U.S. patent application number 16/121745 was filed with the patent office on 2019-05-09 for gip-glp-1 dual agonist compounds and methods.
The applicant listed for this patent is Zealand Pharma A/S. Invention is credited to Kate HANSEN, Lene JESSEN, Rasmus JUST, Torben OSTERLUND, Ditte RIBER, Anne Pernille Tofteng SHELTON.
Application Number | 20190135886 16/121745 |
Document ID | / |
Family ID | 48325702 |
Filed Date | 2019-05-09 |
United States Patent
Application |
20190135886 |
Kind Code |
A1 |
JUST; Rasmus ; et
al. |
May 9, 2019 |
GIP-GLP-1 DUAL AGONIST COMPOUNDS AND METHODS
Abstract
The present invention relates to truncated GIP analogues which
comprise one or more substitutions as compared to wild-type GIP and
which may have the property of an altered, preferably increased
GLP-1 activity, e.g. as assessed in in vitro efficacy assays. The
invention provides GIP-GLP-1 dual agonist compounds and associated
methods.
Inventors: |
JUST; Rasmus; (Copenhagen,
DK) ; RIBER; Ditte; (Bronshoj, DK) ; SHELTON;
Anne Pernille Tofteng; (Valby, DK) ; OSTERLUND;
Torben; (Lund, SE) ; HANSEN; Kate; (Copenhagen
NV, DK) ; JESSEN; Lene; (Glostrup, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Zealand Pharma A/S |
Glostrup |
|
DK |
|
|
Family ID: |
48325702 |
Appl. No.: |
16/121745 |
Filed: |
September 5, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14398260 |
Oct 31, 2014 |
10100097 |
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PCT/EP2013/059319 |
May 3, 2013 |
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16121745 |
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61765561 |
Feb 15, 2013 |
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61642439 |
May 3, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 11/16 20180101; A61P 1/04 20180101; A61P 3/06 20180101; C07K
14/575 20130101; A61P 3/10 20180101; A61P 9/12 20180101; A61K 38/00
20130101; A61P 9/14 20180101; A61P 3/04 20180101; A61P 29/00
20180101; A61P 5/50 20180101; C07K 14/605 20130101; A61P 3/08
20180101; A61P 9/10 20180101 |
International
Class: |
C07K 14/575 20060101
C07K014/575; C07K 14/605 20060101 C07K014/605 |
Claims
1. A method of treating a disease or condition in a patient in need
thereof comprising administering an effective amount of a GIP
analogue represented by the general Formula I':
R.sup.1-Tyr-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-X12-X13-X14-X15-X16-Lys-A-
la-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.sup.2 (I') (SEQ ID NO: 61) or a
pharmaceutically acceptable salt thereof, wherein R.sup.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.sup.2 is
--NH.sub.2 or --OH, wherein the disease or condition is selected
from the group consisting of a stomach and/or bowel-related
disorder, a metabolic disease or disorder, a diabetes-related
disorder, and an obesity-related disorder.
2. The method of claim 1, wherein the GIP analogue is represented
by the general Formula I(b)':
R.sup.1-Tyr-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-X12-X13-X14-X15-X16-Lys-A-
la-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.sup.2 (I(b)') (SEQ ID NO: 63) 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.sup.2 is
--NH.sub.2 or --OH.
3. A method of treating a disease or condition in a patient in need
thereof comprising administering an effective amount of a GIP
analogue represented by the general Formula II':
R.sup.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.sup.2
(II') (SEQ ID NO: 64), 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,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH, wherein the disease or condition is selected
from the group consisting of a stomach and/or bowel-related
disorder, a metabolic disease or disorder, a diabetes-related
disorder, and an obesity-related disorder.
4. The method of claim 3, wherein the GIP analogue is represented
by the general Formula II(a)':
R.sup.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.sup.2
(II(a)') (SEQ ID NO: 65) wherein R.sup.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, Lys, Ala or Glu; 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,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
5. The method of claim 4, wherein the GIP analogue is represented
by the general Formula II(b)':
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-Ly-
s-Ala-Gln-X20-X21-Phe-X23-Glu-Trp-Leu-X27-X28-Ala-X30-Y1-R.sup.2
(II(b)') (SEQ ID NO: 66) or a pharmaceutically acceptable salt
thereof, wherein R.sup.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,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
6. The method of claim 4, wherein the GIP analogue is represented
by the general Formula II(c)':
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-Ly-
s-Ala-Gln-X20-X21-Phe-Val-X24-Trp-Leu-X27-Ala-X29-X30-Y1-R.sup.2
(II(c)) (SEQ ID NO: 67) or a pharmaceutically acceptable salt
thereof, wherein R.sup.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,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
7. The method of claim 5, wherein the GIP analogue is represented
by the general Formula II(d)':
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-Ly-
s-Ala-Gln-X20-Ala-Phe-Val-Glu-Trp-Leu-X27-Ala-Gln-X30-Y1-R.sup.2
(II(d)) (SEQ ID NO: 68) or a pharmaceutically acceptable salt
thereof, wherein R.sup.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,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
8. The method 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. The method 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. The method 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. The method of claim 1 wherein: X24 is Glu and/or X21 is Ala; or
X7 is Thr and X14 is Leu; or X7 is Thr, X14 is Leu and X18 is Ala;
or X2 is Aib, X7 is Thr and X14 is Leu; or X2 is Aib, X7 is Thr,
X14 is Leu and X13 and/or X29 is Aib; or X2 is Aib, X7 is Thr, X14
is Leu and X24 is Glu; or X2 is Aib, X7 is Thr, X14 is Leu, X24 is
Glu and X29 is Gln; or X2 is Aib, X7 is Thr, X14 is Leu, X21 is
Ala, X24 is Glu and X29 is Gln; or X2 is Aib, X7 is Thr, X14 is
Leu, X24 is Glu, X27 is Leu and X28 is Ser; or X2 is Aib, X7 is
Thr, X14 is Leu, X24 is Glu, X27 is Glu and X28 is Ser; or X2 is
Aib, X7 is Thr, X14 is Leu, X20 is His, X24 is Glu, X27 is Leu and
X28 is Ser.
12-21. (canceled)
22. A method of treating a disease or condition in a patient in
need thereof comprising administering an effective amount of a GIP
analogue selected from:
Hy-Y-Aib-EGTFISDYSIYLEKKAAKEFVNWLLAQK-NH.sub.2 (SEQ ID NO: 3)
(Compound 1);
Hy-Y-Aib-EGTFTSDYSI-Aib-LDKKAQRAFVEWLLAQGPSSGAPPPS-NH.sub.2 (SEQ ID
NO: 4) (Compound 2);
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 7)
(Compound 5); pGlu-YAEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 (SEQ
ID NO: 8) (Compound 6);
Hy-YGEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 9)
(Compound 7); Hy-Y-Aib-EGTFSSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2
(SEQ ID NO: 10) (Compound 8);
Hy-Y-Aib-EGTFTSDLSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 11)
(Compound 9); Hy-Y-Aib-EGTFTSDYLIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2
(SEQ ID NO: 13) (Compound 11);
Hy-Y-Aib-EGTFTSDYSIALDKKAQRAFVNWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 14)
(Compound 12); Hy-Y-Aib-EGTFTSDYSIYSDKKAQRAFVNWLLA-Aib-K-NH.sub.2
(SEQ ID NO: 15) (Compound 13);
Hy-Y-Aib-EGTFTSDYSIYLEKKAQRAFVNWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 16)
(Compound 14); Hy-Y-Aib-EGTFTSDYSIALEKKAQRAFVNWLLA-Aib-K-NH.sub.2
(SEQ ID NO: 17) (Compound 15);
Hy-Y-Aib-EGTFTSDYSIYLDSKAQRAFVNWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 18)
(Compound 16); Hy-Y-Aib-EGTFTSDYSIYLDEKAQRAFVNWLLA-Aib-K-NH.sub.2
(SEQ ID NO: 19) (Compound 17);
Hy-Y-Aib-EGTFTSDYSIYLDSKAKRAFVNWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 20)
(Compound 18); Hy-Y-Aib-EGTFTSDYSIYLDKKAQKEFVNWLLA-Aib-K-NH.sub.2
(SEQ ID NO: 21) (Compound 19);
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVKWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 22)
(Compound 20); Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLVA-Aib-K-NH.sub.2
(SEQ ID NO: 23) (Compound 21);
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLKA-Aib-K-NH.sub.2 (SEQ ID NO: 25)
(Compound 23); Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLL-Aib-K-NH.sub.2
(SEQ ID NO: 26) (Compound 24);
Hy-Y-Aib-EGTFTSDYSIYLDKKAEKAFVNWLLA-Aib-K-NH.sub.2 (SEQ ID NO: 29)
(Compound 27);
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-GPSSGAPPPS-NH.sub.2 (SEQ ID
NO: 30) (Compound 28);
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-GPSSGAPPS-NH.sub.2 (SEQ ID
NO: 31) (Compound 29);
Hy-Y-Aib-EGTFTSDYSIYLEKKAAKEFVNWLLAQK-NH.sub.2 (SEQ ID NO: 32)
(Compound 30);
Hy-Y-Aib-EGTFTSDYSIYLDK-K(15-carboxy-pentadecanoyl-isoGlu)-AQRAFVNWLLA-Ai-
b-K-NH.sub.2 (SEQ ID NO: 35) (Compound 31);
Hy-Y-Aib-EGTFTSDYSI-Aib-LDK-K(Hexadecanoyl-isoGlu)-AQRAFVEWLLAQGPSSGAPPPS-
-NH.sub.2 (SEQ ID NO: 36) (Compound 32);
Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-AQRAFVEWLLAQGPSSGAPPPS-NH.-
sub.2 (SEQ ID NO: 37) (Compound 33);
Hy-Y-Aib-EGTFTSDYSIYLDE-K(hexadecanoyl-isoGlu)-AAKEFIEWLESA-NH.sub.2
(SEQ ID NO: 38) (Compound 34);
Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-AQRAFVNWLLA-Aib-KPSSGAPPPS-
-NH.sub.2 (SEQ ID NO: 39) (Compound 35);
Hy-Y-Aib-EGTFTSDYSIALDK-K(hexadecanoyl-isoGlu)-AQRAFVNWLVA-Aib-KPSSGAPPPS-
-NH.sub.2 (SEQ ID NO: 40) (Compound 36);
Hy-Y-Aib-EGTFTSDYSIYLE-KKAAKDFVEWLLSA-NH.sub.2 (SEQ ID NO: 41)
(Compound 37); Hy-Y-Aib-EGTFTSDYSIYLE-KKAAHDFVEWLLSA-NH.sub.2 (SEQ
ID NO: 93) (Compound 38);
Hy-Y-Aib-EGTFTSDYSIYLEKKAQKEFVEWLLSA-NH.sub.2 (SEQ ID NO: 42)
(Compound 39); Hy-Y-Aib-EGTFTSDYSIYLDEKAAKDFVEWLLSA-NH.sub.2 (SEQ
ID NO: 43) (Compound 40);
Hy-Y-Aib-EGTFTSDYSIYLESKAAHDFVEWLLSA-NH.sub.2 (SEQ ID NO: 44)
(Compound 41); Hy-Y-Aib-EGTFTSDYSIYLDKKAAHDFVEWLLSA-NH.sub.2 (SEQ
ID NO: 45) (Compound 42);
Hy-Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA-NH.sub.2 (SEQ ID NO: 46)
(Compound 43); Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLRA-NH.sub.2 (SEQ
ID NO: 47) (Compound 44);
Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA-NH.sub.2
(SEQ ID NO: 48) (Compound 45);
Hy-Y-Aib-EGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-AAKEFVEWLLSA-NH.sub.2
(SEQ ID NO: 49) (Compound 46);
Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLRA-NH.sub.2
(SEQ ID NO: 50) (Compound 47);
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFVEWLESA-NH.sub.2
(SEQ ID NO: 51) (Compound 48);
Hy-Y-Aib-EGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA-NH.sub.2
(SEQ ID NO: 52) (Compound 49);
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA-NH.sub.2
(SEQ ID NO: 53) (Compound 50);
Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLRA-NH.sub.2
(SEQ ID NO: 54) (Compound 51);
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFVEWLLSA-NH.sub.2
(SEQ ID NO: 55) (Compound 52);
Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSAGPSSGAPPPS-NH.-
sub.2 (SEQ ID NO: 56) (Compound 53);
Hy-Y-Aib-EGTFTSDYSIYLEK-K-(Hexadecanoyl-isoGlu)-AAKEFVEWLLSAGPSSGAPPPS-NH-
.sub.2 (SEQ ID NO: 57) (Compound 54);
Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS-NH.sub.2 (SEQ ID NO:
58) (Compound 55); and
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA-NH.sub.2
(SEQ ID NO: 69) (Compound 57), or a pharmaceutically acceptable
salt thereof, wherein the disease or condition is selected from the
group consisting of a stomach and/or bowel-related disorder, a
metabolic disease or disorder, a diabetes-related disorder, and an
obesity-related disorder.
23. The method 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.
24-43. (canceled)
44. The method of claim 1, wherein the disease or condition is a
stomach and/or bowel-related disorder.
45. The method of claim 1, wherein the disease or condition is a
metabolic disease or disorder.
46. The method of claim 45, wherein the metabolic disease or
disorder is selected from diabetes and obesity.
47. The method of claim 1, wherein the disease or condition is a
diabetes-related disorder.
48. The method of claim 1, wherein the disease or condition is an
obesity-related disorder.
49. The method of claim 47, wherein the diabetes-related disorder
is selected from insulin resistance, glucose intolerance, increased
fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes,
gestational diabetes hypertension, dyslipidemia, or a combination
thereof.
50. The method of claim 47, wherein the diabetes-related disorder
is selected from atherosclerosis, arteriosclerosis, coronary heart
disease, peripheral artery disease and stroke; or is associated
with a condition selected from atherogenic dyslipidemia, blood fat
disorders, elevated blood pressure, hypertension, a prothrombotic
state, and a proinflammatory state, or a combination thereof.
51. The method of claim 50, wherein the blood fat disorder is
selected from high triglycerides, low HDL cholesterol, high LDL
cholesterol, plaque buildup in artery walls, or a combination
thereof.
52. The method of claim 50, wherein the prothrombotic state is
selected from high fibrinogen levels in the blood and high
plasminogen activator inhibitor-1 levels in the blood.
53. The method of claim 50, wherein the proinflammatory state is an
elevated C-reactive protein level in the blood.
54. The method of claim 48, wherein the obesity-related disorder is
selected from obesity linked inflammation, obesity linked
gallbladder disease and obesity induced sleep apnea.
55-67. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] Diabetes and obesity are increasing health problems globally
and are associated with various other diseases, particularly
cardiovascular diseases (CVD), obstructive sleep apnea, stroke,
peripheral artery disease, microvascular complications and
osteoarthritis. There are 246 million people worldwide with
diabetes, and by 2025 it is estimated that 380 million will have
diabetes. Many have additional cardiovascular risk factors
including high/aberrant LDL and triglycerides and low HDL.
Cardiovascular diseases account for about 50% of the mortality in
people with diabetes, and the morbidity and mortality rates
relating to obesity and diabetes underscore the medical need for
efficacious treatment options.
[0002] Incretins are gastrointestinal hormones that regulate blood
glucose by enhancing glucose-stimulated insulin secretion (Drucker,
D J and Nauck, M A, Lancet 368: 1696-705 (2006)). To date there are
two known incretins: glucagon-like peptide-1 (GLP-1), and
glucose-dependent insulinotropic polypeptide (GIP). The incretin
GLP-1 is derived from the pre-proglucagon gene. Pre-proglucagon is
a 158-amino acid precursor polypeptide that is processed in
different tissues to form a number of different proglucagon-derived
peptides, including glucagon, GLP-1, glucagon-like peptide-2
(GLP-2) and oxyntomodulin (OXM). Glucagon is a 29-amino acid
peptide that corresponds to amino acids 33 through 61 of
pre-proglucagon, while GLP-1 is produced as a 37-amino acid peptide
that corresponds to amino acids 72 through 108 of pre-proglucagon.
GIP is a 42-amino acid peptide derived by proteolytic processing
from a 133-amino acid precursor, pre-pro-GIP. All the peptides are
involved in a wide variety of physiological functions, including
glucose homeostasis, insulin secretion, gastric emptying, and
intestinal growth, as well as the regulation of food intake.
[0003] The discovery of the incretins has led to the development of
two new classes of drugs for the treatment of diabetes mellitus.
Thus, injectable GLP-1 receptor agonists, and small molecule
compounds (oral DPP-4 inhibitors) that inhibit enzymatic
inactivation of both endogenous GLP-1 and GIP, are now on the
market (GLP-1 receptor agonists: Byetta.TM., Bydureon.TM. and
Victoza.TM.; and DPP-4 inhibitors: Januvia.TM., Galvus.TM.,
Onglyza.TM. and Trajenta.TM.). Apart from the acute effects of
GLP-1 and GIP on insulin secretion, the incretins have some
long-term effects. Evidence from several laboratories shows that
GLP-1 receptor agonists protect pancreatic .beta.-cells by
inhibiting apoptosis and enhancing proliferation. For instance, a
study by Farilla et al. showed that GLP-1 has anti-apoptotic
effects in human islets (Farilla, L, Endocrinology 144: 5149-58
(2003)). Such effects have not been reported for GIP until
recently. Weidenmaier et al. reported that a DPP-4 resistant GIP
analogue had anti-apoptotic effects (Weidenmaier, SD, PLOS One
5(3): e9590 (2010)). Interestingly, in mouse models of diabetes and
obesity, the combination of the GLP-1 receptor agonist Liraglutide
and GIP showed superior glucose-lowering and insulinotropic effects
compared to treatment with Liraglutide and GIP alone (Gault, VA,
Clinical Science 121: 107-117 (2011)).
[0004] Chronic treatment with GLP-1 receptor agonists causes
significant weight loss in diabetic humans. Interestingly, extended
use of DPP-4 inhibitors in similar patients does not consistently
change body weight. Evidence suggests (Matthias Tschop oral
presentation at ADA (American Diabetes Association), 2011) that
body weight loss associated with GLP-1 agonist treatment is
enhanced when GLP-1 and GIP are co-administered. In rodents,
co-administration of GLP-1 and GIP results in greater body weight
loss than GLP-1 treatment alone. Thus, in addition to improving
blood glucose control, GIP may also enhance GLP-1-mediated body
weight loss.
SUMMARY OF THE INVENTION
[0005] Broadly, the present invention concerns truncated GIP
analogues which comprise one or more substitutions as compared to
wild-type GIP and which may have the property of an altered,
preferably increased GLP-1 activity, e.g., as assessed in in vitro
efficacy assays. In the present invention it has been found that
GIP-GLP1 dual acting receptor agonists are superior to existing and
marketed GLP-1 analogues because the dual agonists offer improved
glycemic control, and enhanced body weight loss. The GIP-GLP1 dual
agonists (also known as GIP analogues) may thus be used as
therapeutics for type 2 diabetes mellitus, obesity and related
disorders.
