy-
nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-
Peg3)-AQRAFVEWLLAQGPSSGAPPPS;
(SEQ ID NO: 52)
Y-Aib-EGTFTSDYSIALDK-K((19-Carboxy-
nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-
Peg3)-AQKEFVEWLLAAGPSSGAPPPS;
(SEQ ID NO: 53)
Y-Aib-EGTFTSDYSIYLDK-K([19-Carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAEGPSSGAPPPS;
(SEQ ID NO: 54)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAEGPSSGAPPPS;
or
(SEQ ID NO: 55)
Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-
nonadecanoyl]-isoGlu-Peg3-Peg3)-
AQRAFVEWLLAEPSSGAPPPS.
14. A pharmaceutical composition comprising a GIP analogue according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a carrier, wherein preferably the composition is formulated as a liquid suitable for administration by injection or infusion, or formulated to cause slow release of said GIP analogue.
15. A method of treatment and/or prevention of diabetes or a diabetes related disorder, or obesity or an obesity related disorder, comprising administering to a subject in need thereof a GIP analogue according to claim 1 , or a pharmaceutically acceptable salt thereof.
16. The method according to claim 15 , wherein:
(a) the diabetes related disorder is insulin resistance, glucose intolerance, increased fasting glucose, hypoglycemia pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, bone related disorder or a combination thereof; or
(b) the diabetes related disorder is atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke, or a condition associated with atherogenic dyslipidemia, a blood fat disorder, elevated blood pressure, hypertension, a prothrombotic state, or a proinflammatory state; or
(c) the obesity related disorder is obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, or a condition associated with atherogenic dyslipidemia, a blood fat disorder, elevated blood pressure, hypertension, a prothrombotic state, a proinflammatory state, or a combination thereof.
17. The method according to claim 16 , wherein the bone related disorder is osteoporosis.
18. The method according to claim 16 , wherein the condition associated with a blood fat disorder is high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof.
19. A GIP analog according to the following formula:
R 1 —Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-R 2 (SEQ ID NO: 34);
R 1 —Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-IsoGlu)-AQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 35)-R 2 ;
R 1 —Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-R 2 (SEQ ID NO: 36);
R 1 —Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQ-R 2 (SEQ ID NO: 156);
R 1 —Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-IsoGlu)-AQRAFVEWLLAQ-R 2 (SEQ ID NO: 157); or
R 1 —Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQ-R 2 (SEQ ID NO: 158)
wherein R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu; and
R 2 is —NH 2 or —OH,
or a pharmaceutically acceptable salt thereof.