Glucagon-GLP-1-GIP triple agonist compounds

1. A glucagon-GLP-1-GIP triple agonist compound having the general formula I:

R 1 -Tyr-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R 2 (SEQ ID NO: 52)  (I)

wherein

R 1 is H—, C 1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;

X2 is Aib, Gly, Ala, D-Ala, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c;

X10 is Tyr or Leu;

X12 is Lys, Ile or ψ;

X13 is Ala, Tyr or Aib;

X15 is Asp or Glu;

X16 is Ser, Glu, Lys or ψ;

X17 is Lys or ψ;

X19 is Gln or Ala;

X20 is Lys, His, Arg or ψ;

X21 is Ala, Asp or Glu;

X23 is Val or Ile;

X24 is Asn, Glu or ψ;

X27 is Leu, Glu or Val;

X28 is Ala, Ser, Arg or ψ;

X29 is Aib, Ala, Gln or Lys;

X30 is Lys, Gly, or is absent;

Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 53), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 54), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 55), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 56), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 57) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 58), or is absent;

ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a lipophilic substituent;

and

R 2 is —NH 2 or —OH;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein ψ is present at one of positions X12, X16 or X17.

3. The compound according to claim 1 wherein the compound contains only one residue ψ.

4. The compound according to claim 1 wherein the compound possesses one or more of the following sets of residues:

K12 and Y13; I12 and Y13; K12 and A13; I12 and A13; or ψ12 and Y13;

D15 and S16; D15 and E16; E15 and K16; D15 and ψ16; E15 and S16; or E15 and ψ16;

A19, H20, and D21; A19, K20, and D21; A19, R20, and D21; Q19, K20, and E21; A19, K20, and E21; or Q19, R20, and A21;

I23 and E24; V23 and E24; or V23 and N24;

L27, R28, and A29; L27, S28, and A29; L27, A28, and Q29; E27, S28, and A29; or V27, A28, and Aib29; E15 and K17;

E15 and ψ17;

E15, ψ17, and Q19;

Q19 and E24;

E16, ψ17, and Q19; or

K16, ψ17, and Q19.

5. The compound according to claim 1 wherein positions 1 to 29 have the sequence:

(SEQ ID NO: 1)

YSQGTFTSDYSKYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 59)

YSQGTFTSDYSKYLDψKAAHDFVEWLLRA;

(SEQ ID NO: 5)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA;

(SEQ ID NO: 9)

Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA;

(SEQ ID NO: 14)

Y-Aib-QGTFTSDYSIYLEKKAAHDFVEWLLSA;

(SEQ ID NO: 17)

Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA;

(SEQ ID NO: 18)

Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA;

(SEQ ID NO: 60)

Y-Aib-QGTFTSDYSIYLDEψAAHDFVEWLLSA;

(SEQ ID NO: 61)

Y-Aib-QGTFTSDYSIYLDSψAAHDFVEWLLSA;

(SEQ ID NO: 62)

Y-Aib-QGTFTSDYSKYLDSψAAHDFVEWLLSA;

(SEQ ID NO: 7)

Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA;

(SEQ ID NO: 8)

Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA;

(SEQ ID NO: 10)

Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA;

(SEQ ID NO: 16)

Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA;

(SEQ ID NO: 6)

Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA;

(SEQ ID NO: 15)

Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA;

(SEQ ID NO: 21)

Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA;

(SEQ ID NO: 19)

Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA;

(SEQ ID NO: 20)

Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA;

(SEQ ID NO: 63)

Y-Aib-QGTFTSDYSIYLEKψAAKEFVEWLLSA;

(SEQ ID NO: 64)

Y-Aib-QGTFTSDYSIYLEψKAAKEFVEWLLSA;

(SEQ ID NO: 65)

Y-Aib-QGTFTSDYSψYLEKKAAKEFVEWLLSA;

(SEQ ID NO: 11)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA;

(SEQ ID NO: 66)

Y-Aib-QGTFTSDLSIALEKψAQRAFVEWLLAQK;

(SEQ ID NO: 67)

Y-Aib-QGTFTSDYSKYLDEψAAKDFIEWLESA;

(SEQ ID NO: 68)

Y-Aib-QGTFTSDYSIYLDEψAAKDFVEWLESA;

(SEQ ID NO: 69)