[0006] More particularly, preferred GIP analogues of the present
invention comprise non-conservative substitutions at one or more of
amino acid positions 1, 2, 3, 7, 9, 13, 14, 15, 17, 19, 20, 21, 22,
23, 24, 27, 28, 29, and 30 of the wild-type GIP sequence in
combination with Ile, Gln, Lys, Arg or Glu in position 17,
optionally in combination with further conservative or
non-conservative substitutions at one or more of amino acid
positions 10, 11, and 16; and acylation of one or more of amino
acid positions 15, 16, 17, 19, 20, 24, 27, 28 and 30 and/or a
substitution or deletion of one or more of amino acids
corresponding to positions 30 to 42 of the wild-type GIP
sequence.
[0007] In some embodiments, a GIP analogue of the invention is
represented by the general Formula I:
R.sup.1-X1-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-Ile-X13-X14-X15-X16-X17-A-
la-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.sup.2 (I) (SEQ ID NO 59)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X1 is: His or Tyr;
X2 is Ala, Aib or Gly;
X3 is Glu or Asp;
X7 is Thr, Ser or Ile;
X9 is Asp, Glu;
X10 is Tyr, Leu or Ser;
X11 is Ser or Leu;
X13 is Ala, Tyr or Aib;
X14 is Met, Leu or Ser;
X15 is Asp or Glu;
X16 is Lys, Gly, Ser or Glu;
X17 is Ile, Lys, Gln, Arg or Glu;
X19 is Gln, Ala, Glu or Lys;
X20 is Gln, Lys or Arg;
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, Glu, Lys, Gly or Tyr;
[0008] 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.sup.2 is --NH.sub.2 or --OH.
[0009] In some embodiments, a GIP analogue of the invention is
represented by the general Formula
R.sup.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-X3-
6-X37-X38-X39-X40-X41-X42-R.sup.2 (I') (SEQ ID NO 61)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.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;
[0010] 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
[0011] R.sup.2 is --NH.sub.2 or --OH.
[0012] In other embodiments, a GIP analogue of the invention is
represented by the general Formula I(a):
R.sup.1-X1-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-Ile-X13-X14-X15-X16-X17-A-
la-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.sup.2 (I(a)) (SEQ ID NO 33)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X1 is His or Tyr;
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;
X13 is Ala, Tyr or Aib;
X14 is Met, Leu or Ser;
X15 is Asp or Glu;
X16 is Lys, Gly, Ser or Glu;
X17 is Ile, Lys, Gln, Arg or Glu;
X19 is Gln, Ala, Glu or Lys;
X20 is Gln, Lys or Arg;
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, Glu, Lys or Tyr;
[0013] 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.sup.2 is --NH.sub.2 or --OH.
[0014] In other embodiments, a GIP analogue of the invention is
represented by the general Formula I(a)':
R.sup.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-X3-
6-X37-X38-X39-X40-X41-X42-R.sup.2 (I(a)') (SEQ ID NO 62)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.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 Leu or Ser;
X15 is Asp or Glu;
X16 is Lys, Gly, Ser or Glu;
X17 is Ile, Gln, Arg 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;
[0015] 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.sup.2 is --NH.sub.2 or --OH.
[0016] In other embodiments, a GIP analogue of the invention is
represented by the general Formula I(b):
X1-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-Ile-X13-X14-X15-X16-X17-Ala-X19-X-
20-X21-X22-X23-X24-Trp-Leu-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-
-X39-X40-X41-X42-R.sup.2 (I(b)) (SEQ ID NO 1)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X1 is His or Tyr;
X2 is Ala, Aib or Gly;
X3 is Glu or Asp;
X7 is Thr or Ser;
X9 is Asp or Glu;
X10 is Tyr, Leu or Ser;
X11 is Ser or Leu;
X13 is Ala, Tyr or Aib;
X14 is Met, Leu or Ser;
X15 is Asp or Glu;
X16 is Lys, Gly, Ser or Glu;
X17 is Ile, Lys, Gln, Arg or Glu;
X19 is Gln, Ala, Glu or Lys;
X20 is Gln, Lys or Arg;
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 or Ser;
X28 is Ala or Aib;
X29 is Gln, Gly, Aib or Tyr;
[0017] 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.sup.2 is --NH.sub.2 or --OH.
[0018] In other embodiments, a GIP analogue of the invention is
represented by the general Formula I(b)':
R.sup.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-X3-
6-X37-X38-X39-X40-X41-X42-R.sup.2 (I(b)') (SEQ ID NO 63)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 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;
[0019] 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.sup.2 is --NH.sub.2 or --OH.
[0020] In some embodiments, a GIP analogue of the invention is
represented by the general Formula II:
R.sup.1-Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-Ile-X13-X14-X15-X16-X1-
7-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R.sup.2
(II) (SEQ ID NO 60)
wherein R.sup.1 is Hy-, Ac or pGlu;
X2 is Aib or Gly;
X7 is Thr, Ile or Ser;
X10 is Tyr, Leu or Ser
X11 is Ser or Leu;
X13 is Ala, Tyr or Aib;
X14 is Leu;
X15 is Asp or Glu;
X16 is Ser, Glu or Lys;
X17 is Ile or Lys;
X19 is Gln, Lys, Ala or Glu;
X20 is Lys or Arg;
X21 is Ala or Glu;
X23 is Val or Ile;
X24 is Asn or Glu;
X27 is Leu, Glu, Ser, Lys or Val;
X28 is Aib, Ala, Ser or Arg;
X29 is Aib, Glu, Gly or Lys;
[0021] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
[0022] In some embodiments, a GIP analogue of the invention is
represented by the general Formula II':
R.sup.1-Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-X12-X13-Leu-X15-X16-Ly-
s-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R.sup.2
(II') (SEQ ID NO 64)
wherein R.sup.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;
X12 is Ile or Lys;
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, Gly or Lys;
[0023] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
[0024] In other embodiments, a GIP analogue of the invention is
represented by the general Formula II(a):
R.sup.1-Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-Ile-X13-X14-X15-X16-X1-
7-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R.sup.2
(II(a)) (SEQ ID NO 34)
wherein R.sup.1 is Hy-, Ac or pGlu;
X2 is Aib or Gly;
X7 is Thr, Ile or Ser;
X10 is Tyr, Leu or Ser
X11 is Ser or Leu;
X13 is Ala, Tyr or Aib;
X14 is Leu;
X15 is Asp or Glu;
X16 is Ser, Glu or Lys;
X17 is Ile or Lys;
X19 is Gln, Lys, Ala or Glu;
X20 is Lys or Arg;
X21 is Ala or Glu;
X23 is Val or Ile;
X24 is Asn or Glu;
X27 is Leu, Glu, Ser, Lys or Val;
X28 is Aib, Ala, Ser or Arg;
X29 is Aib, Glu or Lys;
[0025] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
[0026] In other embodiments, a GIP analogue of the invention is
represented by the general Formula II(a)':
R.sup.1-Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-Ly-
s-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R.sup.2
(II(a)') (SEQ ID NO 65)
wherein R.sup.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, Lys, Ala or Glu;
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;
[0027] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
[0028] In other embodiments, a GIP analogue of the invention is
represented by the general Formula II(b):
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-X14-X15-Lys-X-
17-Ala-Gln-X20-X21-Phe-X23-X24-Trp-Leu-X27-Ala-X29-X30-Y1-R.sup.2
(II(b)) (SEQ ID NO 2)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X7 is Thr or Ser;
X13 is Ala, Tyr or Aib;
X14 is Leu;
X15 is Asp or Glu;
X17 is Ile or Lys;
X20 is Lys or Arg;
X21 is Ala or Glu;
X23 is Val or Ile;
X24 is Asn or Glu;
X27 is Leu or Val;
X29 is Aib or Gly;
[0029] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
[0030] In other embodiments, a GIP analogue of the invention is
represented by the general Formula II(b)':
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-L-
ys-Ala-Gln-X20-X21-Phe-X23-Glu-Trp-Leu-X27-X28-Ala-X30-Y1-R.sup.2
(II(b)') (SEQ ID NO: 66)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X7 is Thr or Ser;
X13 is Ala or Tyr;
X15 is Asp or Glu;
X16 is Lys 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;
[0031] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
[0032] In other embodiments, a GIP analogue of the invention is
represented by the general Formula II(c):
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-L-
ys-Ala-Gln-X20-X21-Phe-Val-X24-Trp-Leu-X27-Ala-X29-X30-Y1-R.sup.2
(II(c)) (SEQ ID NO: 67)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X7 is Thr or Ser;
X13 is 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;
[0033] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
[0034] In other embodiments, a GIP analogue of the invention is
represented by the general Formula II(d):
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-L-
ys-Ala-Gln-X20-Ala-Phe-Val-Glu-Trp-Leu-X27-Ala-Gln-X30-Y1-R.sup.2
(II(d)) (SEQ ID NO: 68)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X7 is Thr or Ser;
X13 is 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;
[0035] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH.
[0036] Without wishing to be bound by any particular theory, the
Isoleucine at position 7 of native GIP appears to provide
significant selectivity for the GIP receptor. A small polar residue
(e.g. Thr or Ser) at position 7 may increase potency and/or
selectivity at the GLP-1 receptor.
[0037] Without wishing to be bound by any particular theory, it is
believed that substitution of Met found in position 14 of native
GIP with a hydrophobic residue like leucine is important for
enhancing GLP-1 receptor activity and so increase potency and/or
selectivity at the GLP-1 receptor. The substitution of Met at
position 14 with leucine also reduces the potential for oxidation,
so increasing the chemical stability of the compounds. The
non-conservative and non-obvious substitution of Ile for Lys in
position 17 may enhance GLP-1 receptor activity and in addition
provide a handle for acylation to prolong half life of the
peptide.
[0038] Without wishing to be bound by any particular theory, the
histidine at position 18 of native GIP appears to provide
significant selectivity for the GIP receptor. A non-conservative
substitution of histidine in position 18 with a small hydrophobic
residue (e.g. Ala) may increase potency and/or selectivity at the
GLP-1 receptor.
[0039] Without wishing to be bound by any particular theory, it is
believed that a truncation of the C-terminal of native GIP may be
performed without affecting the GIP receptor activity. The
truncation can be of any length (1-13 amino acids) down to a 29
amino acid GIP peptide.
[0040] Without wishing to be bound by any particular theory, the
addition of Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser at or after position 29 or at or
after position 30 of a native GIP or a GIP analogue may increase
GLP1 receptor activity.
[0041] Aib in amino acid position 2 may render GIP peptide having
from 42 amino acids down to 29 amino acids resistant to DPP-IV
cleavage.
[0042] Aib in amino acid position 13 and/or 29 will enhance the
stability of the peptide towards enzymatic degradation. In
addition, without wishing to be bound by any particular theory, the
Aib mayenhance the helicity of the peptide and hence enhance the
GLP-1 receptor activity. Furthermore, Nal1 in position 22 may also
render the peptide stable to enzymatic degradation.
[0043] In a preferred embodiment, the GIP analogue of the invention
comprises: Glu at position 24 and/or Ala at position 21, truncated
or full length, which may be combined with any of the
following:
Thr at position 7, Leu at position 14, truncated or full length;
Thr at position 7, Leu at position 14, Ala at position 18,
truncated or full length; Thr at position 7, Leu at position 14,
Lys at position 17, truncated or full length; Thr at position 7,
Leu at position 14, Lys at position 17, Ala at position 18,
truncated or full length; Aib at position 2, Thr at position 7, Leu
at position 14, Lys at position 17, Ala at position 18, truncated
or full length; Aib at position 2, Thr at position 7, Leu at
position 14, Lys at position 17, Ala at position 18, (Aib at
position 13 and/or 29), truncated or full length; Thr at position
7, Leu at position 14, Ala at position 19, truncated or full
length; Thr at position 7, Leu at position 14, Lys at position 17,
Ala at position 19, truncated or full length; Aib at position 2,
Thr at position 7, Leu at position 14, Lys at position 17, Ala at
position 18, Ala at position 19, truncated or full length; Aib at
position 2, Thr at position 7, Leu at position 14, Lys at position
17, Ala at position 18, Ala at position 19, (Aib at position 13
and/or 29), truncated or full length; Thr at position 7, Leu at
position 14, Gln at position 19, truncated or full length; Thr at
position 7, Leu at position 14, Lys at position 17, Gln at position
19, truncated or full length; Aib at position 2, Thr at position 7,
Leu at position 14, Lys at position 17, Ala at position 18, Gln at
position 19, truncated or full length; or Aib at position 2, Thr at
position 7, Leu at position 14, Lys at position 17, Ala at position
18, Gln at position 19, (Aib at position 13 and/or 29), truncated
or full length. Aib at position 2, Thr at position 7, Leu at
position 14, Lys at position 17, Ala at position 18, Ala at
position 19, truncated or full length; Aib at position 2, Thr at
position 7, Leu at position 14, Lys at position 17, Ala at position
18, Ala at position 19, Leu at position 27, Ser at position 28 and
Ala at position 29, truncated or full length; or Aib at position 2,
Thr at position 7, Leu at position 14, Lys at position 17, Ala at
position 18, Ala at position 19, Glu at position 27, Ser at
position 28 and Ala at position 29, truncated or full length.
[0044] Some embodiments of the invention are:
1. A GIP analogue represented by the general Formula I:
R.sup.1-X1-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-Ile-X13-X14-X15-X16-X17-A-
la-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.sup.2 (I) (SEQ ID NO 59)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X1 is His or Tyr;
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;
X13 is Ala, Tyr or Aib;
X14 is Met, Leu or Ser;
X15 is Asp or Glu;
X16 is Lys, Gly, Ser or Glu;
X17 is Ile, Lys, Gln, Arg or Glu;
X19 is Gln, Ala, Glu or Lys;
X20 is Gln, Lys or Arg;
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, Glu, Lys, Gly or Tyr;
[0045] 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.sup.2 is --NH.sub.2 or --OH. 2. The GIP analogue of
embodiment 1, wherein the GIP analogue is represented by the
general Formula I(a):
R.sup.1-X1-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-Ile-X13-X14-X15-X16-X17-A-
la-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.sup.2 (I(a)) (SEQ ID NO 33)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X1 is His or Tyr;
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;
X13 is Ala, Tyr or Aib;
X14 is Met, Leu or Ser;
X15 is Asp or Glu;
X16 is Lys, Gly, Ser or Glu;
X17 is Ile, Lys, Gln, Arg or Glu;
X19 is Gln, Ala, Glu or Lys;
X20 is Gln, Lys or Arg;
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, Glu, Lys or Tyr;
[0046] 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.sup.2 is --NH.sub.2 or --OH. 3. The GIP analogue of
embodiment 1, wherein the GIP analogue is represented by the
general Formula I(b):
R.sup.1-X1-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-Ile-X13-X14-X15-X16-X17-A-
la-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.sup.2 (I(b)) (SEQ ID NO 1)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X1 is His or Tyr;
X2 is Ala, Aib or Gly;
X3 is Glu or Asp;
X7 is Thr or Ser;
X9 is Asp or Glu;
X10 is Tyr, Leu or Ser;
X11 is Ser or Leu;
X13 is Ala, Tyr or Aib;
X14 is Met, Leu or Ser;
X15 is Asp or Glu;
X16 is Lys, Gly, Ser or Glu;
[0047] X17 is lie, Lys, Gln, Arg or Glu;
X19 is Gln, Ala, Glu or Lys;
X20 is Gln, Lys or Arg;
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 or Ser;
X28 is Ala or Aib;
X29 is Gln, Gly, Aib or Tyr;
[0048] 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.sup.2 is --NH.sub.2 or --OH. 4. A GIP analogue
represented by the general Formula II:
R.sup.1-Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-Ile-X13-X14-X15-X16-X1-
7-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R.sup.2
(II) (SEQ ID NO 60)
wherein R.sup.1 is Hy-, Ac or pGlu;
X2 is Aib or Gly;
X7 is Thr, Ile or Ser;
X10 is Tyr, Leu or Ser
X11 is Ser or Leu;
X13 is Ala, Tyr or Aib;
X14 is Leu;
X15 is Asp or Glu;
X16 is Ser, Glu or Lys;
X17 is Ile or Lys;
X19 is Gln, Lys, Ala or Glu;
X20 is Lys or Arg;
X21 is Ala or Glu;
X23 is Val or Ile;
X24 is Asn or Glu;
X27 is Leu, Glu, Ser, Lys or Val;
X28 is Aib, Ala, Ser or Arg;
X29 is Aib, Glu, Gly or Lys;
[0049] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH. 5. The GIP analogue of embodiment 4, wherein
the GIP analogue is represented by the general Formula II(a):
R.sup.1-Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-Ile-X13-X14-X15-X16-X1-
7-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R.sup.2
(II(a)) (SEQ ID NO 34)
wherein R.sup.1 is Hy-, Ac or pGlu;
X2 is Aib or Gly;
X7 is Thr, Ile or Ser;
X10 is Tyr, Leu or Ser
X11 is Ser or Leu;
X13 is Ala, Tyr or Aib;
X14 is Leu;
X15 is Asp or Glu;
X16 is Ser, Glu or Lys;
X17 is Ile or Lys;
X19 is Gln, Lys, Ala or Glu;
X20 is Lys or Arg;
X21 is Ala or Glu;
X23 is Val or Ile;
X24 is Asn or Glu;
X27 is Leu, Glu, Ser, Lys or Val;
X28 is Aib, Ala, Ser or Arg;
X29 is Aib, Glu or Lys;
[0050] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH. 6. The GIP analogue of embodiment 4, wherein
the GIP analogue is represented by the general Formula II(b):
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-X14-X15-Lys-X-
17-Ala-Gln-X20-X21-Phe-X23-X24-Trp-Leu-X27-Ala-X29-X30-Y1-R.sup.2
(II(b)) (SEQ ID NO 2)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X7 is Thr or Ser;
X13 is Ala, Tyr or Aib;
X14 is Leu;
X15 is Asp or Glu;
X17 is Ile or Lys;
X20 is Lys or Arg;
X21 is Ala or Glu;
X23 is Val or Ile;
X24 is Asn or Glu;
X27 is Leu or Val;
X29 is Aib or Gly;
[0051] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH. 7. A GIP analogue represented by the general
Formula I':
R.sup.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-X3-
6-X37-X38-X39-X40-X41-X42-R.sup.2 (I') (SEQ ID NO 61)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.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;
[0052] 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.sup.2 is --NH.sub.2 or --OH. 8. The GIP analogue of
embodiment 7, wherein the GIP analogue is represented by the
general Formula I(a)':
R.sup.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-X3-
6-X37-X38-X39-X40-X41-X42-R.sup.2 (I(a)') (SEQ ID NO 62)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.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 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;
[0053] 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.sup.2 is --NH.sub.2 or --OH. 9. The GIP analogue of
embodiment 7, wherein the GIP analogue is represented by the
general Formula I(b)':
R.sup.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-X3-
6-X37-X38-X39-X40-X41-X42-R.sup.2 (I(b)') (SEQ ID NO 63)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 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;
[0054] 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.sup.2 is --NH.sub.2 or --OH. 10. A GIP analogue
represented by the general Formula II':
R.sup.1-Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-X12-X13-Leu-X15-X16-Ly-
s-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R.sup.2
(II') (SEQ ID NO 64)
wherein R.sup.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;
X12 is Ile or Lys;
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, Gly or Lys;
[0055] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH. 11. The GIP analogue of embodiment 10, wherein
the GIP analogue is represented by the general Formula II(a)':
R.sup.1-Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-Ly-
s-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R.sup.2
(II(a)') (SEQ ID NO 65)
wherein R.sup.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, Lys, Ala or Glu;
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;
[0056] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH. 12. The GIP analogue of embodiment 10, wherein
the GIP analogue is represented by the general Formula II(b)':
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-L-
ys-Ala-Gln-X20-X21-Phe-X23-Glu-Trp-Leu-X27-X28-Ala-X30-Y1-R.sup.2
(II(b)') (SEQ ID NO: 66)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 is Hy-, Ac or pGlu;
X7 is Thr or Ser;
X13 is Ala, Tyr or Aib;
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;
[0057] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH. 13. The GIP analogue of embodiment 10, wherein
the GIP analogue is represented by the general Formula II(c):
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-L-
ys-Ala-Gln-X20-X21-Phe-Val-X24-Trp-Leu-X27-Ala-X29-X30-Y1-R.sup.2
(II(c)) (SEQ ID NO: 67)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.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;
[0058] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH. 14. The GIP analogue of embodiment 13, wherein
the GIP analogue is represented by the general Formula II(d):
R.sup.1-Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-L-
ys-Ala-Gln-X20-Ala-Phe-Val-Glu-Trp-Leu-X27-Ala-Gln-X30-Y1-R.sup.2
(II(d)) (SEQ ID NO: 68)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.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;
[0059] X30 is Lys, Gly or absent; Y1 is
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser,
Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and R.sup.2 is
--NH.sub.2 or --OH. 15. A GIP analogue compound according to any
one of embodiments 1 to 14 wherein X24 is Glu and/or X21 is Ala.
