GIP-GLP-1 dual agonist compounds and methods

1. A GIP analogue represented by the general formula I′:

(I')

(SEQ 10 NO: 61)

R 1 -Tyr-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-X12-

X13-X14-X15-X16-Lys-Ala-X19-X20-X21-X22-X23-X24-

Trp-Leu-X27-X28-X29-X30-X31-X32-X33-X34-X35-

X36-X37-X38-X39-X40-X41-X42-R 2

or a pharmaceutically acceptable salt thereof,

wherein

R 1 is Hy-, Ac or pGlu;

X2 is Ala, Aib or Gly;

X3 is Glu or Asp;

X7 is Thr, Ser, or Ile;

X9 is Asp or Glu;

X10 is Tyr, Leu or Ser;

X11 is Ser or Leu;

X12 is Ile or Lys;

X13 is Ala, Tyr or Aib;

X14 is Met, Leu or Ser;

X15 is Asp or Glu;

X16 is Lys, Gly, Ser or Glu;

X19 is Gln, Ala, Glu or Lys;

X20 is Gln, Lys, Arg or His;

X21 is Asp, Ala or Glu;

X22 is Phe or 1Nal;

X23 is Val, Ile or Leu;

X24 is Asn, Glu, Arg or Lys;

X27 is Leu, Val, Ile, Lys, Glu or Ser;

X28 is Ala, Ser, Arg or Aib;

X29 is Gln, Aib, Lys, Gly or Ala;

X30 is Lys, Gly, Pro or absent;

X31 is Gly, Pro, Ser, Glu or absent;

X32 is Lys, Ser or absent;

X33 is Lys, Ser, Glu or absent;

X34 is Asn, Gly, Ala, Lys or absent;

X35 is Asp, Ala, Pro, Glu or absent;

X36 is Trp, Pro, Lys or absent;

X37 is Lys, Pro, Glu or absent;

X38 is His, Pro, Ser, Lys or absent;

X39 is Asn, Ser or absent;

X40 is Ile or absent;

X41 is Thr or absent;

X42 is Gln or absent; and

R 2 is —NH2 or —OH.

2. The GIP analogue of claim 1 , wherein the GIP analogue is represented by the general Formula I(b)′:

(I(b)')

(SEQ ID NO: 63)

R 1 -Tyr-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-X12-

X13-X14-X15-X16-Lys-Ala-X19-X20-X21-Phe-X23-X24-

Trp-Leu-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-

X37-X38-X39-X40-X41-X42-R 2

or a pharmaceutically acceptable salt thereof,

wherein

R1 is Hy-, Ac or pGlu;

X2 is Ala, Aib or Gly;

X3 is Glu or Asp;

X7 is Thr or Ser;

X9 is Asp or Glu;

X10 is Tyr or Leu;

X11 is Ser or Leu;

X12 is Ile or Lys;

X13 is Ala, Tyr or Aib;

X14 is Leu or Ser;

X15 is Asp or Glu;

X16 is Lys, Ser or Glu;

X19 is Gln, Ala, Glu or Lys;

X20 is Gln, Lys, Arg or His;

X21 is Asp, Ala or Glu;

X23 is Val, Ile or Leu;

X24 is Asn, Glu, Arg or Lys;

X27 is Leu, Glu, Val or Ile;

X28 is Ala, Ser, Arg or Aib;

X29 is Gln, Gly, Aib or Ala;

X30 is Lys, Gly, Pro or absent;

X31 is Gly, Pro, Ser, Glu or absent;

X32 is Lys, Ser or absent;

X33 is Lys, Ser, Glu or absent;

X34 is Asn, Gly, Ala, Lys or absent;

X35 is Asp, Ala, Pro, Glu or absent;

X36 is Trp, Pro, Lys or absent;

X37 is Lys, Pro, Glu or absent;

X38 is His, Pro, Ser, Lys or absent;

X39 is Asn, Ser or absent;

X40 is Ile or absent;

X41 is Thr or absent;

X42 is Gln or absent; and

R 2 is —NH 2 or —OH.