Y-Aib-QGTFTSDYSIYLDEψAAKDFIEWLESA;

(SEQ ID NO: 70)

Y-Aib-QGTFTSDYSIYLDEψAAKEFIEWLESA;

(SEQ ID NO: 3)

Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 12)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 71)

Y-Aib-QGTFTSDYSIYLDSψAAHDFVEWLLRA;

(SEQ ID NO: 72)

Y-Aib-QGTFTSDYSIYLEKψAQRAFVEWLLRA;

(SEQ ID NO: 73)

Y-Aib-QGTFTSDYSIALDKψAQRAFVNWLVA-Aib;

(SEQ ID NO: 74)

Y-Ac4c-QGTFTSDYSIYLDEψAAKEFIEWLESA;

(SEQ ID NO: 75)

Y-Ac4c-QGTFTSDYSIALEKψAQRAFVEWLLAQ; or

(SEQ ID NO: 76)

Y-Ac4c-QGTFTSDYSIYLDKψAQRAFVEWLLAQ.

6. The compound according to claim 1 which differs at up to 4 positions from any of the sequences:

(SEQ ID NO: 1)

YSQGTFTSDYSKYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 59)

YSQGTFTSDYSKYLDψKAAHDFVEWLLRA;

(SEQ ID NO: 5)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA;

(SEQ ID NO: 9)

Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA;

(SEQ ID NO: 14)

Y-Aib-QGTFTSDYSIYLEKKAAHDFVEWLLSA;

(SEQ ID NO: 17)

Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA;

(SEQ ID NO: 18)

Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA;

(SEQ ID NO: 60)

Y-Aib-QGTFTSDYSIYLDEψAAHDFVEWLLSA;

(SEQ ID NO: 61)

Y-Aib-QGTFTSDYSIYLDSψAAHDFVEWLLSA;

(SEQ ID NO: 62)

Y-Aib-QGTFTSDYSKYLDSψAAHDFVEWLLSA;

(SEQ ID NO: 7)

Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA;

(SEQ ID NO: 8)

Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA;

(SEQ ID NO: 10)

Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA;

(SEQ ID NO: 16)

Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA;

(SEQ ID NO: 6)

Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA;

(SEQ ID NO: 15)

Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA;

(SEQ ID NO: 21)

Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA;

(SEQ ID NO: 19)

Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA;

(SEQ ID NO: 20)

Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA;

(SEQ ID NO: 63)

Y-Aib-QGTFTSDYSIYLEKψAAKEFVEWLLSA;

(SEQ ID NO: 64)

Y-Aib-QGTFTSDYSIYLEψKAAKEFVEWLLSA;

(SEQ ID NO: 65)

Y-Aib-QGTFTSDYSψYLEKKAAKEFVEWLLSA;

(SEQ ID NO: 11)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA;

(SEQ ID NO: 66)

Y-Aib-QGTFTSDLSIALEKψAQRAFVEWLLAQK;

(SEQ ID NO: 67)

Y-Aib-QGTFTSDYSKYLDEψAAKDFIEWLESA;

(SEQ ID NO: 68)

Y-Aib-QGTFTSDYSIYLDEψAAKDFVEWLESA;

(SEQ ID NO: 69)

Y-Aib-QGTFTSDYSIYLDEψAAKDFIEWLESA;

(SEQ ID NO: 70)

Y-Aib-QGTFTSDYSIYLDEψAAKEFIEWLESA;

(SEQ ID NO: 3)

Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 12)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 71)

Y-Aib-QGTFTSDYSIYLDSψAAHDFVEWLLRA;

(SEQ ID NO: 72)

Y-Aib-QGTFTSDYSIYLEKψAQRAFVEWLLRA;

(SEQ ID NO: 73)

Y-Aib-QGTFTSDYSIALDKψAQRAFVNWLVA-Aib;

(SEQ ID NO: 74)

Y-Ac4c-QGTFTSDYSIYLDEψAAKEFIEWLESA;

(SEQ ID NO: 75)

Y-Ac4c-QGTFTSDYSIALEKψAQRAFVEWLLAQ;

and

(SEQ ID NO: 76)

Y-Ac4c-QGTFTSDYSIYLDKψAQRAFVEWLLAQ.