16. A GIP analogue compound according to any one of embodiments 1
to 15, wherein X7 is Thr and X14 is Leu. 17. A GIP analogue
according to any one of embodiments 1 to 15, wherein X7 is Thr, X14
is Leu and X18 is Ala. 18. A GIP analogue according to any one of
embodiments 1 to 15, wherein X7 is Thr, X14 is Leu and X17 is Lys.
19. A GIP analogue according to any one of embodiments 1 to 15,
wherein X7 is Thr, X14 is Leu, X17 is Lys and X18 is Ala. 20. A GIP
analogue according to any one of embodiments 1 to 15, wherein X2 is
Aib, X7 is Thr, X14 is Leu and X17 is Lys. 21. A GIP analogue
according to any one of embodiments 1 to 15, wherein X2 is Aib, X7
is Thr, X14 is Leu, X17 is Lys, and X13 and/or X29 is Aib. 22. A
GIP analogue according to any one of embodiments 1 to 15, wherein
X2 is Aib, X7 is Thr, X14 is Leu, X17 is Lys, X27 is Leu or Glu and
X28 is Ser. 23. A GIP analogue according to any one of embodiments
1 to 15, wherein X2 is Aib, X7 is Thr, X14 is Leu, X17 is Lys and
X24 is Glu. 24. A GIP analogue according to any one of embodiments
1 to 15, wherein X2 is Aib, X7 is Thr, X14 is Leu, X17 is Lys, X24
is Glu and X29 is Gln. 25. A GIP analogue according to any one of
claims 1 to 15, wherein X2 is Aib, X7 is Thr, X14 is Leu, X17 is
Lys, X21 is Ala, X24 is Glu and X29 is Gln 26. A GIP analogue
according to any one of embodiments 1 to 15, wherein X2 is Aib, X7
is Thr, X14 is Leu, X17 is Lys, X24 is Glu, X27 is Leu and X28 is
Ser. 27. A GIP analogue according to any one of embodiments 1 to
15, wherein X2 is Aib, X7 is Thr, X14 is Leu, X17 is Lys, X24 is
Glu, X27 is Glu and X28 is Ser. 28. A GIP analogue according to any
one of claims 1 to 15, wherein X2 is Aib, X7 is Thr, X14 is Leu,
X17 is Lys, X20 is His, X24 is Glu, X27 is Leu and X28 is Ser. 29.
A GIP analogue selected from:
Hy-Y-Aib-EGTFISDYSIYLEKKAAKEFVNWLLAQK-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSI-Aib-LDKKAQRAFVEWLLAQGPSSGAPPPS-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIALDKIAQRAFVNWLVA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFISDYSIYLEKIAAKEFVNWLLAQK-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2,
[0060] pGlu-YAEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-YGEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFSSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDLSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYLIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIALDKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYSDKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLEKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIALEKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDSKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDEKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDSKAKRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQKEFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLVA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLKA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLL-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-KYG-1Nal-LDF-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLAYG-1Nal-LDF-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAEKAFVNWLLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-GPSSGAPPPS-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-GPSSGAPPS-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLEKKAAKEFVNWLLAQK-NH.sub.2;
[0061]
Hy-Y-Aib-EGTFTSDYSIYLDK-K(15-carboxy-pentadecanoyl-isoGlu)-AQRAFVNW-
LLA-Aib-K-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSI-Aib-LDK-K(Hexadecanoyl-isoGlu)-AQRAFVEWLLAQGPSSGAPPPS--
NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-AQRAFVEWLLAQGPSSGAPPPS-NH.s-
ub.2;
Hy-Y-Aib-EGTFTSDYSIYLDE-K(hexadecanoyl-isoGlu)-AAKEFIEWLESA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-AQRAFVNWLLA-Aib-KPSSGAPPPS--
NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIALDK-K(hexadecanoyl-isoGlu)-AQRAFVNWLVA-Aib-KPSSGAPPPS--
NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLE-KKAAKDFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLE-KKAAHDFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLEKKAQKEFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDEKAAKDFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLESKAAHDFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDKKAAHDFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLESKAAKEFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLRA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-AAKEFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLRA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFVEWLESA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLRA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFVEWLLSA-NH.sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSAGPSSGAPPPS-NH.s-
ub.2;
Hy-Y-Aib-EGTFTSDYSIYLEK-K-(Hexadecanoyl-isoGlu)-AAKEFVEWLLSAGPSSGAPPPS-NH.-
sub.2;
Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS-NH.sub.2; and
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA-NH.sub.2,
[0062] or a pharmaceutically acceptable salt or solvate thereof.
30. A GIP analogue according to any one of the preceding
embodiments with a lipophilic substituent conjugated to one or more
of positions 15, 16, 17, 19, 20, 24, 27, 28 and 30. 31. A GIP
analogue according to any one of the preceding embodiments for use
in a therapeutic method. 32. A pharmaceutical composition
comprising a GIP analogue of any one of the preceding embodiments,
or a salt, solvate or derivative thereof, in admixture with a
carrier. 33. The pharmaceutical composition of embodiment 32,
wherein the GIP analogue is a pharmaceutically acceptable acid
addition salt. 34. The pharmaceutical composition of embodiment 32
or embodiment 33, 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. 35. Use of a GIP analogue
of any one of embodiments 1 to 30 for the preparation of a
medicament for the treatment and/or prevention of metabolic
diseases. 36. Use of a GIP analogue of any one of embodiments 1 to
30 for the preparation of a medicament for the treatment and/or
prevention of diabetes or a diabetes related disorder. 37. Use of a
GIP analogue of any one of embodiments 1 to 30 for the preparation
of a medicament for the treatment and/or prevention of obesity or
an obesity related disorder. 38. The use of embodiment 37, wherein
the diabetes related disorder is selected from insulin resistance,
glucose intolerance, increased fasting glucose, pre-diabetes, type
1 diabetes, type 2 diabetes, gestational diabetes hypertension,
dyslipidemia, or a combination thereof. 39. The use of embodiment
37, wherein the diabetes related disorder is selected from
atherosclerosis, arteriosclerosis, coronary heart disease,
peripheral artery disease and stroke; or is associated with a
condition selected from atherogenic dyslipidemia, blood fat
disorders, elevated blood pressure, hypertension, a prothrombotic
state, and proinflammatory state, or a combination thereof. 40. The
use of embodiment 39, wherein the blood fat disorder is selected
from high triglycerides, low HDL cholesterol, high LDL cholesterol,
and plaque buildup in artery walls, or a combination thereof. 41.
The use of embodiment 39, wherein the prothrombotic state is
selected from high fibrinogen levels in the blood and high
plasminogen activator inhibitor-1 levels in the blood. 42. The use
of embodiment 39, wherein the proinflammatory state is an elevated
C-reactive protein level in the blood. 43. The use of embodiment
37, wherein the obesity related disorder is selected from obesity
linked inflammation, obesity linked gallbladder disease and obesity
induced sleep apnea, or is associated with a condition selected
from atherogenic dyslipidemia, blood fat disorders, elevated blood
pressure, hypertension, a prothrombotic state, and a
proinflammatory state, or a combination thereof. 44. A nucleic acid
molecule comprising a nucleic acid sequence encoding a GIP analogue
of any one of embodiments 1 to 30. 45. An expression vector
comprising the nucleic acid sequence of embodiment 44, in
combination with control sequences to direct its expression. 46. A
host cell transformed with the expression vector of embodiment 45.
47. A method of producing the GIP analogue of any one of
embodiments 1 to 30, the method comprising culturing the host cells
of embodiment 46 under conditions suitable for expressing the GIP
analogue and purifying the GIP analogue thus produced. 48. A
nucleic acid molecule according to embodiment 44, an expression
vector according to embodiment 45, or a host cell according to
embodiment 46 for use in therapy. 49. Use of a nucleic acid
molecule according to embodiment 44, an expression vector according
to embodiment 45 or a host cell according to embodiment 46, in the
preparation of a medicament for the treatment and/or prevention of
a metabolic disorder. 50. The use of embodiment 49, wherein the
metabolic disorder is selected from diabetes and obesity. 51. A
method of treating a stomach and/or bowel-related disorder in a
patient in need thereof by administering an effective amount a GIP
analogue of any one of embodiments 1 to 30, a nucleic acid molecule
according to embodiment 44, an expression vector according to
embodiment 45, or a host cell according to embodiment 46. 52. A
method of treatment and/or prevention of a metabolic disease or
disorder in a patient in need thereof comprising administering to
said patient an effective amount of the GIP analogue of any one of
embodiments 1 to 30, a nucleic acid molecule according to
embodiment 44, an expression vector according to embodiment 45, or
a host cell according to embodiment 46. 53. The method of
embodiment 52, wherein the metabolic disease or disorder is
selected from diabetes and obesity. 54. A method of treatment
and/or prevention of a diabetes related disorder in a patient in
need thereof comprising the step of administering to said patient
an effective amount of the GIP analogue of any one of embodiments 1
to 30, a nucleic acid molecule according to embodiment 44, an
expression vector according to embodiment 45, or a host cell
according to embodiment 46. 55. A method of treatment and/or
prevention of an obesity related disorder in a patient in need
thereof comprising the step of administering to said patient an
effective amount of the GIP analogue of any one of embodiments 1 to
30, a nucleic acid molecule according to embodiment 44, an
expression vector according to embodiment 45, or a host cell
according to embodiment 46. 56. The method of embodiment 54,
wherein the diabetes related disorder is selected from insulin
resistance, glucose intolerance, increased fasting glucose,
pre-diabetes, type 1 diabetes, type 2 diabetes, gestational
diabetes hypertension, dyslipidemia, or a combination thereof. 57.
The method of embodiment 54, wherein the diabetes related disorder
is selected from atherosclerosis, arteriosclerosis, coronary heart
disease, peripheral artery disease and stroke; or is associated
with a condition selected from atherogenic dyslipidemia, blood fat
disorders, elevated blood pressure, hypertension, a prothrombotic
state, and a proinflammatory state, or a combination thereof. 58.
The method of embodiment 57, wherein the blood fat disorder is
selected from high triglyceride level, low HDL cholesterol level,
high LDL cholesterol level, plaque buildup in artery walls, or a
combination thereof. 59. The method of embodiment 57, wherein the
prothrombotic state is selected from high fibrinogen levels in the
blood and high plasminogen activator inhibitor-1 levels in the
blood. 60. The method of embodiment 57, wherein the proinflammatory
state is an elevated C-reactive protein level in the blood. 61. The
method of embodiment 55, wherein the obesity related disorder is
selected from obesity linked inflammation, obesity linked
gallbladder disease and obesity induced sleep apnea. 62. A
therapeutic kit comprising a GIP analogue according to any one of
embodiments 1 to 30, a nucleic acid molecule according to
embodiment 44, an expression vector according to embodiment 45, or
a host cell according to embodiment 46, each optionally in
combination with a pharmaceutically acceptable carrier. 63. A
device comprising a GIP analogue according to any one of
embodiments 1 to 30, a nucleic acid molecule according to
embodiment 44, an expression vector according to embodiment 45, or
a host cell according to embodiment 46, for delivery of the GIP
analogue to a subject. 64. A pharmaceutical composition comprising
the GIP analogue of any one of embodiments 1 to 30 for use in
treating a stomach and bowel-related disorder in a patient in need
thereof. 65. A pharmaceutical composition comprising the GIP
analogue of any one of embodiments 1 to 30 for use in treatment
and/or prevention of a metabolic disease or disorder in a patient
in need thereof. 66. The pharmaceutical composition of embodiment
65, wherein the metabolic disorder is selected from diabetes and
obesity. 67. A pharmaceutical composition comprising the GIP
analogue of any one of embodiments 1 to 30 for use in treatment
and/or prevention of a diabetes related disorder in a patient in
need thereof. 68. A pharmaceutical composition comprising the GIP
analogue of any one of embodiments 1 to 30 for use in treatment
and/or prevention of an obesity related disorder in a patient in
need thereof. 69. The pharmaceutical composition of embodiment 67,
wherein the diabetes related disorder is selected from insulin
resistance, glucose intolerance, increased fasting glucose,
pre-diabetes, type 1 diabetes, type 2 diabetes, gestational
diabetes hypertension and dyslipidemia, or a combination thereof.
70. The pharmaceutical composition of embodiment 67, wherein the
diabetes related disorder is selected from atherosclerosis,
arteriosclerosis, coronary heart disease, peripheral artery disease
and stroke; or is associated with a condition selected from
atherogenic dyslipidemia, blood fat disorders, elevated blood
pressure, hypertension, a prothrombotic state, and a
proinflammatory state, or a combination thereof. 71. The
pharmaceutical composition of embodiment 70, wherein the blood fat
disorder is selected from high triglyceride level, low HDL
cholesterol level, high LDL cholesterol level, plaque buildup in
artery walls, or a combination thereof. 72. The pharmaceutical
composition of embodiment 70, wherein the prothrombotic state is
selected from high fibrinogen levels in the blood, and high
plasminogen activator inhibitor-1 levels in the blood. 73. The
pharmaceutical composition of embodiment 70, wherein the
proinflammatory state is an elevated C-reactive protein level in
the blood. 74. The pharmaceutical composition of embodiment 68,
wherein the obesity related disorder is selected from obesity
linked inflammation, obesity linked gallbladder disease, and
obesity induced sleep apnea.
[0063] In Formulae I, Ia, Ib, I', Ia' and Ib', residues X30 to X42
may be present or absent. They are not present or absent
independently of one another. If any one of these residues is
absent, then all residues C-terminus of that residue are also
absent. Thus, the only combinations of residues which can be absent
are X42; X41-X42; X40-X41-X42; X39-X40-X41-X42;
X38-X39-X40-X41-X42; X37-X38-X39-X40-X41-X42; X36-X37 X38 X39 X40
X41 X42; X35 X36 X37 X38 X39 X40 X41 X42;
X34-X35-X36-X37-X38-X39-X40-X41-X42;
X33-X34-X35-X36-X37-X38-X39-X40-X41-X42;
X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42;
X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42;
X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42. To put it
another way, if residue XN is present (where N is an integer
between 30 and 42) then residue X(N-1) is also present.
[0064] For all of the embodiments described above, it may be
desirable that the amino acid sequence X1-X29 has no more than 6
amino acid differences from the sequence
Y-Aib-EGTFTSDYSIYLDKKAQRAFVEWLLAQ (SEQ ID NO: 70). The amino acid
sequence X1-X29 may, for example, have no more than 5, 4, 3, 2 or 1
amino acid differences from that sequence.
[0065] For all of the embodiments described above, it may be
desirable that the amino acid sequence X1-X29 has no more than 6
amino acid differences from the sequence
Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA (SEQ ID NO: 71). The amino acid
sequence X1-X29 may, for example, have no more than 5, 4, 3, 2 or 1
amino acid differences from that sequence.
[0066] For all of the embodiments described above, it may be
desirable that the amino acid sequence X1-X29 has no more than 5
amino acid differences from the sequence
Y-Aib-EGTFTSDYSIYLDEKAAKEFIEWLESA (SEQ ID NO: 72). The amino acid
sequence X1-X29 may, for example, have no more than 4, 3, 2 or 1
amino acid differences from that sequence.
BRIEF DESCRIPTION OF THE DRAWINGS
[0067] FIG. 1: Effect of Compounds 32 and 33 on glucose tolerance.
Compound 32, Compound 33 and liraglutide significantly improved
glucose tolerance as compared to vehicle at all time points
(p<0.05). At time t=60 min, Compound 33 caused a statistically
significant greater reduction (p<0.05) in blood glucose than
liraglutide. *, p<0.05 vs. vehicle; #, p<0.05 vs.
liraglutide. Two-way ANOVA followed by Bonferroni post-tests were
used for the statistical analysis. Data are mean.+-.SEM; n=2-6.
[0068] FIG. 2: Body weight during the 21-days treatment period (A)
and absolute body weight changes (delta .DELTA.=body weight at day
21-body weight at day 0) (B). Data are means.+-.SEM; n=7-10.
[0069] FIG. 3: Percent body fat mass (delta .DELTA.=fat mass at day
19-fat mass before treatment) (A) and percent body lean mass (delta
.DELTA.=lean mass at day 19-lean mass before treatment) (B) on day
19. Data are means.+-.SEM; n=7-10.
[0070] FIG. 4: Accumulated food intake. Food intake was not
measured on day 14. Data are means.+-.SEM; n=7-10.
[0071] FIG. 5: Blood glucose (A) and plasma insulin (B) on day 13.
The blood samples were taken from 4-hour fasted mice. The mice were
not dosed in the morning prior to the blood sampling. Data are
means.+-.SEM; n=7-10.
[0072] FIG. 6: Blood glucose (A) and plasma insulin (B) on day 21.
The mice were injected with vehicle, liraglutide or test substance
2 hours prior to the blood sampling. Data are means.+-.SEM;
n=7-10.
[0073] FIG. 7: Plasma total cholesterol (A), plasma LDL cholesterol
(B), plasma HDL cholesterol (C), and plasma triglycerides (D) on
day 21. Data are means.+-.SEM; n=7-10.
DETAILED DESCRIPTION OF THE INVENTION
[0074] Unless otherwise defined herein, scientific and technical
terms used in this application shall have the meanings that are
commonly understood by those of ordinary skill in the art.
Generally, nomenclature used in connection with, and techniques of,
chemistry, molecular biology, cell and cancer biology, immunology,
microbiology, pharmacology, and protein and nucleic acid chemistry,
described herein, are those well known and commonly used in the
art.
[0075] All publications, patents and published patent applications
referred to in this application are specifically incorporated by
reference herein. In case of conflict, the present specification,
including its specific definitions, will control.
[0076] Each embodiment of the invention described herein may be
taken alone or in combination with one or more other embodiments of
the invention.
Definitions
[0077] Unless specified otherwise, the following definitions are
provided for specific terms, which are used in the above written
description.