3. A GIP analogue represented by the general Formula II′:

(II')

(SEQ ID NO: 64)

R 1 -Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-

X12-X13-Leu-X15-X16-Lys-Ala-X19-X20-X21-Phe-X23-

X24-Trp-Leu-X27-X28-X29-X30-Y1-R 2

or a pharmaceutically acceptable salt thereof,

wherein

R1 is Hy-, Ac or pGlu;

X2 is Aib or Gly;

X7 is Thr, Ile or Ser;

X10 is Tyr or Leu;

X11 is Ser or Leu;

X12 is Ile or Lys;

X13 is Ala, Tyr or Aib;

X15 is Asp or Glu;

X16 is Ser, Glu or Lys;

X17 is Ile or Lys;

X19 is Gln or Ala;

X20 is Lys, His or Arg;

X21 is Ala, Asp or Glu;

X23 is Val or Ile;

X24 is Asn, Lys or Glu;

X27 is Leu, Glu, Val or Ile;

X28 is Aib, Ala, Ser or Arg;

X29 is Gln, Aib, Ala, Gly or Lys;

X30 is Lys, Gly or absent;

Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:74), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:75), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:76), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:77) or absent; and

R 2 is —NH 2 or —OH.

4. The GIP analogue of claim 3 , wherein the GIP analogue is represented by the general Formula II(a)′:

(II9a)')

(SEQ ID NO: 65)

R 1 -Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-Ile-

X13-Leu-X15-X16-Lys-Ala-X19-X20-X21-Phe-X23-X24-

Trp-Leu-X27-X28-X29-X30-Y1-R 2

wherein

R 1 is Hy-, Ac or pGlu;

X2 is Aib or Gly;

X7 is Thr, Ile or Ser;

X10 is Tyr or Leu;

X11 is Ser or Leu;

X13 is Ala, Tyr or Aib;

X15 is Asp or Glu;

X16 is Ser, Glu or Lys;

X19 is Gln or Ala;

X20 is Lys, His or Arg;

X21 is Ala, Asp or Glu;

X23 is Val or Ile;

X24 is Asn, Lys or Glu;

X27 is Leu, Glu, Val or Ile;

X28 is Aib, Ala, Ser or Arg;

X29 is Gln, Aib, Ala or Gly;

X30 is Lys, Gly or absent;

Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:74), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:75), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:76), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:77) or absent; and

R 2 is —NH 2 or —OH.

5. The GIP analogue of claim 4 , wherein the GIP analogue is represented by the general Formula II(b)′:

(II(b)')

(SEQ ID NO: 66)

R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-

X13-Leu-X15-X16-Lys-Ala-Gln-X20-X21-Phe-X23-Glu-

Trp-Leu-X27-X28-Ala-X30-Y1-R 2

or a pharmaceutically acceptable salt thereof,

wherein

R 1 is Hy-, Ac or pGlu;

X7 is Thr or Ser;

X13 is Ala or Tyr;

X15 is Asp or Glu;

X16 is Lys, Glu or Ser;

X20 is Lys, His or Arg;

X21 is Ala, Asp or Glu;

X23 is Val or Ile;

X27 is Leu, Glu or Val;

X28 is Arg or Ser;

X30 is Lys, Gly or absent;

Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:74), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:75), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:76), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:77) or absent; and

R 2 is —NH 2 or —OH.

6. The GIP analogue of claim 4 , wherein the GIP analogue is represented by the general Formula II(c)′:

(II(c)')

(SEQ ID NO: 67)

R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-

Ile-X13-Leu-X15-X16-Lys-Ala-Gln-X20-X21-Phe-Val-

X24-Trp-Leu-X27-Ala-X29-X30-Y1-R 2

or a pharmaceutically acceptable salt thereof,

wherein

R 1 is Hy-, Ac or pGlu;

X7 is Thr or Ser;

X13 is Ala, Aib or Tyr;

X15 is Asp or Glu;

X16 is Glu, Lys or Ser;

X20 is Lys, His or Arg;

X21 is Ala, Asp or Glu;

X24 is Glu or Asn;

X27 is Leu, Glu or Val;

X29 is Gln or Aib;

X30 is Lys, Gly or absent;

Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:74), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:75), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:76), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:77) or absent; and

R 2 is —NH 2 or —OH.

7. The GIP analogue of claim 4 , wherein the GIP analogue is represented by the general Formula II(d)′:

(II(d)')

(SEQ ID NO: 68)

R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-

Ile-X13-Leu-X15-X16-Lys-Ala-Gln-X20-Ala-Phe-Val-

Glu-Trp-Leu-X27-Ala-Gln-X30-Y1-R 2

or a pharmaceutically acceptable salt thereof,

wherein

R 1 is Hy-, Ac or pGlu;

X7 is Thr or Ser;

X13 is Ala, Aib or Tyr;

X15 is Asp or Glu;

X16 is Glu, Lys or Ser;

X20 is Lys, His or Arg;

X27 is Leu, Glu or Val;

X30 is Lys, Gly or absent;

Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:74), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:75), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:76), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:77) or absent; and

R 2 is —NH 2 or —OH.

8. A GIP analogue of claim 1 , wherein the amino acid sequence X1-X29 has no more than 6 amino acid differences from the sequence

Y-Aib-EGTFTSDYSIYLDKKAQRAFVEWLLAQ (SEQ ID NO: 70).