7. The compound according to claim 1 wherein the peptide backbone of Formula I has the sequence:

(SEQ ID NO: 1)

YSQGTFTSDYSKYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 59)

YSQGTFTSDYSKYLDψKAAHDFVEWLLRA;

(SEQ ID NO: 5)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA;

(SEQ ID NO: 9)

Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA;

(SEQ ID NO: 13)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 14)

Y-Aib-QGTFTSDYSIYLEKKAAHDFVEWLLSA;

(SEQ ID NO: 17)

Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA;

(SEQ ID NO: 18)

Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA;

(SEQ ID NO: 60)

Y-Aib-QGTFTSDYSIYLDEψAAHDFVEWLLSA;

(SEQ ID NO: 78)

Y-Aib-QGTFTSDYSIYLDSψAAHDFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 62)

Y-Aib-QGTFTSDYSKYLDSψAAHDFVEWLLSA;

(SEQ ID NO: 7)

Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA;

(SEQ ID NO: 8)

Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA;

(SEQ ID NO: 10)

Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA;

(SEQ ID NO: 16)

Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA;

(SEQ ID NO: 6)

Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA;

(SEQ ID NO: 15)

Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA;

(SEQ ID NO: 21)

Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA;

(SEQ ID NO: 19)

Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA;

(SEQ ID NO: 20)

Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA;

(SEQ ID NO: 63)

Y-Aib-QGTFTSDYSIYLEKψAAKEFVEWLLSA;

(SEQ ID NO: 64)

Y-Aib-QGTFTSDYSIYLEψKAAKEFVEWLLSA;

(SEQ ID NO: 65)

Y-Aib-QGTFTSDYSψYLEKKAAKEFVEWLLSA;

(SEQ ID NO: 79)

Y-Aib-QGTFTSDYSIYLEKψAAKEFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 11)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA;

(SEQ ID NO: 80)

Y-Aib-QGTFTSDYSIYLDKψAQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 81)

Y-Aib-QGTFTSDYSIALEKψAQRAFVEWLLAQK;

(SEQ ID NO: 66)

Y-Aib-QGTFTSDLSIALEKψAQRAFVEWLLAQK;

(SEQ ID NO: 67)

Y-Aib-QGTFTSDYSKYLDEψAAKDFIEWLESA;

(SEQ ID NO: 68)

Y-Aib-QGTFTSDYSIYLDEψAAKDFVEWLESA;

(SEQ ID NO: 69)

Y-Aib-QGTFTSDYSIYLDEψAAKDFIEWLESA;

(SEQ ID NO: 70)

Y-Aib-QGTFTSDYSIYLDEψAAKEFIEWLESA;

(SEQ ID NO: 3)

Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 12)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 71)

Y-Aib-QGTFTSDYSIYLDSψAAHDFVEWLLRA;

(SEQ ID NO: 72)

Y-Aib-QGTFTSDYSIYLEKψAQRAFVEWLLRA;

(SEQ ID NO: 82)

Y-Aib-QGTFTSDYSIALDKψAQRAFVNWLVA-Aib-KPSSGAPPPS;

(SEQ ID NO: 74)

Y-Ac4c-QGTFTSDYSIYLDEψAAKEFIEWLESA;

(SEQ ID NO: 83)

Y-Ac4c-QGTFTSDYSIALEKψAQRAFVEWLLAQK; or

(SEQ ID NO: 84)

Y-Ac4c-QGTFTSDYSIYLDKψAQRAFVEWLLAQGPSSGAPPPS.

8. The compound according to claim 1 wherein the peptide backbone of Formula I has a sequence which differs at up to 5 positions from one of the sequences:

(SEQ ID NO: 1)

YSQGTFTSDYSKYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 59)

YSQGTFTSDYSKYLDψKAAHDFVEWLLRA;

(SEQ ID NO: 5)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA;

(SEQ ID NO: 9)

Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA;

(SEQ ID NO: 13)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 14)

Y-Aib-QGTFTSDYSIYLEKKAAHDFVEWLLSA;

(SEQ ID NO: 17)

Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA;

(SEQ ID NO: 18)

Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA;

(SEQ ID NO: 60)

Y-Aib-QGTFTSDYSIYLDEψAAHDFVEWLLSA;

(SEQ ID NO: 78)

Y-Aib-QGTFTSDYSIYLDSψAAHDFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 62)

Y-Aib-QGTFTSDYSKYLDSψAAHDFVEWLLSA;

(SEQ ID NO: 7)

Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA;

(SEQ ID NO: 8)

Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA;

(SEQ ID NO: 10)

Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA;

(SEQ ID NO: 16)

Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA;

(SEQ ID NO: 6)

Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA;

(SEQ ID NO: 15)

Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA;

(SEQ ID NO: 21)

Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA;

(SEQ ID NO: 19)

Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA;

(SEQ ID NO: 20)

Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA;

(SEQ ID NO: 63)

Y-Aib-QGTFTSDYSIYLEKψAAKEFVEWLLSA;

(SEQ ID NO: 64)

Y-Aib-QGTFTSDYSIYLEψKAAKEFVEWLLSA;

(SEQ ID NO: 65)

Y-Aib-QGTFTSDYSψYLEKKAAKEFVEWLLSA;

(SEQ ID NO: 79)

Y-Aib-QGTFTSDYSIYLEKψAAKEFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 11)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA;

(SEQ ID NO: 80)

Y-Aib-QGTFTSDYSIYLDKψAQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 81)

Y-Aib-QGTFTSDYSIALEKψAQRAFVEWLLAQK;

(SEQ ID NO: 66)

Y-Aib-QGTFTSDLSIALEKψAQRAFVEWLLAQK;

(SEQ ID NO: 67)

Y-Aib-QGTFTSDYSKYLDEψAAKDFIEWLESA;

(SEQ ID NO: 68)

Y-Aib-QGTFTSDYSIYLDEψAAKDFVEWLESA;

(SEQ ID NO: 69)

Y-Aib-QGTFTSDYSIYLDEψAAKDFIEWLESA;

(SEQ ID NO: 70)

Y-Aib-QGTFTSDYSIYLDEψAAKEFIEWLESA;

(SEQ ID NO: 3)

Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 12)

Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA;

(SEQ ID NO: 71)

Y-Aib-QGTFTSDYSIYLDSψAAHDFVEWLLRA;

(SEQ ID NO: 72)

Y-Aib-QGTFTSDYSIYLEKψAQRAFVEWLLRA;

(SEQ ID NO: 82)

Y-Aib-QGTFTSDYSIALDKψAQRAFVNWLVA-Aib-KPSSGAPPPS;

(SEQ ID NO: 74)

Y-Ac4c-QGTFTSDYSIYLDEψAAKEFIEWLESA;

(SEQ ID NO: 83)

Y-Ac4c-QGTFTSDYSIALEKψAQRAFVEWLLAQK;

and

(SEQ ID NO: 84)

Y-Ac4c-QGTFTSDYSIYLDKψAQRAFVEWLLAQGPSSGAPPPS,

optionally, wherein the compound differs at up to 5 positions from one of the sequences:

(SEQ ID NO: 79)

Y-Aib-QGTFTSDYSIYLEKψAAKEFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 60)

Y-Aib-QGTFTSDYSIYLDEψAAHDFVEWLLSA;

or

(SEQ ID NO: 81)

Y-Aib-QGTFTSDYSIALEKψAQRAFVEWLLAQK.

9. The compound according to claim 1 wherein ψ is a residue of Lys in which the side chain is conjugated to a lipophilic substituent.

10. The compound according to claim 1 wherein the lipophilic substituent has the formula —Z 1 or —Z 2 —Z 1 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;

and wherein —Z 2 —, if present, is a spacer of formula:

connecting Z 1 to ψ;

wherein:

each Y is independently —NH, —NR, —S or —O, where R is alkyl, a protecting group or forms a linkage to another part of the spacer Z 2 ;

each X is independently a bond, CO—, SO—, or SO 2 —;

with the proviso that when Y is —S, the X to which it is bound is a bond;

each V is independently a bivalent organic moiety linking Y and X;

and n is 1-10.

11. The compound according to claim 10 wherein the lipophilic substituent has the formula —Z 2 —Z 1 .

12. The compound according to claim 9 wherein Z 1 is A-B-alkylene-CO— wherein A is H or —COOH and B is a bond.

13. The compound according to claim 12 wherein Z 1 is A-B—C 16-20 alkylene-(CO)—.

14. The compound according to claim 10 wherein Z 1 is:

hexadecanoyl; 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)—].