[0078] Throughout this specification, the word "comprise" or
variations such as "comprises" or "comprising" will be understood
to imply the inclusion of a stated integer (or components) or group
of integers (or components), but not the exclusion of any other
integer (or components) or group of integers (or components).
[0079] The singular forms "a," "an," and "the" include the plurals
unless the context clearly dictates otherwise.
[0080] The term "including" is used to mean "including but not
limited to." "Including" and "including but not limited to" are
used interchangeably.
[0081] The terms "patient," "subject," and "individual" may be used
interchangeably and refer to either a human or a non-human animal.
These terms include mammals such as humans, primates, livestock
animals (e.g., bovines, porcines), companion animals (e.g.,
canines, felines) and rodents (e.g., mice and rats).
[0082] The term "solvate" in the context of the present invention
refers to a complex of defined stoichiometry formed between a
solute (in casu, a peptide conjugate or pharmaceutically acceptable
salt thereof according to the invention) and a solvent. The solvent
in this connection may, for example, be water, ethanol or another
pharmaceutically acceptable, typically small-molecular organic
species, such as, but not limited to, acetic acid or lactic acid.
When the solvent in question is water, such a solvate is normally
referred to as a hydrate.
[0083] The term "agonist" as employed in the context of the
invention refers to a substance (ligand) that activates the
receptor type in question.
[0084] Throughout the description and claims the conventional
one-letter and three-letter codes for natural amino acids are used
as well as generally accepted three letter codes for other
.alpha.-amino acids, such as sarcosine (Sar), norleucine (Nle),
.alpha.-aminoisobutyric acid (Aib) and .beta.-(1-naphthyl)-alanine
(1Nal). All amino acid residues in peptides of the invention are
preferably of the L-configuration. However, D-configuration amino
acids may also be present.
[0085] Among sequences disclosed herein are sequences incorporating
an "Hy-" moiety at the amino terminus (N-terminus) of the sequence,
and either an "--OH" moiety or an "--NH.sub.2" moiety at the
carboxy terminus (C-terminus) of the sequence. In such cases, and
unless otherwise indicated, an "Hy-" moiety at the N-terminus of
the sequence in question indicates a hydrogen atom [e.g.,
R.sup.1=Hy-in formulas II(a), I(b), II, II(a) or II(b);
corresponding to the presence of a free primary or secondary amino
group at the N-terminus], while an "--OH" or an "--NH.sub.2" moiety
at the C-terminus of the sequence indicates a hydroxy group [e.g.,
R.sup.2.dbd.OH in formulas II(a), I(b), II, II(a) or II(b);
corresponding to the presence of a carboxy (COOH) group at the
C-terminus] or an amino group [e.g., R.sup.2.dbd.NH.sub.2 in
formulas II(a), I(b), II, II(a) or II(b); corresponding to the
presence of an amido (CONH.sub.2) group at the C-terminus],
respectively. In each sequence of the invention, a C-terminal
"--OH" moiety may be substituted for a C-terminal "--NH.sub.2"
moiety, and vice-versa.
[0086] As used herein "conservative substitution" means that an
amino acid residue belonging to a certain position of the native
human GIP peptide sequence has been exchanged with an amino acid
residue belonging to the same group (I, II, III, IV, V, 1, 2, 3) as
defined in the following table:
TABLE-US-00001 I II III IV V A N H M F S D R L Y T E K I W P Q V G
C
[0087] In the scheme below, conservative substitutions of amino
acids are grouped by physicochemical properties. I: neutral or
hydrophobic, II: acidic, III: basic, IV: polar, V: aromatic.
TABLE-US-00002 I II III IV V A E H M F L D R S Y I K T W P C G N V
Q
[0088] A "non-conservative" substitution as used herein means any
other substitution of an amino acid residue of the native human GIP
sequence, e.g. such as substituting with a non-protein amino acid
(Sar, Nle, Aib, 1Nal) or substituting with an amino acid which does
not belong to the same group. In some embodiments, the peptide
conjugate of the invention may comprise functional fragments or
variants thereof that have at most 34, 33, 32, 31 30, 29, 28, 27,
26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,
9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitutions compared to
one or more of the specific sequences recited below.
[0089] Preferred compounds of the present invention have at least
one GIP and one GLP-1 biological activity, in particular in
treatment of metabolic diseases such as diabetes and obesity. This
can be assessed, e.g., in in viva assays, for example as described
in the examples, in which the blood glucose level or another
biological activity is determined after a test animal has been
treated or exposed to a GIP analogue. In particular, compounds of
the invention may be capable of improving glycaemic control when
adminstered to a diabetic subject. Additionally or alternatively,
they may be capable of reducing body weight when administered to an
overweight or obese subject. In either case, the effect may be
superior to that obtained with an equivalent quantity (by mass, or
molar ratio) of wild type human GIP or GLP-1 in comparable subjects
when given according to a comparable dosing regime.
[0090] Activity in in vitro assays may also be used as a measure of
the compounds' activity. Typically the compounds have activity at
both the GLP-1 and GIP receptors. EC.sub.50 values may be used as a
numerical measure of agonist potency at a given receptor. An
EC.sub.50 value is a measure of the concentration of a compound
required to achieve half of that compound's maximal activity in a
particular assay. Thus, for example, a compound having EC.sub.50
[GLP-1R] lower than the EC.sub.50 [GLP-1R] of native glucagon in a
particular assay may be considered to have higher potency at the
GLP-1R than glucagon. In some embodiments of the present invention,
the EC.sub.50 GLP-1-R and/or EC.sub.50 GIP-R is below 1.0 nM, below
0.9 nM, below 0.8 nM, below 0.7 nM, below 0.6 nM, below 0.5 nM,
below 0.4 nM, below 0.3 nM, below 0.2 nM, below 0.1 nM, below 0.09
nM, below 0.08 nM, below 0.07 nM, below 0.06 nM, below 0.05 nM,
below 0.04 nM, below 0.03 nM, below 0.02 nM, below 0.01 nM, below
0.009 nM, below 0.008 nM, below 0.007 nM, below 0.006 nM, or below
0.005 nM, e.g. when assessed using the assay described in Example
2. In any given assay, the EC.sub.50 value of a compound in a given
assay may be assessed relative to the EC.sub.50 of human GIP. Thus,
the ratio of the EC.sub.50 value of the test compound to the
EC.sub.50 value of wild type human GIP (EC.sub.50[test
compound]/EC.sub.50[GIP]) at the human GIP receptor may be less
than 10, less than 5, less than 1, less than 0.1, less than 0.05 or
less than 0.01. The ratio of the EC.sub.50 value of the test
compound to the EC.sub.50 value of wild type human GIP
(EC.sub.50[test compound]/EC.sub.50[GIP]) at the GLP-1 receptor may
be less than 10, less than 5, less than 1, less than 0.1, less than
0.05 or less than 0.01. It may also be desirable to compare the
ratio of EC.sub.50 values at the two receptors for the test
compound and for human GIP. Preferably the test compound has an
EC.sub.50[GIP]/EC.sub.50[GLP-1] which is greater than the
equivalent ratio for GIP in the same assays.
[0091] The GIP analogue compounds of the present invention have one
or more amino acid substitutions, deletions, inversions, or
additions compared with native GIP and as defined above. This
definition also includes the synonym terms GIP mimetics and/or
GIP-GLP1 agonists. Further, the analogue of the present invention
may additionally have chemical modification of one or more of its
amino acid side groups, .alpha.-carbon atoms, terminal amino group,
or terminal carboxylic acid group. A chemical modification
includes, but is not limited to, adding chemical moieties, creating
new bonds, and removing chemical moieties. Modifications at amino
acid side groups include, without limitation, acylation of lysine
s-amino groups, N-alkylation of arginine, histidine, or lysine,
alkylation of glutamic or aspartic carboxylic acid groups, and
deamidation of glutamine or asparagine. Modifications of the
terminal amino include, without limitation, the des-amino, N-lower
alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of
the terminal carboxy group include, without limitation, the amide,
lower alkyl amide, dialkyl amide, and lower alkyl ester
modifications. Preferably herein lower alkyl is C.sub.1-C.sub.4
alkyl. Furthermore, one or more side groups, or terminal groups,
may be protected by protective groups known to the
ordinarily-skilled peptide chemist. The .alpha.-carbon of an amino
acid may be mono- or di-methylated.
[0092] Exemplary GIP analogue compounds of the present invention
(formulae I, II, III or IV) are described below, where said
compounds may be modified at the N-terminus and C-terminus as
described for R1 and R2, and include a pharmaceutically acceptable
salt, solvate or derivative thereof:
TABLE-US-00003 Y-Aib-EGTFISDYSIYLEKAKEFVNWLLAQK SEQ ID NO. 3
Y-Aib-EGTFTSDYSI-Aib- SEQ ID NO. 4 LDKKAQRAFVEWLLAQGPSSGAPPPS
Y-Aib-EGTFTSDYSIALDKIAQRAFVNWLVA-Aib-K SEQ ID NO. 5
Y-Aib-EGTFISDYSIYLEKIKEFVNWLLAQK SEQ ID NO. 6
Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 7
YAEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 8
YGEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 9
Y-Aib-EGTFSSDYSIYLDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 10
Y-Aib-EGTFTSDLSIYLDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 11
Y-Aib-EGTFTSDSSIYLDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 12
Y-Aib-EGTFTSDYLIYLDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 13
Y-Aib-EGTFTSDYSIALDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 14
Y-Aib-EGTFTSDYSIYSDKKAQRAFVNWLLA-Aib-K SEQ ID NO. 15
Y-Aib-EGTFTSDYSIYLEKKAQRAFVNWLLA-Aib-K SEQ ID NO. 16
Y-Aib-EGTFTSDYSIALEKKAQRAFVNWLLA-Aib-K SEQ ID NO. 17
Y-Aib-EGTFTSDYSIYLDSKAQRAFVNWLLA-Aib-K SEQ ID NO. 18
Y-Aib-EGTFTSDYSIYLDEKAQRAFVNWLLA-Aib-K SEQ ID NO. 19
Y-Aib-EGTFTSDYSIYLDSKAKRAFVNWLLA-Aib-K SEQ ID NO. 20
Y-Aib-EGTFTSDYSIYLDKKAQKEFVNWLLA-Aib-K SEQ ID NO. 21
Y-Aib-EGTFTSDYSIYLDKKAQRAFVKVVLLA-Aib-K SEQ ID NO. 22
Y-Aib-EGTFTSDYSIYLDKKAQFVNWLVA-Aib-K SEQ ID NO. 23
Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLSA-Aib-K SEQ ID NO. 24
Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLKA-Aib-K SEQ ID NO. 25
Y-Aib-EGTFTSDYSIYLDKKAQFVNWLL-Aib-K SEQ ID NO. 26
Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-KYG-1Nal- SEQ ID NO. 27 LDF
Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLAYG-1Nal-LDF SEQ ID NO. 28
Y-Aib-EGTFTSDYSIYLDKKAEKAFVNWLLA-Aib-K SEQ ID NO. 29
Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib- SEQ ID NO. 30 GPSSGAPPPS
Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib- SEQ ID NO. 31 GPSSGAPPS
Y-Aib-EGTFTSDYSIYLEKAAKEFVNWLLAQK SEQ ID NO. 32
Y-Aib-EGTFTSDYSIYLDK-K(15-carboxy-pentadecanoyl- SEQ ID NO. 35
isoGlu)-AQRAFVNWLLA-Aib-K
Y-Aib-EGTFTSDYSI-Aib-LDK-K(Hexadecanoyl-isoGlu)- SEQ ID NO. 36
AQ-AFVEWLLAQGPSSGAPPPS Y-Aib-EGTFTSDYSIYLDE-K(hexadecanoyl-isoGlu)-
SEQ ID NO. 38 AAKEFIEWLESA
Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)- SEQ ID NO. 39
AQRAFVNWLLA-Aib-KPSSGAPPPS
Y-Aib-EGTFTSDYSIALDK-K(hexadecanoyl-isoGlu)- SEQ ID NO. 40
AQRAFVNWLVA-Aib-KPSSGAPPPS Y-Aib-EGTFTSDYSIYLE-KAAKDFVEWLLSA SEQ ID
NO. 41 Y-Aib-EGTFTSDYSIYLE-KKAAHDFVEWLLSA
Y-Aib-EGTFTSDYSIYLEKKAQKEFVEWLLSA SEQ ID NO. 42
Y-Aib-EGTFTSDYSIYLDEAAKDFVEWLLSA SEQ ID NO. 43
Y-Aib-EGTFTSDYSIYLESAAHDFVEWLLSA SEQ ID NO. 44
Y-Aib-EGTFTSDYSIYLDKAHDFVEWLLSA SEQ ID NO. 45
Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA SEQ ID NO. 46
Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLRA SEQ ID NO. 47
Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)- SEQ ID NO. 48
AAHDFVEWLLSA Y-Aib-EGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)- SEQ ID
NO. 49 AAKEFVEWLLSA Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-
SEQ ID NO. 50 HDFVEVVLLRA
Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- SEQ ID NO. 51
AAKDFVEWLESA Y-Aib-EGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)- SEQ ID
NO. 52 AAKDFIEWLESA Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-
SEQ ID NO. 53 KDFIEWLESA
Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)- SEQ ID NO. 54
AAHDFVEWLLRA Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- SEQ ID
NO. 55 AAKDFVEWLLSA Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-
SEQ ID NO. 56 AAHDFVEWLLSAGPSSGAPPPS
Y-Aib-EGTFTSDYSIYLEK-K-(Hexadecanoyl-isoGlu)- SEQ ID NO. 57
AAKEFVEWLLSAGPSSGAPPPS Y-Aib-EGTFTSDYSIYLDSAAHDFVEWLLSAGPSSGAPPPS
SEQ ID NO. 58 Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- SEQ ID
NO: 69 AAHDFVEWLLSA
Lipophilic Substituents
[0093] One or more of the amino acid side chains in a compound
employed in the context of the invention may be conjugated to a
lipophilic substituent Z.sup.1. Without wishing to be bound by
theory, it is thought that the lipophilic substituent binds albumin
in the blood stream, thus shielding the compounds employed in the
context of the invention from enzymatic degradation which can
enhance the half-life of the compounds. The lipophilic substituent
may also modulate the potency of the compound, e.g., with respect
to the GIP receptor and/or the GLP-1 receptor.
[0094] In certain embodiments, only one amino acid side chain is
conjugated to a lipophilic substituent. In other embodiments, two
amino acid side chains are each conjugated to a lipophilic
substituent. In yet further embodiments, three or even more amino
acid side chains are each conjugated to a lipophilic substituent.
When a compound contains two or more lipophilic substituents, they
may be the same or different.
[0095] The lipophilic substituent Z.sup.1 may be covalently bonded
to an atom in the amino acid side chain, or alternatively may be
conjugated to the amino acid side chain by one or more spacers
Z.sup.2.
[0096] The term "conjugated" is used here to describe the covalent
attachment of one identifiable chemical moiety to another, and the
structural relationship between such moieties. It should not be
taken to imply any particular method of synthesis. The spacer
Z.sup.2, when present, is used to provide a spacing between the
compound and the lipophilic moiety.
[0097] The lipophilic substituent may be attached to the amino acid
side chain or to the spacer via an ester, a sulphonyl ester, a
thioester, an amide or a sulphonamide. Accordingly it will be
understood that preferably the lipophilic substituent includes an
acyl group, a sulphonyl group, an N atom, an O atom or an S atom
which forms part of the ester, sulphonyl ester, thioester, amide or
sulphonamide. Preferably, an acyl group in the lipophilic
substituent forms part of an amide or ester with the amino acid
side chain or the spacer.
[0098] The lipophilic substituent may include a hydrocarbon chain
having 10 to 24 carbon (C) atoms, e.g. 10 to 22 C atoms, e.g. 10 to
20 C atoms. Preferably it has at least 11 C atoms, and preferably
it has 18 C atoms or fewer. For example, the hydrocarbon chain may
contain 12, 13, 14, 15, 16, 17 or 18 carbon atoms. The hydrocarbon
chain may be linear or branched and may be saturated or
unsaturated. Furthermore, it can include a functional group in the
end of the lipophilic chain, e.g., carboxylic acid which may or may
not be protected during synthesis. From the discussion above it
will be understood that the hydrocarbon chain is preferably
substituted with a moiety which forms part of the attachment to the
amino acid side chain or the spacer, for example an acyl group, a
sulphonyl group, an N atom, an O atom or an S atom.
[0099] Most preferably, the hydrocarbon chain is substituted with
acyl, and accordingly the hydrocarbon chain may be part of an
alkanoyl group, for example a dodecanoyl, 2-butyloctanoyl,
tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl or
eicosanoyl group. An example of a functionalized hydrocarbon chain
is the 15-carboxy-pentadecanoyl.
[0100] As mentioned above, the lipophilic substituent Z.sup.1 may
be conjugated to the amino acid side chain by one or more spacers
Z.sup.2. When present, the spacer is attached to the lipophilic
substituent and to the amino acid side chain. The spacer may be
attached to the lipophilic substituent and to the amino acid side
chain independently by an ester, a sulphonyl ester, a thioester, an
amide or a sulphonamide. Accordingly, it may include two moieties
independently selected from acyl, sulphonyl, an N atom, an O atom
or an S atom. The spacer may consist of a linear C1-10 hydrocarbon
chain or more preferably a linear C1-5 hydrocarbon chain.
Furthermore, the spacer may be substituted with one or more
substituents selected from C1-6 alkyl, C1-6 alkyl amine, C1-6 alkyl
hydroxy and C1-6 alkyl carboxy.
[0101] The spacer may be, for example, a residue of any naturally
occurring or unnatural amino acid. For example, the spacer may be a
residue of Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp,
His, Lys, Arg, Gln, Asn, .alpha.-Glu, .gamma.-Glu, .epsilon.-Lys,
Asp, Ser, Thr, Gaba, Aib, .beta.-Ala (i.e. 3-aminopropanoyl),
4-aminobutanoyl, 5-aminopentanoyl, 6-aminohexanoyl,
7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl,
10-aminodecanoyl or 8-amino-3,6-dioxaoctanoyl. In certain
embodiments, the spacer is a residue of Glu, .gamma.-Glu,
.epsilon.-Lys, .beta.-Ala (i.e. 3-aminopropanoyl), 4-aminobutanoyl,
8-aminooctanoyl or 8-amino-3,6-dioxaoctanoyl. In the present
context, .gamma.-Glu and isoGlu are used interchangeably. The amino
acid side chain to which the lipophilic substituent is conjugated
is a side chain, e.g., of a Glu, Lys, Ser, Cys, Dbu, Dpr or Orn
residue. For example, it may be a side chain of a Lys, Glu or Cys
residue. Where two or more side chains carry a lipophilic
substituent, they may be independently selected from these
residues. Thus the amino acid side chain includes a carboxy,
hydroxyl, thiol, amide or amine group, for forming an ester, a
sulphonyl ester, a thioester, an amide, or a sulphonamide with the
spacer or lipophilic substituent.