9. A GIP analogue of claim 1 , wherein the amino acid sequence X1-X29 has no more than 6 amino acid differences from the sequence Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA (SEQ ID NO: 71).

10. A GIP analogue of claim 1 , wherein the amino acid sequence X1-X29 has no more than 5 amino acid differences from sequence

Y-Aib-EGTFTSDYSIYLDEKAAKEFIEWLESA (SEQ ID NO: 72).

11. A GIP analogue according to claim 1 , wherein X24 is Glu and/or X21 is Ala.

12. A GIP analogue according to claim 1 , wherein X7 is Thr and X14 is Leu.

13. A GIP analogue according to claim 1 , wherein X7 is Thr, X14 is Leu and X18 is Ala.

14. A GIP analogue according to claim 1 , wherein X2 is Aib, X7 is Thr and X14 is Leu.

15. A GIP analogue according to claim 1 , wherein X2 is Aib, X7 is Thr, X14 is Leu and X13 and/or X29 is Aib.

16. A GIP analogue according to claim 1 , wherein X2 is Aib, X7 is Thr, X14 is Leu and X24 is Glu.

17. A GIP analogue according to claim 1 , wherein X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu and X29 is Gln.

18. A GIP analogue according to claim 1 , wherein X2 is Aib, X7 is Thr, X14 is Leu, X21 is Ala, X24 is Glu and X29 is Gln.

19. A GIP analogue according to claim 1 , wherein X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu, X27 is Leu and X28 is Ser.

20. A GIP analogue according to claim 1 , wherein X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu, X27 is Glu and X28 is Ser.

21. A GIP analogue according to claim 1 , wherein X2 is Aib, X7 is Thr, X14 is Leu, X20 is His, X24 is Glu, X27 is Leu and X28 is Ser.

22. A GIP analogue according to claim 1 selected from:

(SEQ ID NO: 94)

Hy-Y-Aib-EGTFISDYSIYLEKKAAKEFVNWLLAQK-NH 2

(Compound 1);

(SEQ ID NO: 95)

Hy-Y-Aib-EGTFTSDYSI-Aib-

LDKKAQRAFVEWLLAQGPSSGAPPPS-NH 2 (Compound 2);

(SEQ ID NO: 98)

Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 5);

(SEQ ID NO: 99)

pGlu-YAEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 6);

(SEQ ID NO: 100)

Hy-YGEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 7);

(SEQ ID NO: 101)

Hy-Y-Aib-EGTFSSDYSIYLDKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 8);

(SEQ ID NO: 102)

Hy-Y-Aib-EGTFTSDLSIYLDKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 9);

(SEQ ID NO: 103)

Hy-Y-Aib-EGTFTSDYLIYLDKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 11);

(SEQ ID NO: 104)

Hy-Y-Aib-EGTFTSDYSIALDKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 12);

(SEQ ID NO: 105)

Hy-Y-Aib-EGTFTSDYSIYSDKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 13);

(SEQ ID NO: 106)

Hy-Y-Aib-EGTFTSDYSIYLEKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 14);

(SEQ ID NO: 107)

Hy-Y-Aib-EGTFTSDYSIALEKKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 15);

(SEQ ID NO: 108)

Hy-Y-Aib-EGTFTSDYSIYLDSKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 16);

(SEQ ID NO: 109)

Hy-Y-Aib-EGTFTSDYSIYLDEKAQRAFVNWLLA-Aib-K-

NH 2  (Compound 17);

(SEQ ID NO: 110)

Hy-Y-Aib-EGTFTSDYSIYLDSKAKRAFVNWLLA-Aib-K-

NH 2  (Compound 18);

(SEQ ID NO: 111)

Hy-Y-Aib-EGTFTSDYSIYLDKKAQKEFVNWLLA-Aib-K-

NH 2  (Compound 19);

(SEQ ID NO: 112)

Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVKWLLA-Aib-

K-NH 2  (Compound 20);

(SEQ ID NO: 113)

Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLVA-Aib-

K-NH 2  (Compound 21);

(SEQ ID NO: 114)

Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLKA-Aib-

K-NH 2  (Compound 23);

(SEQ ID NO: 115)

Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLL-Aib-K-

NH 2  (Compound 24);

(SEQ ID NO: 118)

Hy-Y-Aib-EGTFTSDYSIYLDKKAEKAFVNWLLA-Aib-K-

NH 2  (Compound 27);

(SEQ ID NO: 119)

Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-

GPSSGAPPPS-NH 2  (Compound 28);

(SEQ ID NO: 120)

Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-

GPSSGAPPS-NH 2  (Compound 29);

(SEQ ID NO: 121)

Hy-Y-Aib-EGTFTSDYSIYLEKKAAKEFVNWLLAQK-

NH 2  (Compound 30);

(SEQ ID NO: 122)

Hy-Y-Aib-EGTFTSDYSIYLDK-K(15-carboxy-

pentadecanoyl-isoGlu)-AQRAFVNWLLA-Aib-

K-NH 2  (Compound 31);

(SEQ ID NO: 123)

Hy-Y-Aib-EGTFTSDYSI-Aib-LDK-K(Hexadecanoyl-

isoGlu)-AQRAFVEWLLAQGPSSGAPPPS-NH 2 (Compound 32);

(SEQ ID NO: 124)

Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-

AQRAFVEWLLAQGPSSGAPPPS-NH 2 (Compound 33);

(SEQ ID NO: 125)

Hy-Y-Aib-EGTFTSDYSIYLDE-K(hexadecanoyl-isoGlu)-

AAKEFIEWLESA-NH 2 (Compound 34);

(SEQ ID NO: 126)

Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-

AQRAFVNWLLA-Aib-KPSSGAPPPS-NH 2 (Compound 35);

(SEQ ID NO: 127)

Hy-Y-Aib-EGTFTSDYSIALDK-K(hexadecanoyl-isoGlu)-

AQRAFVNWLVA-Aib-KPSSGAPPPS-NH 2  (Compound 36);

(SEQ ID NO: 128)

Hy-Y-Aib-EGTFTSDYSIYLE-KKAAKDFVEWLLSA-NH 2

(Compound 37);

(SEQ ID NO: 129)

Hy-Y-Aib-EGTFTSDYSIYLE-KKAAHDFVEWLLSA-NH 2

(Compound 38);

(SEQ ID NO: 130)

Hy-Y-Aib-EGTFTSDYSIYLEKKAQKEFVEWLLSA-NH 2

(Compound 39);

(SEQ ID NO: 131)

Hy-Y-Aib-EGTFTSDYSIYLDEKAAKDFVEWLLSA-NH 2

(Compound 40);

(SEQ ID NO: 132)

Hy-Y-Aib-EGTFTSDYSIYLESKAAHDFVEWLLSA-NH 2

(Compound 41);

(SEQ ID NO: 133)

Hy-Y-Aib-EGTFTSDYSIYLDKKAAHDFVEWLLSA-NH 2

(Compound 42);

(SEQ ID NO: 134)

Hy-Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA-NH 2

(Compound 43);

(SEQ ID NO: 135)

Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLRA-NH 2

(Compound 44);

(SEQ ID NO: 136)

Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLSA-NH 2  (Compound 45);

(SEQ ID NO: 137)

Hy-Y-Aib-EGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-

AAKEFVEWLLSA-NH 2 (Compound 46);

(SEQ ID NO: 138)

Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLRA-NH 2  (Compound 47);

(SEQ ID NO: 139)

Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFVEWLESA-NH 2  (Compound 48);

(SEQ ID NO: 140)

Hy-Y-Aib-EGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA-NH 2  (Compound 49);

(SEQ ID NO: 141)

Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA-NH 2  (Compound 50);

(SEQ ID NO: 142)

Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLRA-NH 2  (Compound 51);

(SEQ ID NO: 143)

Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFVEWLLSA-NH 2 (Compound 52);

(SEQ ID NO: 144)

Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLSAGPSSGAPPPS-NH 2 (Compound 53);

(SEQ ID NO: 145)

Hy-Y-Aib-EGTFTSDYSIYLEK-K-(Hexadecanoyl-isoGlu)-

AAKEFVEWLLSAGPSSGAPPPS-NH 2 (Compound 54);

and

(SEQ ID NO: 146)

Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS-

NH 2  (Compound 55); 

and

(SEQ ID NO: 147)

Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLSA-NH 2  (Compound 57),

or a pharmaceutically acceptable salt thereof.

23. A GIP analogue according to claim 1 with a lipophilic substituent conjugated to one or more of positions 15, 16, 17, 19, 20, 24, 27, 28 and 30.

24. A pharmaceutical composition comprising a GIP analogue of claim 1 , or a salt thereof, in admixture with a carrier.

25. The pharmaceutical composition of claim 24 , wherein the GIP analogue is a pharmaceutically acceptable acid addition salt.

26. The pharmaceutical composition of claim 24 , which is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of said GIP analogue.

27. A therapeutic kit comprising a GIP analogue according to claim 1 , optionally in combination with a pharmaceutically acceptable carrier.

28. A device comprising a GIP analogue according to claim 1 , for delivery of the GIP analogue to a subject.