15. The compound according to claim 10 wherein Z 2 comprises a residue selected from isoGlu or Dapa.

16. The compound according to claim 10 wherein —Z 1 or —Z 2 —Z 1 is:

(i) [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3

(ii) [17-carboxy-heptadecanoyl]-isoGlu

(iii) Octadecanoyl-isoGlu-Peg3-Peg3

(iv) Eicosanoyl-isoGlu-Peg3-Peg3

(v) [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3

(vi) Octadecanoyl-Dapa-Peg3-Peg3

or

(vii) Hexadecanoyl-isoGlu

17. The compound according to claim 1 wherein:

(a) positions 1 to 29 have the sequence:

(SEQ ID NO: 4)

YSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)-KAAHDFVEWLLRA;

(SEQ ID NO: 27)

Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA;

(SEQ ID NO: 85)

Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA;

(SEQ ID NO: 2)

Y-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA;

(SEQ ID NO: 22)

Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-AAKEFVEWLLSA;

(SEQ ID NO: 23)

Y-Aib-QGTFTSDYSIYLE-K(Hexadecanoyl-isoGlu)-KAAKEFVEWLLSA;

(SEQ ID NO: 24)

Y-Aib-QGTFTSDYS-K(Hexadecanoyl-isoGlu)-YLEKKAAKEFVEWLLSA;

(SEQ ID NO: 86)

Y-Aib-QGTFTSDYSIYLEK-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AAKEFVEWLLSA;

(SEQ ID NO: 87)

Y-Aib-QGTFTSDYSIYLEK-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-

AAKEFVEWLLSA;

(SEQ ID NO: 88)

Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQ;

(SEQ ID NO: 89)

Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]-isoGlu)-

AQRAFVEWLLAQ;

(SEQ ID NO: 90)

Y-Aib-QGTFTSDYSIYLDK-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;

(SEQ ID NO: 91)

Y-Aib-QGTFTSDYSIYLD-K(eicosanoyl-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQ;

(SEQ ID NO: 92)

Y-Aib-QGTFTSDYSIALEK-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQ;

(SEQ ID NO: 93)

Y-Aib-QGTFTSDYSIALEK-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;

(SEQ ID NO: 94)

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

AQRAFVEWLLAQ;

(SEQ ID NO: 95)

Y-Aib-QGTFTSDLSIALE-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ;

(SEQ ID NO: 25)

Y-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA;

(SEQ ID NO: 29)

Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFVEWLESA;

(SEQ ID NO: 30)

Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA;

(SEQ ID NO: 38)

Y-Aib-QGTFTSDYSIYLDE-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AAKEFIEWLESA;

(SEQ ID NO: 39)

Y-Aib-QGTFTSDYSIYLDE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-

AAKEFIEWLESA;

(SEQ ID NO: 26)

Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLRA;

(SEQ ID NO: 96)

Y-Aib-QGTFTSDYSIYLE-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLRA;

(SEQ ID NO: 97)

Y-Aib-QGTFTSDYSIYLE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLRA;

(SEQ ID NO: 98)

Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-

Aib;

(SEQ ID NO: 99)

Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-Dapa-Peg3-Peg3)-AQRAFVNWLVA-Aib;

(SEQ ID NO: 100)

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

AQRAFVNWLVA-Aib;

(SEQ ID NO: 40)

Y-Ac4c-QGTFTSDYSIYLDE-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAKEFIEWLESA;

(SEQ ID NO: 101)

Y-Ac4c-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQ; or

(SEQ ID NO: 102)

Y-Ac4c-QGTFTSDYSIYLDK-K(19-carboxy-heptadecanoyl-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQ.

18. A pharmaceutical composition comprising the triple agonist compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a carrier, wherein the pharmaceutical composition is formulated as a liquid suitable for administration by injection or infusion, or formulated to cause slow release of said triple agonist compound.

19. 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 the triple agonist compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

20. The method according to claim 19 wherein:

(a) the diabetes related disorder is insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, bone related disorder or a combination thereof;

(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, wherein optionally 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; or

(c) the obesity related disorder is obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, or associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, a proinflammatory state, or a combination thereof.

21. The compound according to claim 4 , further comprising:

Aib2, Ser2 or Ac4c2; or

Tyr10; or

Leu10.