[0102] An example of a lipophilic substituent comprising a
lipophilic moiety Z.sup.1 and spacer Z.sup.2 is shown in the
formula below:
##STR00001##
[0103] Here, the side chain of a Lys residue is covalently attached
to a .gamma.-Glu spacer (Z.sup.2) via an amide linkage. A
hexadecanoyl group (Z.sup.1, R.dbd.CH.sub.3) is covalently attached
to the .gamma.-Glu spacer via an amide linkage. This combination of
lipophilic moiety and spacer, conjugated to a Lys residue, may be
referred to by the short-hand notation K(Hexadecanoyl-.gamma.-Glu),
e.g., when shown in formulae of specific compounds. .gamma.-Glu can
also be referred to as isoGlu, and a hexadecanoyl group as a
palmitoyl group. Thus it will be apparent that the notation
(Hexadecanoyl-.gamma.-Glu) is equivalent to the notations
(isoGlu(Palm)) or (isoGlu(Palmitoyl)) as used for example in
PCT/GB2008/004121. In different embodiments, the
15-carboxy-pentadecanoyl group (Z.sup.2, R.dbd.COOH) is covalently
attached to the .gamma.-Glu spacer via an amide linkage. The
combination of lipophilic moiety with a functional group like COOH
and a spacer, conjugated to a Lys residue may be referred to as
K(15-carboxy-pentadecanoyl-.gamma.-Glu) or
K(15-carboxy-pentadecanoyl-isoGlu).
[0104] In certain embodiments, a GIP analogue of the invention is
conjugated with a lipophilic substituent to one or more of amino
acid positions 16, 17,19, 20, 24, 27, 28, 30 and 32.
[0105] The skilled person will be well aware of suitable techniques
for preparing the compounds employed in the context of the
invention. For examples of suitable chemistry, see, e.g.,
WO98/08871, WO00/55184, WO00/55119, Madsen et al. (J. Med. Chem.
2007, 50, 6126-32), and Knudsen et al. 2000 (J. Med Chem. 43,
1664-1669).
Non-Proteinogenic Amino Acids
[0106] One or more of the amino acids of a GIP analogue compound
may be a non-proteinogenic (non-naturally occurring) amino acid.
Non-proteinogenic amino acids may include those amino acids not
encompassed by the 20 "standard" amino acids used in protein
synthesis, e.g., alanine, arginine, aspartate, asparagine,
cysteine, glutamate, glutamine, glycine, histidine, isoleucine,
leucine, lysine, methionine, phenylalanine, praline, serine,
threonine, tryptophan, tyrosine, and valine. Examples of
non-proteinogenic amino acids include, but are not limited to, para
amino benzoic acid (PABA), 2-amino benzoic acid, anthranilic acid,
p-hydroxybenzoic acid (PHBA), 3-amino benzoic acid, 4-aminomethyl
benzoic acid, 4-amino salicylic acid (PAS), 4-amino cyclohexanoic
acid 4-aminophenyl acetic acid, 4-amino-hippuric acid,
4-amino-2-chlorobenzoic acid, 6-aminonicotinic acid,
methyl-6-aminonicotinate, 4-amino methyl salicylate, 2-amino
thiazole-4-acetic acid, 2-amino-4-(2-aminophenyl)-4-oxobutanoic
acid (L-kynurenine), O-methyl serine, acetylamino alanine,
.beta.-alanine, .beta.-(acetylamino)alanine, .beta.-aminoalanine,
.beta.-chloroalanine, citrulline, homocitrulline, hydroxyproline,
homoarginine, homoserine, homotyrosine, homoproline, ornithine,
4-amino-phenylalanine, sarcosine, biphenylalanine,
homophenylalanine, 4-nitro-phenylalanine, 4-fluoro-phenylalanine,
2,3,4,5,6-pentafluoro-phenylalanine, norleucine, cyclohexylalanine,
N-methyl-alanine, N-methyl-glycine, N-methyl-glutamic acid,
tert-butylglycine, .alpha.-aminobutyric acid,
.alpha.-aminoisobutyric acid (AIB), 2-aminoisobutyric acid,
2-aminoindane-2-carboxylic acid, selenomethionine, lanthionine,
dehydroalanine, .gamma.-aminobutyric acid, naphthylalanine,
aminohexanoic acid, phenylglycine, pipecolic acid,
2,3-diaminoproprionic acid, tetrahydroisoquinoline-3-carboxylic
acid, taurine, tert-leucine, tert-butylalanine, cyclohexylglycine,
diethylglycine, and dipropylglycine.
C-Terminal Amidation
[0107] The major biologically active fragment of a GIP analogue is
produced as a 42-amino acid peptide with a free carboxylic acid at
the C-terminal. In some embodiments, a compound employed in the
context of the invention may also comprise a truncated or full
length analogue of naturally occurring GIP and further comprise a
C-terminal modification, e.g., amidation.
Clinical Utility
[0108] The GIP analogue compounds employed in the context of the
invention may provide an attractive treatment option for metabolic
diseases including obesity, diabetes mellitus (diabetes),
obesity-related disorders, and diabetes-related disorders. Diabetes
comprises a group of metabolic diseases characterized by
hyperglycemia resulting from defects in insulin secretion, insulin
action, or both. Diabetes is classified into type 1 diabetes, type
2 diabetes and gestational diabetes on the basis on pathogenic
characteristics. Type 1 diabetes accounts for 5-10% of all diabetes
cases and is caused by auto-immune destruction of insulin-secreting
pancreatic .beta.-cells. Acute signs of diabetes include excessive
urine production, resulting compensatory thirst and increased fluid
intake, blurred vision, unexplained weight loss, lethargy, and
changes in energy metabolism. However, in type 2 diabetes symptoms
are often not severe or may be absent. The chronic hyperglycemia of
diabetes is associated with long-term damage, dysfunction, and
failure of various organs, notably the eyes, kidneys, nerves, heart
and blood vessels.
[0109] Type 2 diabetes accounts for 90-95% of diabetes cases and is
a result of a complex set of metabolic disorders. However, symptoms
are often not severe or may be absent. Type 2 diabetes is the
consequence of endogenous insulin production becoming insufficient
to maintain plasma glucose levels below diagnostic thresholds.
[0110] Gestational diabetes refers to any degree of glucose
intolerance identified during pregnancy.
[0111] Pre-diabetes includes impaired fasting glucose and impaired
glucose tolerance and refers to those states that occur when blood
glucose levels are elevated but below the levels that are
established for the clinical diagnosis for diabetes.
[0112] A large proportion of people with type 2 diabetes and
pre-diabetes are at increased risk of morbidity and mortality due
to the high prevalence of additional metabolic risk factors,
including abdominal obesity (excessive fat tissue around the
abdominal internal organs), atherogenic dyslipidemia (blood fat
disorders including high triglycerides, low HDL cholesterol and/or
high LDL cholesterol, which foster plaque buildup in artery walls),
elevated blood pressure (hypertension) a prothrombotic state (e.g.
high fibrinogen or plasminogen activator inhibitor-1 in the blood),
and/or a proinflammatory state (e.g., elevated C-reactive protein
in the blood).
[0113] Conversely, obesity confers an increased risk of developing
pre-diabetes, type 2 diabetes as well as, e.g., certain types of
cancer, obstructive sleep apnea and gall-bladder disease.
Dyslipidemia is associated with increased risk of cardiovascular
disease. High Density Lipoprotein (HDL) is of clinical importance
since an inverse correlation exists between plasma HDL
concentrations and risk of atherosclerotic disease. The majority of
cholesterol stored in atherosclerotic plaques originates from LDL
and hence an elevated concentration of Low Density Lipoproteins
(LDL) is closely associated with atherosclerosis. The HDL/LDL ratio
is a clinical risk indictor for atherosclerosis and coronary
atherosclerosis in particular.
[0114] Compounds employed in the context of the invention act as
GIP-GLP1 dual agonists. The dual agonist may combine the effect of
GIP, e.g., on fat metabolism and weight loss, and blood glucose,
with the effect of GLP-1, e.g., on blood glucose levels and food
intake. They may therefore act to accelerate elimination of
excessive adipose tissue, induce sustainable weight loss, and
improve glycemic control. Dual GIP-GLP1 agonists may also act to
reduce cardiovascular risk factors such as high cholesterol, such
as high LDL-cholesterol.
[0115] The GIP-GLP1 dual agonist compounds of the present invention
may therefore be used as pharmaceutical agents for preventing
weight gain, promoting weight loss, reducing excess body weight or
treating obesity (e.g., by control of appetite, feeding, food
intake, calorie intake, and/or energy expenditure and lipolysis),
including morbid obesity, as well as associated diseases and health
conditions including but not limited to obesity linked
inflammation, obesity linked gallbladder disease and obesity
induced sleep apnea. The GIP-GLP1 dual agonist compounds employed
in the context of the invention may also be used for treatment of
insulin resistance, glucose intolerance, pre-diabetes, increased
fasting glucose, type 2 diabetes, hypertension, dyslipidemia (or a
combination of these metabolic risk factors), atherosclerosis,
arteriosclerosis, coronary heart disease, peripheral artery disease
and stroke. These are all conditions which may be associated with
obesity. However, the effects of the compounds employed in the
context of the invention on these conditions may be mediated in
whole or in part via an effect on body weight, or may be
independent thereof. The GIP-GLP1 dual agonist compounds employed
in the context of the invention may also be used for treating a
stomach and/or bowel-related disorder.
[0116] The GIP-GLP1 dual agonist compounds, nucleic acids, vectors,
host cells, and pharmaceutical compositions thereof, also may be
used for the treatment and/or prevention of any of the diseases,
disorders, or conditions described herein, including metabolic
diseases, diabetes or diabetes related disorders, stomach and/or
bowel related disorder, and/or obesity or obesity related
disorders. In some embodiments, the GIP-GLP1 dual agonist
compounds, nucleic acids, vectors, host cells, also may be used for
the preparation of a medicament for the treatment and/or prevention
of any of the diseases, disorders, or conditions described herein,
including metabolic diseases, diabetes or diabetes related
disorders, and/or obesity or obesity related disorders. In certain
embodiments, the diabetes related disorder is selected from insulin
resistance, glucose intolerance, increased fasting glucose,
pre-diabetes, type 1 diabetes, type 2 diabetes, gestational
diabetes hypertension, dyslipidemia, or a combination thereof. In
certain embodiments, the diabetes related disorder is selected from
atherosclerosis, arteriosclerosis, coronary heart disease,
peripheral artery disease and stroke; or associated with a
condition selected from atherogenic dyslipidemia, blood fat
disorders, elevated blood pressure, hypertension, a prothrombotic
state, and proinflammatory state, or a combination thereof. In
certain embodiments, the blood fat disorder is selected from high
triglycerides, low HDL cholesterol, high LDL cholesterol, plaque
buildup in artery walls, or a combination thereof. In certain
embodiments, the prothrombotic state is selected from high
fibrinogen levels in the blood and high plasminogen activator
inhibitor-1 levels in the blood. In certain embodiments, the
proinflammatory state is an elevated C-reactive protein level in
the blood. In certain embodiments, the obesity related disorder is
selected from obesity linked inflammation, obesity linked
gallbladder disease and obesity induced sleep apnea.
[0117] In some embodiments, the invention also provides a
therapeutic kit comprising a GIP analogue of the invention, a
nucleic acid molecule of the invention, an expression vector of the
invention, or a host cell of the invention, each optionally in
combination with a pharmaceutically acceptable carrier. In some
embodiments, the invention provides a device comprising a GIP
analogue of the invention, a nucleic acid molecule of the
invention, an expression vector of the invention, or a host cell of
the invention for delivery of the GIP analogue to a subject.
Pharmaceutical Compositions
[0118] The GIP-GLP1 dual agonist compounds of the present
invention, or salts or solvates thereof, may be formulated as
pharmaceutical compositions prepared for storage or administration,
which typically comprise a therapeutically effective amount of a
compound employed in the context of the invention, or a salt or
solvate thereof, in a pharmaceutically acceptable carrier. In some
embodiments, the pharmaceutical composition is formulated as a
liquid suitable for administration by injection or infusion, or
which is formulated to cause slow release of the GIP-GLP1 dual
agonist compound
[0119] The therapeutically effective amount of a compound of the
present invention will depend, e.g., on the route of
administration, the type of mammal being treated, and the physical
characteristics of the specific mammal under consideration. These
factors and their relationship to determining this amount are well
known to skilled practitioners in the medical arts. This amount and
the method of administration can be tailored to achieve optimal
efficacy, and may depend on such factors as weight, diet,
concurrent medication and other factors, well known to those
skilled in the medical arts. The dosage sizes and dosing regimen
most appropriate for human use may be guided by the results
obtained by the present invention, and may be confirmed in properly
designed clinical trials.
[0120] An effective dosage and treatment protocol may be determined
by conventional means, starting with a low dose in laboratory
animals and then increasing the dosage while monitoring the
effects, and systematically varying the dosage regimen as well.
Numerous factors may be taken into consideration by a clinician
when determining an optimal dosage for a given subject. Such
considerations are known to the skilled person. The term
"pharmaceutically acceptable carrier" includes any of the standard
pharmaceutical carriers. Pharmaceutically acceptable carriers for
therapeutic use are well known in the pharmaceutical art, and are
described, for example, in Remington's Pharmaceutical Sciences,
Mack Publishing Co. (A. R. Gennaro edit. 1985). For example,
sterile saline and phosphate-buffered saline at slightly acidic or
physiological pH may be used. Suitable pH buffering agents may be,
e.g., phosphate, citrate, acetate, lactate, maleate,
tris/hydroxymethyl)aminomethane (TRIS),
N-Tris(hydroxymethyl)methyl-3-aminopropanesulphonic acid (TAPS),
ammonium bicarbonate, diethanolamine, histidine, which in certain
embodiments is a preferred buffer, arginine, lysine, or acetate or
mixtures thereof. The term further encompasses any agents listed in
the US Pharmacopeia for use in animals, including humans.
[0121] The term "pharmaceutically acceptable salt" refers to a salt
of the compound. Salts include pharmaceutically acceptable salts,
such as, e.g., acid addition salts and basic salts. Examples of
acid addition salts include hydrochloride salts, citrate salts and
acetate salts. Examples of basic salts include salts where the
cation is selected from alkali metals, such as sodium and
potassium, alkaline earth metals such as calcium, and ammonium ions
.sup.+N(R.sup.3).sub.3(R.sup.4), where R.sup.3 and R.sup.4
independently designate optionally substituted C.sub.1-6-alkyl,
optionally substituted C.sub.2-6-alkenyl, optionally substituted
aryl, or optionally substituted heteroaryl. Other examples of
pharmaceutically acceptable salts are described in "Remington's
Pharmaceutical Sciences", 17th edition. Ed. Alfonso R. Gennaro
(Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and more
recent editions, and in the Encyclopaedia of Pharmaceutical
Technology.
[0122] "Treatment" is an approach for obtaining beneficial or
desired clinical results. For purposes of this invention,
beneficial or desired clinical results include, but are not limited
to, alleviation of symptoms, diminishment of extent of disease,
stabilized (i.e., not worsening) state of disease, delay or slowing
of disease progression, amelioration or palliation of the disease
state, and remission (whether partial or total), whether detectable
or undetectable. "Treatment" may also mean prolonging survival as
compared to expected survival if not receiving treatment.
"Treatment" is an intervention performed with the intention of
preventing the development or altering the pathology of a disorder.
Accordingly, "treatment" refers to both therapeutic treatment and
prophylactic or preventative measures in certain embodiments. Those
in need of treatment include those already with the disorder as
well as those in which the disorder is to be prevented. By
treatment is meant inhibiting or reducing an increase in pathology
or symptoms (e.g. weight gain, hyperglycemia) when compared to the
absence of treatment, and is not necessarily meant to imply
complete cessation of the relevant condition.
[0123] The pharmaceutical compositions of the invention may be in
unit dosage form. In such form, the composition is divided into
unit doses containing appropriate quantities of the active
component. The unit dosage form can be a packaged preparation, the
package containing discrete quantities of the preparations, for
example, packeted tablets, capsules, and powders in vials or
ampoules. The unit dosage form can also be a capsule, cachet, or
tablet itself, or it can be the appropriate number of any of these
packaged forms. It may be provided in single dose injectable form,
for example in the form of an injection pen. Compositions may be
formulated for any suitable route and means of administration.
Pharmaceutically acceptable carriers or diluents include those used
in formulations suitable for oral, rectal, nasal or parenteral
(including subcutaneous, intramuscular, intravenous, intradermal,
and transdermal) administration. The formulations may conveniently
be presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. Subcutaneous or
transdermal modes of administration may be particularly suitable
for certain of the compounds described herein.
Combination Therapy
[0124] In certain embodiments, a GIP-GLP-1 dual agonist compound
employed in the context of the invention may be administered as
part of a combination therapy with at least one other agent for
treatment of diabetes, obesity, dyslipidemia, or hypertension.
[0125] In such cases, the at least two active agents may be given
together or separately, and as part of the same pharmaceutical
formulation or as separate formulations. Thus, the GIP-GLP-1 dual
agonist compound employed in the context of the invention (or the
salt or solvate thereof) may be used in combination with an
antidiabetic agent including but not limited to metformin, a
sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, or
insulin. In certain embodiments, the compound or salt or solvate
thereof is used in combination with insulin, DPP-IV inhibitor,
sulfonylurea or metformin, particularly sulfonylurea or metformin,
for achieving adequate glycemic control. In certain preferred
embodiments, the compound or salt or solvate thereof is used in
combination with insulin or an insulin analogue for achieving
adequate glycemic control. Examples of insulin analogues include
but are not limited to Lantus.RTM., NovoRapid.RTM., Humalog.RTM.,
NovoMix.RTM., Actraphane HM.RTM., Levemir.RTM. and Apidra.RTM..
[0126] In certain embodiments, the GIP-GLP-1 dual agonist compound
or salt or solvate thereof may further be used in combination with
one or more of an anti-obesity agent, including but not limited to
a glucagon-like peptide receptor 1 agonist, peptide YY or analogue
thereof, cannabinoid receptor 1 antagonist, lipase inhibitor,
melanocortin receptor 4 agonist, or melanin concentrating hormone
receptor 1 antagonist.
[0127] In certain embodiments, the GIP-GLP-1 dual agonist compound
or salt or solvate thereof may be used in combination with an
anti-hypertension agent, including but not limited to an
angiotensin-converting enzyme inhibitor, angiotensin II receptor
blocker, diuretics, beta-blocker, or calcium channel blocker.
[0128] In certain embodiments, the GIP-GLP-1 dual agonist compound
or salt thereof may be used in combination with an
anti-dyslipidemia agent, including but not limited to a statin, a
fibrate, a niacin and/or a cholesterol absorption inhibitor.
Nucleic Acids, Vectors, and Host Cells
[0129] In some embodiments, the invention provides a nucleic acid
molecule comprising a nucleic acid sequence encoding a GIP analogue
of the invention. In some embodiments, the invention provides an
expression vector comprising a nucleic acid sequence encoding a GIP
analogue of the invention, in combination with control sequences to
direct its expression. In some embodiments, the invention provides
a host cell transformed with such an expression vector. In some
embodiments, the invention provides a method of producing a GIP
analogue of the invention, the method comprising culturing the host
cells described above under conditions suitable for expressing the
GIP analogue and purifying the GIP analogue thus produced. In some
embodiments, the invention provides a nucleic acid molecule, an
expression vector, or a host cell, as described above, for use in
therapy. In some embodiments, the invention provides the use of a
nucleic acid molecule according, an expression vector, or a host
cell, as described above, in the preparation of a medicament for
the treatment and/or prevention of a metabolic disorder.
[0130] It will be understood that a nucleic acid will typically
only be capable of encoding a polypeptide of the invention when the
polypeptide sequence consists entirely of the 20 naturally
occurring (proteinogenic) amino acids. However, nucleic acids may
be employed which encode a fragment or precursor of the compound of
the invention.
[0131] The peptide compounds of the invention may be manufactured
by standard peptide synthetic methods, by use of recombinant
expression systems, or by any other suitable method. Thus, the
compounds may be synthesized in a number of ways, including, e.g.,
methods comprising:
(a) synthesizing the peptide compound by standard solid-phase or
liquid-phase methodology, either stepwise or by fragment assembly,
and isolating and purifying the final peptide compound product; (b)
expressing a nucleic acid construct that encodes the peptide
compound or a fragment or precursor thereof in a host cell and
recovering the expression product from the host cell culture; or
(c) effecting cell-free in vitro expression of a nucleic acid
construct encoding the peptide compound or a fragment or precursor
thereof, and recovering the expression product; or by any
combination of the methods of (a), (b) or (c) to obtain fragments
of the peptide compound, subsequently joining (e.g., ligating) the
fragments to obtain the peptide compound, and recovering the
peptide compound.
[0132] The method of synthesis may comprise the step of chemically
modifying one of more amino acid side chains in a precursor peptide
to yield a compound of the invention. Such modification may, for
example, introduce a non-naturally occurring amino acid, convert
one or more amino acids into non-naturally occurring amino acids,
introduce an intramolecular bridge between two amino acid side
chains, e.g. by forming a lactam ring between a Glu and a Lys
residue, or introduce a lipophilic substituent at a lysine
residue.
[0133] It may be preferable to synthesize the peptide compounds of
the invention by means of solid-phase or liquid-phase peptide
synthesis. In this context, reference may be made to WO 98/11125
or, inter alia, Fields, G. B. et al., "Principles and Practice of
Solid-Phase Peptide Synthesis"; in: Synthetic Peptides, Gregory A.
Grant (ed.), Oxford University Press (2nd edition, 2002) and the
synthesis examples herein.
[0134] Accordingly, the present invention also provides methods for
producing a polypeptide of the invention according to above recited
methods; a nucleic acid molecule encoding part or all of a
polypeptide of the invention or a precursor thereof, a vector
comprising at least one nucleic acid of the invention, expression
vectors comprising at least one nucleic acid of the invention
capable of producing a polypeptide of the invention when introduced
into a host cell, and a host cell comprising a nucleic acid
molecule, vector or expression vector of the invention.
EXAMPLES
[0135] The following examples demonstrate certain embodiments of
the present invention. However, it is to be understood that these
examples neither purport nor are they intended to be wholly
definitive as to conditions and scope of this invention. The
examples were carried out using standard techniques, which are well
known and routine to those of skill in the art, except where
otherwise described in detail. The following examples are presented
for illustrative purposes only, and should not be construed in any
way as limiting the scope of this invention.
[0136] Disclosed are GIP-GLP1 dual agonist compounds that exhibit
signaling selectivity, and methods for screening these compounds.
Signaling selectivity may be, for example, preferential pathway
activation or preferential pathway inhibition, or both. The
GIP-GLP1 dual agonist compounds may be useful for the treatment
and/or prevention of diseases or conditions caused or characterized
by excess body weight, including, but not limited to, obesity,
morbid obesity, obesity linked inflammation, obesity linked
gallbladder disease, obesity induced sleep apnea, metabolic
syndrome, pre-diabetes, insulin resistance, glucose intolerance,
type 2 diabetes, type I diabetes, hypertension, atherogenic
dyslipidaemia, atherosclerosis, arteriosclerosis, coronary heart
disease, peripheral artery disease, and stroke or microvascular
disease.
[0137] While some embodiments of the invention have been described
by way of illustration, it will be apparent that the invention can
be put into practice with many different modifications, variations
and adaptations, and with the use of numerous equivalents or
alternative solutions that are within the scope of persons skilled
in the art, without departing from the spirit of the invention or
exceeding the scope of the claims.
[0138] All publications, patents, and patent applications referred
to herein are herein incorporated by reference in their entirety to
the same extent as if each individual publication, patent or patent
application was specifically and individually indicated to be
incorporated by reference in its entirety.
Example 1
[0139] The methods used in the instant invention are described
below, except where expressly indicated otherwise.
General Synthesis of Acylated GIP Analogues
[0140] Solid phase peptide synthesis was performed on a CEM Liberty
Peptide Synthesizer using standard Fmoc chemistry. TentaGel S Ram
resin (1 g; 0.25 mmol/g) was swelled in NMP (10 ml) prior to use
and transferred between tube and reaction vessel using DCM and
NMP.
Coupling
[0141] An Fmoc-amino acid in NMP/DMF/DCM (1:1:1; 0.2 M; 5 ml) was
added to the resin in a CEM Discover microwave unit together with
HATU/DMF or COMU/DMF (0.5 M; 2 ml) and DIPEA/NMP (2.0 M; 1 ml). The
coupling mixture was heated to 75.degree. C. for 5 min while
nitrogen was bubbled through the mixture. The resin was then washed
with NMP (4.times.10 ml).
Deprotection
[0142] Piperidine/DMF (20%; 10 ml) was added to the resin for
initial deprotection and the mixture was heated by microwaves (30
sec; 40.degree. C.). The reaction vessel was drained and a second
portion of piperidine/NMP (20%; 10 ml) was added and heated
(75.degree. C.; 3 min.) again. The resin was then washed with DMF
(6.times.10 ml).
Side Chain Acylation
[0143] Fmoc-Lys(ivDde)-OH or alternatively another amino acid with
an orthogonal side chain protective group was introduced at the
position of the acylation. The N-terminal of the peptide backbone
was then Boc-protected using Boc2O or alternatively by using a
Boc-protected amino acid in the last coupling. While the peptide
was still attached to the resin, the orthogonal side chain
protective group was selectively cleaved using freshly prepared
hydrazine hydrate (2-4%) in NMP for 2.times.15 min. The unprotected
lysine side chain was first coupled with Fmoc-Glu-OtBu or another
spacer amino acid, which was deprotected with piperidine and
acylated with a lipophilic moiety using the peptide coupling
methodology as described above. Alternatively, the acylation moiety
was introduced as a premade building block e.g.
Fmoc-Lys(hexadecanoyl-gamma-Glu)-OH where gamm-Glu is the coupling
of Glutamic acid through the side-chain. Abbreviations employed are
as follows:
COMU:
1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpho-
linomethylene)]methanaminium hexaflourophosphate ivDde:
1-(4,4-dimethyl-2,6-dioxocyclohexylidene)3-methyl-butyl Dde:
1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl DCM:
dichloromethane
DMF: N,N-dimethylformamide
[0144] DIPEA: diisopropylethylamine EtOH: ethanol Et.sub.2O:
diethyl ether HATU:
N-[(dimethylamino)-1H-1,2,3-triazol[4,5-b]pyridine-1-ylmethylene]-N-
-methylmethanaminium hexafluorophosphate N-oxide MeCN:
acetonitrile
NMP: N-methylpyrrolidone
[0145] TFA: trifluoroacetic acid TIS: triisopropylsilane
Cleavage
[0146] The resin was washed with EtOH (3.times.10 ml) and Et.sub.2O
(3.times.10 ml) and dried to constant weight at room temperature
(r.t.). The crude peptide was cleaved from the resin by treatment
with TFA/TIS/water (95/2.5/2.5; 40 ml, 2 h; r.t.). Most of the TFA
was removed at reduced pressure and the crude peptide was
precipitated and washed three times with diethylether and dried to
constant weight at room temperature.
HPLC Purification of the Crude Peptide
[0147] The crude peptide was purified to greater than 90% by
preparative reverse phase HPLC using a PerSeptive Biosystems VISION
Workstation equipped with a C-18 column (5 cm; 10 .mu.m) and a
fraction collector and run at 35 ml/min with a gradient of buffer A
(0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.). Fractions
were analyzed by analytical HPLC and MS and relevant fractions were
pooled and lyophilized. The final product was characterized by HPLC
and MS.
[0148] The synthesized compounds are shown in Table 1 and Table
2.
TABLE-US-00004 TABLE 1 Compound No. Sequence 1
Hy-Y-Aib-EGTFISDYSIYLEKKAAKEFVNWLLAQK-NH.sub.2 2
Hy-Y-Aib-EGTFTSDYSI-Aib- LDKKAQRAFVEWLLAQGPSSGAPPPS-NH.sub.2 3
Hy-Y-Aib-EGTFTSDYSIALDKIAQRAFVNWLVA-Aib-K-NH.sub.2 4
Hy-Y-Aib-EGTFISDYSIYLEKIAAKEFVNWLLAQK-NH.sub.2 5
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2
TABLE-US-00005 TABLE 2 Compound No. Sequence 6
pGlu-YAEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 7
Hy-YGEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 8
Hy-Y-Aib-EGTFSSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 9
Hy-Y-Aib-EGTFTSDLSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 10
Hy-Y-Aib-EGTFTSDSSIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 11
Hy-Y-Aub-EGTFTSDYLIYLDKKAQRAFVNWLLA-Aib-K-NH.sub.2 12
Hy-Y-Aib-EGTFTSDYSIALDKKAQRAFVNWLLA-Aib-K-NH.sub.2 13
Hy-Y-Aib-EGTFTSDYSIYSDKKAQRAFVNWLLA-Aib-K-NH.sub.2 14
Hy-Y-Aib-EGTFTSDYSIYLEKKAQRAFVNWLLA-Aib-K-NH.sub.2 15
Hy-Y-Aib-EGTFTSDYSIALEKKAQRAFVNWLLA-Aib-K-NH.sub.2 16
Hy-Y-Aib-EGTFTSDYSIYLDSKAQRAFVNWLLA-Aib-K-NH.sub.2 17
Hy-Y-Aib-EGTFTSDYSIYLDEKAQRAFVNWLLA-Aib-K-NH.sub.2 18
Hy-Y-Aib-EGTFTSDYSIYLDSKAKRAFVNWLLA-Aib-K-NH.sub.2 19
Hy-Y-Aib-EGTFTSDYSIYLDKKAQKEFVNWLLA-Aib-K-NH.sub.2 20
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVKWLLA-Aib-K-NH.sub.2 21
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLVA-Aib-K-NH.sub.2 22
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLSA-Aib-K-NH.sub.2 23
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLKA-Aib-K-NH.sub.2 24
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLL-Ab-K-NH.sub.2 25
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-KYG- 1Nal-LDF-NH.sub.2 26
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLAYG-1Nal- LDF-NH.sub.2 27
Hy-Y-Aib-EGTFTSDYSIYLDKKAEKAFVNWLLA-Aib-K-NH.sub.2 28
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib- GPSSGAPPPS-NH.sub.2 29
Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib- GPSSGAPPS-NH.sub.2 30
Hy-Y-Aib-EGTFTSDYSIYLEKAAKEFVNWLLAQK-NH.sub.2 31
Hy-Y-Aib-EGTFTSDYSIYLDK-K(15-carboxy-pentadecanoyl-
isoGlu)-AQRAFVNWLLA-Aib-K-NH.sub.2 32
Hy-Y-Aib-EGTFTSDYSI-Aib-LDK-K(Hexadecanoyl-isoGlu)-
AQRAFVEWLLAQGPSSGAPPPS-NH.sub.2 33
Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-
AQRAFVEWLLAQGPSSGAPPPS-NH.sub.2 34
Hy-Y-Aib-EGTFTSDYSIYLDE-K(hexadecanoyl-isoGlu)-
AAKEFIEWLESA-NH.sub.2 35
Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-
AQRAFVNWLLA-Aib-KPSSGAPPPS-NH.sub.2 36
Hy-Y-Aib-EGTFTSDYSIALDK-K(hexadecanoyl-isoGlu)-
AQRAFVNWLVA-Aib-KPSSGAPPPS-NH.sub.2 37
Hy-Y-Aib-EGTFTSDYSIYLE-KKAAKDFVEWLLSA-NH.sub.2 38
Hy-Y-Aib-EGTFTSDYSIYLE-KAAHDFVEWLLSA-NH.sub.2 39
Hy-Y-Aib-EGTFTSDYSIYLEKMQKEFVEWLLSA-NH.sub.2 40
Hy-Y-Aib-EGTFTSDYSIYLDEAKDFVEWLLSA-NH.sub.2 41
Hy-Y-Aib-EGTFTSDYSIYLESAHDFVEWLLSA-NH.sub.2 42
Hy-Y-Aib-EGTFTSDYSIYLDKAAHDFVEWLLSA-NH.sub.2 43
Hy-Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA-NH.sub.2 44
Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLRA-NH.sub.2 45
Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLSA-NH.sub.2 46
Hy-Y-Aib-EGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-
AAKEFVEWLLSA-NH.sub.2 47
Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLRA-NH.sub.2 48
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-
AAKDFVEWLESA-NH.sub.2 49
Hy-Y-Aib-EGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-
AAKDFIEWLESA-NH.sub.2 50
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-
AAKDFIEWLESA-NH.sub.2 51
Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLRA-NH.sub.2 52
Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-
AAKDFVEWLLSA-NH.sub.2 53
Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLSAGPSSGAPPPS-NH.sub.2 54
Hy-Y-Aib-EGTFTSDYSIYLEK-K-(Hexadecanoyl-isoGlu)-
AAKEFVEWLLSAGPSSGAPPPS-NH.sub.2 55 Hy-Y-Aib-
EGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS-NH.sub.2 56
Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLSA
Synthesis of Compound No. 36
[0149] Solid phase peptide synthesis was performed on a CEM Liberty
Peptide Synthesizer using standard Fmoc chemistry. TentaGel S Ram S
resin (1.05 g; 0.25 mmol/g) was swelled in DMF (10 ml) prior to use
and transferred between tube and reaction vessel using DCM and
DMF.
Coupling
[0150] An Fmoc-amino acid in DMF/DCM (2:1; 0.2 M; 5 ml) was added
to the resin in a CEM Discover microwave unit together with
COMU/DMF (0.5 M; 2 ml) and DIPEA&DMF (2.0 M; 1 ml). The
coupling mixture was heated to 75.degree. C. for 5 min while
nitrogen was bubbled through the mixture. The resin was then washed
with DMF (4.times.10 ml). Fmoc-Tyr(OtBu)-Ser(Psi Me,Me)-OH
pseudoproline was used for amino acid number 29 and 30 counting
from the C-terminal. Fmoc-Lys(hexadecanoyl-gamma-Glu)-OH (2:1; 0.2
M; 5 ml) was incorporated as a premade building block using
standard Fmoc coupling chemistry. The first 9 amino acids and amino
acid number 24 (counting from the C-terminal) was double couple
meaning the building block was coupled twice before
deprotection.
Deprotection
[0151] Piperidine/DMF (20%; 10 ml) was added to the resin for
initial deprotection and the mixture was heated by microwaves (30
sec; 40.degree. C.). The reaction vessel was drained and a second
portion of piperidine/DMF (20%; 10 ml) was added and heated
(75.degree. C.; 3 min.) again. The resin was then washed with DMF
(6.times.10 ml).
[0152] The resin was washed with EtOH (3.times.10 ml) and Et2O
(3.times.10 ml) and dried to constant weight at room temperature
(r.t.). The crude peptide was cleaved from the resin by treatment
with TFA/TIS/H.sub.2O (95/2.5/2.5; 60 ml, 2 h; r.t.). Most of the
TFA was removed at reduced pressure and the crude peptide was
precipitated and washed three times with diethylether and dried to
constant weight at room temperature.
HPLC Purification of the Crude Peptide
[0153] The crude peptide was first purified to 45% by preparative
reverse phase HPLC using a PerSeptive Biosystems VISION Workstation
equipped with a Gemini NX 5.mu. C-18 110 A, 10.times.250 mm column
and a fraction collector and run at 35 ml/min with a gradient of
buffer A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.).
Fractions were analyzed by analytical HPLC and MS and relevant
fractions were pooled and lyophilized. The product (138 mg) was
analysed to give a purity of 96% as characterized by HPLC and MS.
Calculated monoisotopic mass=4534.42, found 4534.43.
Example 2
Human GIP Receptor (GIP R) and GLP-1 Receptor (GLP-1 R) Activity
Assay
[0154] In vitro effects of peptide conjugates of the invention were
assessed by measuring the induction of cAMP following stimulation
of the respective receptor by GIP, GLP1 or analogues of these, as
outlined in the invention, using the AlphaSceen.RTM. cAMP kit from
Perkin-Elmer according to instructions. Briefly, HEK293 cells
expressing the human GIP R or GLP-1 R (stable cell lines generated
through transfection of the cDNA for human GIP R or GLP-1 and
selection of stable clones) were seeded at 30,000 cells/well in
96-well microtiter plates coated with 0.01% poly-L-lysine, and
grown for 1 day in culture in 200 .mu.l growth medium (DMEM, 10%
FCS, Penicillin (100 IU/ml), Streptomycin (100 .mu.g/ml)). On the
day of analysis, growth medium was removed and the cells were
washed once with 150 ml Tyrode's buffer (Tyrode's Salts (9.6 g/I),
10 mM HEPES, pH 7.4). Cells were then incubated in 100 ml Assay
buffer (0.1% WN Alkali-treated Casein and 100 .mu.M IBMX in
Tyrode's Buffer) containing increasing concentrations of control
and test compounds for 15 min at 37.degree. C. The Assay buffer was
removed and cells are lysed in 80 .mu.l Lysis buffer (0.1% w/v BSA,
5 mM HEPES, 0.3% v/v Tween-20) per well. From each well 10 .mu.l
lysed cells was transferred to a 384-well plate and mixed with 15
.mu.l bead-mix (1 Unit/15 .mu.l anti-cAMP Acceptor Beads, 1 Unit/15
.mu.l Donor Beads, and 1 Unit/15 .mu.l Biotinylated cAMP in Assay
Buffer). The plates were mixed and incubated in the dark for an
hour at room temperature before measuring using an Envision.TM.
plate reader (Perkin-Elmer). The results are summarized in Table
3.
TABLE-US-00006 TABLE 3 EC.sub.50 average values of the compounds on
the GIP- R and GLP1-R compared to control peptides. GIP R GLP1 R
Compound No (EC.sub.50 in nM) (EC.sub.50 in nM) hGIP 0.0038
Exendin-4 0.0043 2 0.0068 0.015 3 0.015 0.022 4 0.022* 2.6 5 0.031
0.023 6 0.27 0.97 7 0.21 0.024 8 0.10 0.029 9 0.091 0.014 11 0.76
0.47 12 0.050 0.010 13 0.14 0.032 14 0.036 0.0087 15 0.060 0.010 16
0.053 0.012 17 0.021 0.0074 18 0.36 0.015 19 0.015 0.0073 20 0.049
0.0090 21 0.080 0.0090 23 0.42 0.012 24 0.096 0.0085 25 0.12 0.041
26 0.80 0.39 27 0.30 0.074 28 0.020 0.0051 29 0.024 0.0088 30 0.054
0.0093 31 0.022 0.020 32 0.012 0.018 33 0.035 0.031 34 0.045 0.031
35 0.028 0.022 36 0.0099 0.015 37 0.0097 0.018 38 0.0070 0.018 39
0.0083 0.011 40 0.011 0.022 41 0.013 0.011 42 0.0070 0.012 43
0.0091 0.017 44 0.016 0.013 45 0.32 0.11 46 0.088 0.048 47 0.096
0.14 48 0.061 0.041 49 0.092 0.049 50 0.053 0.090 51 0.24 0.11 52
0.087 0.18 53 0.062 0.092 54 0.037 0.033 55 0.0071 0.0087 56 0.14
0.13 *Value is slightly adjusted from that in U.S. application Ser.