22. The compound according to claim 6 which differs at up to 4 positions from one of the sequences:

(SEQ ID NO: 63)

Y-Aib-QGTFTSDYSIYLEKψAAKEFVEWLLSA;

(SEQ ID NO: 60)

Y-Aib-QGTFTSDYSIYLDEψAAHDFVEWLLSA; and

(SEQ ID NO: 77)

Y-Aib-QGTFTSDYSIALEKψAQRAFVEWLLAQ.

23. The compound according to claim 1 , wherein the peptide backbone of Formula (I) has the sequence:

(SEQ ID NO: 4)

YSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)-

KAAHDFVEWLLRA;

(SEQ ID NO: 27)

Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLSA;

(SEQ ID NO: 28)

Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 2)

Y-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLSA;

(SEQ ID NO: 22)

Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-

AAKEFVEWLLSA;

(SEQ ID NO: 23)

Y-Aib-QGTFTSDYSIYLE-K(Hexadecanoyl-isoGlu)-

KAAKEFVEWLLSA;

(SEQ ID NO: 24)

Y-Aib-QGTFTSDYS-K(Hexadecanoyl-isoGlu)-

YLEKKAAKEFVEWLLSA;

(SEQ ID NO: 103)

Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-

AAKEFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 36)

Y-Aib-QGTFTSDYSIYLEK-K(Octadecanoyl-isoGlu-Peg3-

Peg3)-AAKEFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 37)

Y-Aib-QGTFTSDYSIYLEK-K([17-carboxy-heptadecanoyl]-

isoGlu-Peg3-Peg3)-AAKEFVEWLLSAGPSSGAPPPS;

(SEQ ID NO: 32)

Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]-

isoGlu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 33)

Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]-

isoGlu)-AQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 34)

Y-Aib-QGTFTSDYSIYLDK-K(Octadecanoyl-isoGlu-Peg3-

Peg3)-AQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 104)

Y-Aib-QGTFTSDYSIYLD-K(eicosanoyl-isoGlu-Peg3-

Peg3)-AQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 44)

Y-Aib-QGTFTSDYSIALEK-K([17-carboxy-heptadecanoyl]-

isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK;

(SEQ ID NO: 45)

Y-Aib-QGTFTSDYSIALEK-K(Octadecanoyl-isoGlu-Peg3-

Peg3)-AQRAFVEWLLAQK;

(SEQ ID NO: 105)

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

isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK;

(SEQ ID NO: 106)

Y-Aib-QGTFTSDLSIALE-K(Octadecanoyl-isoGlu-Peg3-

Peg3)-AQRAFVEWLLAQK;

(SEQ ID NO: 25)

Y-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA;

(SEQ ID NO: 29)

Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFVEWLESA;

(SEQ ID NO: 30)

Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA;

(SEQ ID NO: 38)

Y-Aib-QGTFTSDYSIYLDE-K(Octadecanoyl-isoGlu-Peg3-

Peg3)-AAKEFIEWLESA;

(SEQ ID NO: 39)

Y-Aib-QGTFTSDYSIYLDE-K([17-carboxy-heptadecanoyl]-

isoGlu-Peg3-Peg3)-AAKEFIEWLESA;

(SEQ ID NO: 26)

Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLRA;

(SEQ ID NO: 96)

Y-Aib-QGTFTSDYSIYLE-K(Octadecanoyl-isoGlu-Peg3-

Peg3)-AQRAFVEWLLRA;

(SEQ ID NO: 97)

Y-Aib-QGTFTSDYSIYLE-K([17-carboxy-heptadecanoyl]-

isoGlu-Peg3-Peg3)-AQRAFVEWLLRA;

(SEQ ID NO: 107)

Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-isoGlu-Peg3-

Peg3)-AQRAFVNWLVA-Aib-KPSSGAPPPS;

(SEQ ID NO: 108)

Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-Dapa-Peg3-

Peg3)-AQRAFVNWLVA-Aib-KPSSGAPPPS;

(SEQ ID NO: 43)

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

isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib-KPSSGAPPPS;

(SEQ ID NO: 40)

Y-Ac4c-QGTFTSDYSIYLDE-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-AAKEFIEWLESA;

(SEQ ID NO: 109)

Y-Ac4c-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK;

or

(SEQ ID NO: 51)

Y-Ac4c-QGTFTSDYSIYLDK-K(19-carboxy-heptadecanoyl-

isoGlu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS.

24. The method according to claim 20 , wherein the bone related disorder is osteoporosis.