No. 61/642,439 due to additional determinations. All values are
based on multiple determinations.
Example 3
Pharmacokinetics of Compounds 32 and 33 in Mice
Method
[0155] C57BL/6J mice were given a single subcutaneous dose of 200
nmol/kg body weight of each peptide to be tested. Blood samples
were drawn 0.5, 2, 4, 6, 8, 16, 24 and 36 hours post-dose by
sublingual bleeding. At each time point, samples from two mice were
taken, i.e. 16 mice per compound. The mice were euthanized
immediately after blood sampling by cervical dislocation. Plasma
samples were analyzed after solid phase extraction (SPE) by liquid
chromatography mass spectrometry (LC-MS/MS). The pharmacokinetic
analyses were performed by using the non-compartmental approach
(see Table 4).
TABLE-US-00007 TABLE 4 Terminal elimination half-life (h) in mice
following subcutaneous administration of 200 nmol/kg body weight.
Compound T.sub.1/2 (h) 32 3.4 33 3.7
Example 4
[0156] IPGTT (Intraperitoneal Glucose Tolerance Test) in Mice.
[0157] Male C57BL/6J mice (Charles River, Germany) were maintained
on normal chow (Altromin 1324, Brogaarden A/S, Gentofte, Denmark)
and domestic quality water with added citric acid to pH .about.3.6.
The animals were housed pair-wise in a light-, temperature-, and
humidity-controlled room (12:12 h light-dark cycle, with lights on
at 06.00-18.00 hr; 20-22.degree. C.; 50-80% relative humidity).
Mice were fasted for 5 hr before the IPGTT. Peptides and vehicle
were administered subcutaneously before the intraperitoneal
injection of glucose (t=0 min; 2 g/kg; 5 ml/kg). Tail vein blood
was sampled at time t=0 (before glucose administration), 15, 30,
45, 60, 90, and 120 min for measurements of blood glucose. Results
are shown in FIG. 1.
Example 5
Sub-Chronic Effects of GIP-GLP-1 Receptor Dual Acting Agonist on
Body Weight, Body Composition, Food Intake, Blood Glucose, Plasma
Insulin, Cholesterol and Triglycerides in Diet-Induced Obese
C57BL/6J Mice
[0158] Male C57BL/6J mice (obtained from Jackson Labs, USA) fed
high-fat diet (60% of total energy from fat, D12492, Research Diet
Inc.) for approximately 6 months were used. The mice were housed
individually, and they were maintained on a 12:12 hour light-dark
cycle (lights on at 05.00-17.00). All mice were mock-treated (once
daily s.c. injection of vehicle) for a week to acclimatize the
animals to handling and injections. Subsequently, the mice were
stratified according to body fat mass (measured by magnetic
resonance technique) and body weight into five groups (n=10).
Animals were thereafter treated twice daily with s.c. injections (5
ml/kg) of vehicle (group 1: 50 mM phosphate buffer, pH 7.5), the
GLP-1 analogue liraglutide (group 2: 2*25 nmol/kg), or test
substance (group 3, 2*5 nmol/kg; group 4, 2*25 nmol/kg, or group 5,
2*100 nmol/kg) for a total of 21 days. The daily injections were
given in the morning (at 8.00-9.00) and in the afternoon
(15.00-16.00 hr). Body weight, food and water intake were
determined daily throughout the study. On day 8 of treatment, the
2*100 nmol/kg dose of test substance was halved due to profound
body weight loss. This dose (2*50 nmol/kg) was used throughout the
remaining treatment period. On day 13, animals were fasted for 4
hours, and blood samples were taken for measurements of blood
glucose and plasma insulin. The animals were not dosed in the
morning before the blood sampling. On day 19, body composition was
measured using a MR scanner. On day 21, blood was sampled for
measurements of blood glucose, plasma insulin, plasma cholesterol,
and plasma triglycerides. Animals were injected with vehicle,
liraglutide or test substance 2 hours before blood sampling. After
the final blood sampling, the mice were euthanized.
[0159] Statistical analyses were performed using Graph Pad Prism
version 5. The measured parameters were compared using one-way or
two-way ANOVAs followed by Tukey's multiple comparison tests or
Bonferroni post tests. Student's two-tailed, unpaired t-test was
used to compare the means of two independent groups. Differences
were considered statistically significant at p<0.05.
Sequence CWU 1
1
149142PRTArtificial sequenceSynthetic sequence GIP Analogue General
Formula I(b) of PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein
R1 is Hy-, Ac or pGluVARIANT(1)..(1)Xaa is His or
TyrVARIANT(2)..(2)Xaa is Ala, Aib or GlyVARIANT(3)..(3)Xaa is Glu
or AspVARIANT(7)..(7)Xaa is Thr or SerVARIANT(9)..(9)Xaa is Asp or
GluVARIANT(10)..(10)Xaa is Tyr, Leu or SerVARIANT(11)..(11)Xaa is
Ser or LeuVARIANT(13)..(13)Xaa is Ala, Tyr or
AibVARIANT(14)..(14)Xaa is Met, Leu or SerVARIANT(15)..(15)Xaa is
Asp or GluVARIANT(16)..(16)Xaa is Lys, Gly, Ser or
GluVARIANT(17)..(17)Xaa is Ile, Lys, Gln, Arg or
GluVARIANT(19)..(19)Xaa is Gln, Ala, Glu or LysVARIANT(20)..(20)Xaa
is Gln, Lys or ArgVARIANT(21)..(21)Xaa is Asp, Ala or
GluVARIANT(22)..(22)Xaa is Phe or 1NalVARIANT(23)..(23)Xaa is Val,
Ile or LeuVARIANT(24)..(24)Xaa is Asn, Glu, Arg or
LysVARIANT(27)..(27)Xaa is Leu, Val, Ile, Lys or
SerVARIANT(28)..(28)Xaa is Ala or AibVARIANT(29)..(29)Xaa is Gln,
Gly, Aib or TyrVARIANT(30)..(30)Xaa is Lys, Gly, Pro or
absentVARIANT(31)..(31)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(32)..(32)Xaa is Lys, Ser or
absentVARIANT(33)..(33)Xaa is Lys, Ser, Glu or
absentVARIANT(34)..(34)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(35)..(35)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(36)..(36)Xaa is Trp, Pro, Lys or
absentVARIANT(37)..(37)Xaa is Lys, Pro, Glu or
absentVARIANT(38)..(38)Xaa is His, Pro, Ser, Lys or
absentVARIANT(39)..(39)Xaa is Asn, Ser or
absentVARIANT(40)..(40)Xaa is Ile or absentVARIANT(41)..(41)Xaa is
Thr or absentVARIANT(42)..(42)Xaa is Gln or absent 1Xaa Xaa Xaa Gly
Thr Phe Xaa Ser Xaa Xaa Xaa Ile Xaa Xaa Xaa Xaa1 5 10 15Xaa Ala Xaa
Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 40240PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(b) of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluMOD_RES(2)..(2)AibVARIANT(7)..(7)Xaa is Thr or
SerVARIANT(13)..(13)Xaa is Ala, Tyr or AibVARIANT(14)..(14)Xaa is
LeuVARIANT(15)..(15)Xaa is Asp or GluVARIANT(17)..(17)Xaa is Ile or
LysVARIANT(20)..(20)Xaa is Lys or ArgVARIANT(21)..(21)Xaa is Ala or
GluVARIANT(23)..(23)Xaa is Val or IleVARIANT(24)..(24)Xaa is Asn or
GluVARIANT(27)..(27)Xaa is Leu or ValVARIANT(29)..(29)Xaa is Aib or
GlyVARIANT(30)..(30)Xaa is Lys, Gly or absentVARIANT(31)..(40)Y1,
which may be present or absent. If present, up to 2 residues may be
present or absent, and Y1 is SEQ ID NO 74, SEQ ID NO 75, SEQ ID NO
76, or SEQ ID NO 77. 2Tyr Ala Glu Gly Thr Phe Xaa Ser Asp Tyr Ser
Ile Xaa Xaa Xaa Lys1 5 10 15Xaa Ala Gln Xaa Xaa Phe Xaa Xaa Trp Leu
Xaa Ala Xaa Xaa Xaa Xaa 20 25 30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35
40330PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)Aib 3Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr
Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala Ala Lys Glu Phe Val Asn Trp
Leu Leu Ala Gln Lys 20 25 30439PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(13)Aib 4Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Ala Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala
Phe Val Glu Trp Leu Leu Ala Gln Gly Pro Ser 20 25 30Ser Gly Ala Pro
Pro Pro Ser 35530PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 5Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Ala Leu Asp Lys1 5 10 15Ile Ala Gln Arg Ala Phe Val Asn
Trp Leu Val Ala Ala Lys 20 25 30630PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(2)Aib 6Tyr Ala Glu Gly Thr Phe
Ile Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Ile Ala Ala Lys Glu
Phe Val Asn Trp Leu Leu Ala Gln Lys 20 25 30730PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(29)Aib 7Tyr Ala
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys
Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25
30830PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(29)..(29)Aib 8Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn
Trp Leu Leu Ala Ala Lys 20 25 30930PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(29)..(29)Aib 9Tyr Gly Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala
Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25 301030PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(29)Aib 10Tyr
Ala Glu Gly Thr Phe Ser Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10
15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25
301130PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 11Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Leu Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn
Trp Leu Leu Ala Ala Lys 20 25 301230PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(29)Aib 12Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Ser Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala
Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25 301330PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(29)Aib 13Tyr
Ala Glu Gly Thr Phe Thr Ser Asp Tyr Leu Ile Tyr Leu Asp Lys1 5 10
15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25
301430PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 14Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Ala Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn
Trp Leu Leu Ala Ala Lys 20 25 301530PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(29)Aib 15Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Ser Asp Lys1 5 10 15Lys Ala Gln Arg Ala
Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25 301630PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(29)Aib 16Tyr
Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10
15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25
301730PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 17Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Ala Leu Glu Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn
Trp Leu Leu Ala Ala Lys 20 25 301830PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(29)Aib 18Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser1 5 10 15Lys Ala Gln Arg Ala
Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25 301930PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(29)Aib 19Tyr
Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1 5 10
15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25
302030PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 20Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Ser1 5 10 15Lys Ala Lys Arg Ala Phe Val Asn
Trp Leu Leu Ala Ala Lys 20 25 302130PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(29)Aib 21Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Lys Glu
Phe Val Asn Trp Leu Leu Ala Ala Lys 20 25 302230PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(29)Aib 22Tyr
Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10
15Lys Ala Gln Arg Ala Phe Val Lys Trp Leu Leu Ala Ala Lys 20 25
302330PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 23Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn
Trp Leu Val Ala Ala Lys 20 25 302430PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(29)Aib 24Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala
Phe Val Asn Trp Leu Ser Ala Ala Lys 20 25 302530PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(29)Aib 25Tyr
Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10
15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Lys Ala Ala Lys 20 25
302629PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 26Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn
Trp Leu Leu Ala Lys 20 252736PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(29)AibSITE(33)..(33)Xaa is 1Nal
27Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1
5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Ala Lys Tyr
Gly 20 25 30Xaa Leu Asp Phe 352834PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(2)AibSITE(31)..(31)Xaa is 1Nal
28Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1
5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Tyr Gly Xaa
Leu 20 25 30Asp Phe2930PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 29Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Glu Lys Ala Phe Val Asn
Trp Leu Leu Ala Ala Lys 20 25 303039PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(29)Aib 30Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala
Phe Val Asn Trp Leu Leu Ala Ala Gly Pro Ser 20 25 30Ser Gly Ala Pro
Pro Pro Ser 353138PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)Aib 31Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn
Trp Leu Leu Ala Ala Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Ser
353230PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)Aib 32Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala Ala Lys Glu Phe Val Asn
Trp Leu Leu Ala Gln Lys 20 25 303342PRTArtificial sequenceSynthetic
sequence GIP Analogue General Formula I(a) of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(1)..(1)Xaa is His or TyrVARIANT(2)..(2)Xaa is Ala, Aib
or GlyVARIANT(3)..(3)Xaa is Glu or AspVARIANT(7)..(7)Xaa is Thr,
Ser or IleVARIANT(9)..(9)Xaa is Asp or GluVARIANT(10)..(10)Xaa is
Tyr, Leu or SerVARIANT(11)..(11)Xaa is Ser or
LeuVARIANT(13)..(13)Xaa is Ala, Tyr or AibVARIANT(14)..(14)Xaa is
Met, Leu or SerVARIANT(15)..(15)Xaa is Asp or
GluVARIANT(16)..(16)Xaa is Lys, Gly, Ser or GluVARIANT(17)..(17)Xaa
is Ile, Lys, Gln, Arg or GluVARIANT(19)..(19)Xaa is Gln, Ala, Glu
or LysVARIANT(20)..(20)Xaa is Gln, Lys or ArgVARIANT(21)..(21)Xaa
is Asp, Ala or GluVARIANT(22)..(22)Xaa is Phe or
1NalVARIANT(23)..(23)Xaa is Val, Ile or LeuVARIANT(24)..(24)Xaa is
Asn, Glu, Arg or LysVARIANT(27)..(27)Xaa is Leu, Val, Ile, Lys, Glu
or SerVARIANT(28)..(28)Xaa is Ala, Ser, Arg or
AibVARIANT(29)..(29)Xaa is Gln, Aib, Glu, Lys or
TyrVARIANT(30)..(30)Xaa is Lys, Gly, Pro or
absentVARIANT(31)..(31)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(32)..(32)Xaa is Lys, Ser or
absentVARIANT(33)..(33)Xaa is Lys, Ser, Glu or
absentVARIANT(34)..(34)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(35)..(35)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(36)..(36)Xaa is Trp, Pro, Lys or
absentVARIANT(37)..(37)Xaa is Lys, Pro, Glu or
absentVARIANT(38)..(38)Xaa is His, Pro, Ser, Lys or
absentVARIANT(39)..(39)Xaa is Asn, Ser or
absentVARIANT(40)..(40)Xaa is Ile or absentVARIANT(41)..(41)Xaa is
Thr or absentVARIANT(42)..(42)Xaa is Gln or absent 33Xaa Xaa Xaa
Gly Thr Phe Xaa Ser Xaa Xaa Xaa Ile Xaa Xaa Xaa Xaa1 5 10 15Xaa Ala
Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 403440PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(a) of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is Aib or GlyVARIANT(7)..(7)Xaa is Thr, Ile
or SerVARIANT(10)..(10)Xaa is Tyr, Leu or SerVARIANT(11)..(11)Xaa
is Ser or LeuVARIANT(13)..(13)Xaa is Ala, Tyr or
AibVARIANT(14)..(14)Xaa is LeuVARIANT(15)..(15)Xaa is Asp or
GluVARIANT(16)..(16)Xaa is Ser, Glu or LysVARIANT(17)..(17)Xaa is
Ile or LysVARIANT(19)..(19)Xaa is Gln, Lys, Ala or
GluVARIANT(20)..(20)Xaa is Lys or ArgVARIANT(21)..(21)Xaa is Ala or
GluVARIANT(23)..(23)Xaa is Val or IleVARIANT(24)..(24)Xaa is Asn or
GluVARIANT(27)..(27)Xaa is Leu, Glu, Ser, Lys or
ValVARIANT(28)..(28)Xaa is Aib, Ala, Ser or ArgVARIANT(29)..(29)Xaa
is Aib, Glu or LysVARIANT(30)..(30)Xaa is Lys, Gly or
absentVARIANT(31)..(40)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 34Tyr Xaa
Glu Gly Thr Phe Xaa Ser Asp Xaa Xaa Ile Xaa Xaa Xaa Xaa1 5 10 15Xaa
Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 403530PRTArtificial
sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)AibSITE(17)..(17)Lys(15-carboxy-pentadecanoyl-iso-
Glu) 35Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp
Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Ala Lys
20 25 303639PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(13)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
36Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ala Leu Asp Lys1
5 10 15Lys Ala Gln Arg Ala Phe Val Glu Trp Leu Leu Ala Gln Gly Pro
Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser 353739PRTArtificial
sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
37Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1
5 10 15Lys Ala Gln Arg Ala Phe Val Glu Trp Leu Leu Ala Gln Gly Pro
Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser 353829PRTArtificial
sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
38Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1
5 10 15Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Glu Ser Ala 20
253939PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
39Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp
Lys1
5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Ala Lys Pro
Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser 354039PRTArtificial
sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(29)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
40Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ala Leu Asp Lys1
5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Val Ala Ala Lys Pro
Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser 354129PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(2)Aib 41Tyr Ala
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys
Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Ser Ala 20
254229PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)Aib 42Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala Gln Lys Glu Phe Val Glu
Trp Leu Leu Ser Ala 20 254329PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(2)Aib 43Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1 5 10 15Lys Ala Ala Lys Asp
Phe Val Glu Trp Leu Leu Ser Ala 20 254429PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(2)Aib 44Tyr Ala
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Ser1 5 10 15Lys
Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20
254529PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)Aib 45Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Ala His Asp Phe Val Glu
Trp Leu Leu Ser Ala 20 254629PRTArtificial sequenceSynthetic
sequence GIP AnalogueMOD_RES(2)..(2)Aib 46Tyr Ala Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala Ala Lys Glu
Phe Val Glu Trp Leu Leu Ser Ala 20 254729PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(2)Aib 47Tyr Ala
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser1 5 10 15Lys
Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20
254829PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
48Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser1
5 10 15Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20
254929PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
49Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1
5 10 15Lys Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Ser Ala 20
255029PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
50Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser1
5 10 15Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20
255129PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
51Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1
5 10 15Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Glu Ser Ala 20
255229PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
52Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu1
5 10 15Lys Ala Ala Lys Asp Phe Ile Glu Trp Leu Glu Ser Ala 20
255329PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
53Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1
5 10 15Lys Ala Ala Lys Asp Phe Ile Glu Trp Leu Glu Ser Ala 20
255429PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
54Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser1
5 10 15Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20
255529PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
55Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1
5 10 15Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Ser Ala 20
255639PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
56Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser1
5 10 15Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala Gly Pro
Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser 355739PRTArtificial
sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
57Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1
5 10 15Lys Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Ser Ala Gly Pro
Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser 355839PRTArtificial
sequenceSynthetic sequence GIP AnalogueMOD_RES(2)..(2)Aib 58Tyr Ala
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser1 5 10 15Lys
Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala Gly Pro Ser 20 25
30Ser Gly Ala Pro Pro Pro Ser 355942PRTArtificial sequenceSynthetic
sequence GIP Analogue General Formula I of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(1)..(1)Xaa is His or TyrVARIANT(2)..(2)Xaa is Ala, Aib
or GlyVARIANT(3)..(3)Xaa is Glu or AspVARIANT(7)..(7)Xaa is Thr,
Ser or IleVARIANT(9)..(9)Xaa is Asp or GluVARIANT(10)..(10)Xaa is
Tyr, Leu or SerVARIANT(11)..(11)Xaa is Ser or
LeuVARIANT(13)..(13)Xaa is Ala, Tyr or AibVARIANT(14)..(14)Xaa is
Met, Leu or SerVARIANT(15)..(15)Xaa is Asp or
GluVARIANT(16)..(16)Xaa is Lys, Gly, Ser or GluVARIANT(17)..(17)Xaa
is Ile, Lys, Gln, Arg or GluVARIANT(19)..(19)Xaa is Gln, Ala, Glu
or LysVARIANT(20)..(20)Xaa is Gln, Lys or ArgVARIANT(21)..(21)Xaa
is Asp, Ala or GluVARIANT(22)..(22)Xaa is Phe or
1NalVARIANT(23)..(23)Xaa is Val, Ile or LeuVARIANT(24)..(24)Xaa is
Asn, Glu, Arg or LysVARIANT(27)..(27)Xaa is Leu, Val, Ile, Lys, Glu
or SerVARIANT(28)..(28)Xaa is Ala, Ser, Arg or
AibVARIANT(29)..(29)Xaa is Gln, Aib, Glu, Lys, Gly or
TyrVARIANT(30)..(30)Xaa is Lys, Gly, Pro or
absentVARIANT(31)..(31)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(32)..(32)Xaa is Lys, Ser or
absentVARIANT(33)..(33)Xaa is Lys, Ser, Glu or
absentVARIANT(34)..(34)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(35)..(35)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(36)..(36)Xaa is Trp, Pro, Lys or
absentVARIANT(37)..(37)Xaa is Lys, Pro, Glu or
absentVARIANT(38)..(38)Xaa is His, Pro, Ser, Lys or
absentVARIANT(39)..(39)Xaa is Asn, Ser or
absentVARIANT(40)..(40)Xaa is Ile or absentVARIANT(41)..(41)Xaa is
Thr or absentVARIANT(42)..(42)Xaa is Gln or absent 59Xaa Xaa Xaa
Gly Thr Phe Xaa Ser Xaa Xaa Xaa Ile Xaa Xaa Xaa Xaa1 5 10 15Xaa Ala
Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406040PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is Aib or GlyVARIANT(7)..(7)Xaa is Thr, Ile
or SerVARIANT(10)..(10)Xaa is Tyr, Leu or SerVARIANT(11)..(11)Xaa
is Ser or LeuVARIANT(13)..(13)Xaa is Ala, Tyr or
AibVARIANT(14)..(14)Xaa is LeuVARIANT(15)..(15)Xaa is Asp or
GluVARIANT(16)..(16)Xaa is Ser, Glu or LysVARIANT(17)..(17)Xaa is
Ile or LysVARIANT(19)..(19)Xaa is Gln, Lys, Ala or
GluVARIANT(20)..(20)Xaa is Lys or ArgVARIANT(21)..(21)Xaa is Ala or
GluVARIANT(23)..(23)Xaa is Val or IleVARIANT(24)..(24)Xaa is Asn or
GluVARIANT(27)..(27)Xaa is Leu, Glu, Ser, Lys or
ValVARIANT(28)..(28)Xaa is Aib, Ala, Ser or ArgVARIANT(29)..(29)Xaa
is Aib, Glu, Gly or LysVARIANT(30)..(30)Xaa is Lys, Gly or
absentVARIANT(31)..(40)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 60Tyr Xaa
Glu Gly Thr Phe Xaa Ser Asp Xaa Xaa Ile Xaa Xaa Xaa Xaa1 5 10 15Xaa
Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406142PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula I' of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is Ala, Aib or GlyVARIANT(3)..(3)Xaa is Glu
or AspVARIANT(7)..(7)Xaa is Thr, Ser or IleVARIANT(9)..(9)Xaa is
Asp or GluVARIANT(10)..(10)Xaa is Tyr, Leu or
SerVARIANT(11)..(11)Xaa is Ser or LeuVARIANT(12)..(12)Xaa is Ile or
LysVARIANT(13)..(13)Xaa is Ala, Tyr or AibVARIANT(14)..(14)Xaa is
Met, Leu or SerVARIANT(15)..(15)Xaa is Asp or
GluVARIANT(16)..(16)Xaa is Lys, Gly, Ser or GluVARIANT(19)..(19)Xaa
is Gln, Ala, Glu or LysVARIANT(20)..(20)Xaa is Gln, Lys, Arg or
HisVARIANT(21)..(21)Xaa is Asp, Ala or GluVARIANT(22)..(22)Xaa is
Phe or 1NalVARIANT(23)..(23)Xaa is Val, Ile or
LeuVARIANT(24)..(24)Xaa is Asn, Glu, Arg or LysVARIANT(27)..(27)Xaa
is Leu, Val, Ile, Lys, Glu or SerVARIANT(28)..(28)Xaa is Ala, Ser,
Arg or AibVARIANT(29)..(29)Xaa is Gln, Aib, Lys, Gly or
AlaVARIANT(30)..(30)Xaa is Lys, Gly, Pro or
absentVARIANT(31)..(31)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(32)..(32)Xaa is Lys, Ser or
absentVARIANT(33)..(33)Xaa is Lys, Ser, Glu or
absentVARIANT(34)..(34)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(35)..(35)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(36)..(36)Xaa is Trp, Pro, Lys or
absentVARIANT(37)..(37)Xaa is Lys, Pro, Glu or
absentVARIANT(38)..(38)Xaa is His, Pro, Ser, Lys or
absentVARIANT(39)..(39)Xaa is Asn, Ser or
absentVARIANT(40)..(40)Xaa is Ile or absentVARIANT(41)..(41)Xaa is
Thr or absentVARIANT(42)..(42)Xaa is Gln or absent 61Tyr Xaa Xaa
Gly Thr Phe Xaa Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Lys Ala
Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406242PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula I(a)' of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is Ala, Aib or GlyVARIANT(3)..(3)Xaa is Glu
or AspVARIANT(7)..(7)Xaa is Thr, Ser or IleVARIANT(9)..(9)Xaa is
Asp or GluVARIANT(10)..(10)Xaa is Tyr, Leu or
SerVARIANT(11)..(11)Xaa is Ser or LeuVARIANT(12)..(12)Xaa is Ile or
LysVARIANT(13)..(13)Xaa is Ala, Tyr or AibVARIANT(14)..(14)Xaa is
Leu or SerVARIANT(15)..(15)Xaa is Asp or GluVARIANT(16)..(16)Xaa is
Lys, Gly, Ser or GluVARIANT(19)..(19)Xaa is Gln, Ala, Glu or
LysVARIANT(20)..(20)Xaa is Gln, Lys, Arg or HisVARIANT(21)..(21)Xaa
is Asp, Ala or GluVARIANT(22)..(22)Xaa is Phe or
1NalVARIANT(23)..(23)Xaa is Val, Ile or LeuVARIANT(24)..(24)Xaa is
Asn, Glu, Arg or LysVARIANT(27)..(27)Xaa is Leu, Val, Ile, Lys, Glu
or SerVARIANT(28)..(28)Xaa is Ala, Ser, Arg or
AibVARIANT(29)..(29)Xaa is Gln, Aib, Lys, Gly or
AlaVARIANT(30)..(30)Xaa is Lys, Gly, Pro or
absentVARIANT(31)..(31)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(32)..(32)Xaa is Lys, Ser or
absentVARIANT(33)..(33)Xaa is Lys, Ser, Glu or
absentVARIANT(34)..(34)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(35)..(35)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(36)..(36)Xaa is Trp, Pro, Lys or
absentVARIANT(37)..(37)Xaa is Lys, Pro, Glu or
absentVARIANT(38)..(38)Xaa is His, Pro, Ser, Lys or
absentVARIANT(39)..(39)Xaa is Asn, Ser or
absentVARIANT(40)..(40)Xaa is Ile or absentVARIANT(41)..(41)Xaa is
Thr or absentVARIANT(42)..(42)Xaa is Gln or absent 62Tyr Xaa Xaa
Gly Thr Phe Xaa Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Lys Ala
Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406342PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula I(b)' of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is Ala, Aib or GlyVARIANT(3)..(3)Xaa is Glu
or AspVARIANT(7)..(7)Xaa is Thr or SerVARIANT(9)..(9)Xaa is Asp or
GluVARIANT(10)..(10)Xaa is Tyr or LeuVARIANT(11)..(11)Xaa is Ser or
LeuVARIANT(12)..(12)Xaa is Ile or LysVARIANT(13)..(13)Xaa is Ala,
Tyr or AibVARIANT(14)..(14)Xaa is Leu or SerVARIANT(15)..(15)Xaa is
Asp or GluVARIANT(16)..(16)Xaa is Lys, Ser or
GluVARIANT(19)..(19)Xaa is Gln, Ala, Glu or LysVARIANT(20)..(20)Xaa
is Gln, Lys, Arg or HisVARIANT(21)..(21)Xaa is Asp, Ala or
GluVARIANT(23)..(23)Xaa is Val, Ile or LeuVARIANT(24)..(24)Xaa is
Asn, Glu, Arg or LysVARIANT(27)..(27)Xaa is Leu, Glu, Val or
IleVARIANT(28)..(28)Xaa is Ala, Ser, Arg or AibVARIANT(29)..(29)Xaa
is Gln, Gly, Aib or AlaVARIANT(30)..(30)Xaa is Lys, Gly, Pro or
absentVARIANT(31)..(31)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(32)..(32)Xaa is Lys, Ser or
absentVARIANT(33)..(33)Xaa is Lys, Ser, Glu or
absentVARIANT(34)..(34)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(35)..(35)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(36)..(36)Xaa is Trp, Pro, Lys or
absentVARIANT(37)..(37)Xaa is Lys, Pro, Glu or
absentVARIANT(38)..(38)Xaa is His, Pro, Ser, Lys or
absentVARIANT(39)..(39)Xaa is Asn, Ser or
absentVARIANT(40)..(40)Xaa is Ile or absentVARIANT(41)..(41)Xaa is
Thr or absentVARIANT(42)..(42)Xaa is Gln or absent 63Tyr Xaa Xaa
Gly Thr Phe Xaa Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Lys Ala
Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406440PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II' of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is Aib or GlyVARIANT(7)..(7)Xaa is Thr, Ile
or SerVARIANT(10)..(10)Xaa is Tyr or LeuVARIANT(11)..(11)Xaa is Ser
or LeuVARIANT(12)..(12)Xaa is Ile or LysVARIANT(13)..(13)Xaa is
Ala, Tyr or AibVARIANT(15)..(15)Xaa is Asp or
GluVARIANT(16)..(16)Xaa is Ser, Glu or LysVARIANT(19)..(19)Xaa is
Gln or AlaVARIANT(20)..(20)Xaa is Lys, His or
ArgVARIANT(21)..(21)Xaa is Ala, Asp or GluVARIANT(23)..(23)Xaa is
Val or IleVARIANT(24)..(24)Xaa is Asn, Lys or
GluVARIANT(27)..(27)Xaa is Leu, Glu, Val or IleVARIANT(28)..(28)Xaa
is Aib, Ala, Ser or ArgVARIANT(29)..(29)Xaa is Gln, Aib, Ala, Gly
or LysVARIANT(30)..(30)Xaa is Lys, Gly or
absentVARIANT(31)..(40)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 64Tyr Xaa
Glu Gly Thr Phe Xaa Ser Asp Xaa Xaa Xaa Xaa Leu Xaa Xaa1 5 10 15Lys
Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406540PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(a)' of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is Aib or GlyVARIANT(7)..(7)Xaa is Thr, Ile
or SerVARIANT(10)..(10)Xaa is Tyr or LeuVARIANT(11)..(11)Xaa is Ser
or LeuVARIANT(13)..(13)Xaa is Ala, Tyr or AibVARIANT(15)..(15)Xaa
is Asp or GluVARIANT(16)..(16)Xaa is Ser, Glu or
LysVARIANT(19)..(19)Xaa is Gln, Lys, Ala or GluVARIANT(20)..(20)Xaa
is Lys, His or ArgVARIANT(21)..(21)Xaa is Ala, Asp or
GluVARIANT(23)..(23)Xaa is Val or IleVARIANT(24)..(24)Xaa is Asn,
Lys or GluVARIANT(27)..(27)Xaa is Leu, Glu, Val or
IleVARIANT(28)..(28)Xaa is Aib, Ala, Ser or ArgVARIANT(29)..(29)Xaa
is Gln, Aib, Ala, or GlyVARIANT(30)..(30)Xaa is Lys, Gly or
absentVARIANT(31)..(40)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 65Tyr Xaa
Glu Gly Thr Phe Xaa Ser Asp Xaa Xaa Ile Xaa Leu Xaa Xaa1 5 10 15Lys
Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406640PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(b)' of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluMOD_RES(2)..(2)AibVARIANT(7)..(7)Xaa is Thr or
SerVARIANT(13)..(13)Xaa is Ala or TyrVARIANT(15)..(15)Xaa is Asp or
GluVARIANT(16)..(16)Xaa is Lys, Glu or SerVARIANT(20)..(20)Xaa is
Lys, His or ArgVARIANT(21)..(21)Xaa is Ala, Asp or
GluVARIANT(23)..(23)Xaa is Val or IleVARIANT(27)..(27)Xaa is Leu,
Glu or ValVARIANT(28)..(28)Xaa is Arg or SerVARIANT(30)..(30)Xaa is
Lys, Gly or absentVARIANT(31)..(40)Y1, which may be present or
absent. If present, up to 2 residues may be present or absent, and
Y1 is SEQ ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77.
66Tyr Ala Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Xaa Leu Xaa Xaa1
5 10 15Lys Ala Gln Xaa Xaa Phe Xaa Glu Trp Leu Xaa Xaa Ala Xaa Xaa
Xaa 20 25 30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406740PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(c) of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluMOD_RES(2)..(2)AibVARIANT(7)..(7)Xaa is Thr or
SerVARIANT(13)..(13)Xaa is Ala, Aib or TyrVARIANT(15)..(15)Xaa is
Asp or GluVARIANT(16)..(16)Xaa is Glu, Lys or
SerVARIANT(20)..(20)Xaa is Lys, His or ArgVARIANT(21)..(21)Xaa is
Ala, Asp or GluVARIANT(24)..(24)Xaa is Glu or
AsnVARIANT(27)..(27)Xaa is Leu, Glu or ValVARIANT(29)..(29)Xaa is
Gln or AibVARIANT(30)..(30)Xaa is Lys, Gly or
absentVARIANT(31)..(40)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 67Tyr Ala
Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Xaa Leu Xaa Xaa1 5 10 15Lys
Ala Gln Xaa Xaa Phe Val Xaa Trp Leu Xaa Ala Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406840PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(d) of
PCT/EP2013/059319SITE(1)..(1)Linked to R1, wherein R1 is Hy-, Ac or
pGluMOD_RES(2)..(2)AibVARIANT(7)..(7)Xaa is Thr or
SerVARIANT(13)..(13)Xaa is Ala, Aib or TyrVARIANT(15)..(15)Xaa is
Asp or GluVARIANT(16)..(16)Xaa is Glu, Lys or
SerVARIANT(20)..(20)Xaa is Lys, His or ArgVARIANT(27)..(27)Xaa is
Leu, Glu or ValVARIANT(30)..(30)Xaa is Lys, Gly or
absentVARIANT(31)..(40)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 68Tyr Ala
Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Xaa Leu Xaa Xaa1 5 10 15Lys
Ala Gln Xaa Ala Phe Val Glu Trp Leu Xaa Ala Gln Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 406929PRTArtificial
sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)AibSITE(17)..(17)Lys(Hexadecanoyl-isoGlu)
69Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1
5 10 15Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20
257029PRTArtificial sequenceSynthetic sequenceMOD_RES(2)..(2)Aib
70Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1
5 10 15Lys Ala Gln Arg Ala Phe Val Glu Trp Leu Leu Ala Gln 20
257129PRTArtificial sequenceSynthetic sequenceMOD_RES(2)..(2)Aib
71Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1
5 10 15Lys Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Ser Ala 20
257229PRTArtificial sequenceSynthetic sequenceMOD_RES(2)..(2)Aib
72Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1
5 10 15Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Glu Ser Ala 20
257329PRTArtificial sequenceSynthetic sequence GIP
AnalogueMOD_RES(2)..(2)Aib 73Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala Ala His Asp Phe Val Glu
Trp Leu Leu Ser Ala 20 257410PRTArtificial sequenceSynthetic
sequence Y1 in SEQ ID NOs 2, 34, 60, 64 - 68, 79, 81, 83, and 87 -
91 74Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser1 5 10759PRTArtificial
sequenceSynthetic sequence Y1 in SEQ ID NOs 2, 34, 60, 64 - 68, 79,
81, 83, and 87 - 91 75Gly Pro Ser Ser Gly Ala Pro Pro Ser1
5769PRTArtificial sequenceSynthetic sequence Y1 in SEQ ID NOs 2,
34, 60, 64 - 68, 79, 81, 83, and 87 - 91 76Pro Ser Ser Gly Ala Pro
Pro Pro Ser1 5778PRTArtificial sequenceSynthetic sequence Y1 in SEQ
ID NOs 2, 34, 60, 64 - 68, 79, 81, 83, and 87 - 91 77Pro Ser Ser
Gly Ala Pro Pro Ser1 57843PRTArtificial sequenceSynthetic sequence
GIP Analogue General Formula I(b) of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is His or TyrVARIANT(3)..(3)Xaa is Ala, Aib
or GlyVARIANT(4)..(4)Xaa is Glu or AspVARIANT(8)..(8)Xaa is Thr or
SerVARIANT(10)..(10)Xaa is Asp or GluVARIANT(11)..(11)Xaa is Tyr,
Leu or SerVARIANT(12)..(12)Xaa is Ser or LeuVARIANT(14)..(14)Xaa is
Ala, Tyr or AibVARIANT(15)..(15)Xaa is Met, Leu or
SerVARIANT(16)..(16)Xaa is Asp or GluVARIANT(17)..(17)Xaa is Lys,
Gly, Ser or GluVARIANT(18)..(18)Xaa is Ile, Lys, Gln, Arg or
GluVARIANT(20)..(20)Xaa is Gln, Ala, Glu or LysVARIANT(21)..(21)Xaa
is Gln, Lys or ArgVARIANT(22)..(22)Xaa is Asp, Ala or
GluVARIANT(23)..(23)Xaa is Phe or 1NalVARIANT(24)..(24)Xaa is Val,
Ile or LeuVARIANT(25)..(25)Xaa is Asn, Glu, Arg or
LysVARIANT(28)..(28)Xaa is Leu, Val, Ile, Lys or
SerVARIANT(29)..(29)Xaa is Ala or AibVARIANT(30)..(30)Xaa is Gln,
Gly, Aib or TyrVARIANT(31)..(31)Xaa is Lys, Gly, Pro or
absentVARIANT(32)..(32)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(33)..(33)Xaa is Lys, Ser or
absentVARIANT(34)..(34)Xaa is Lys, Ser, Glu or
absentVARIANT(35)..(35)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(36)..(36)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(37)..(37)Xaa is Trp, Pro, Lys or
absentVARIANT(38)..(38)Xaa is Lys, Pro, Glu or
absentVARIANT(39)..(39)Xaa is His, Pro, Ser, Lys or
absentVARIANT(40)..(40)Xaa is Asn, Ser or
absentVARIANT(41)..(41)Xaa is Ile or absentVARIANT(42)..(42)Xaa is
Thr or absentVARIANT(43)..(43)Xaa is Gln or absent 78Xaa Xaa Xaa
Xaa Gly Thr Phe Xaa Ser Xaa Xaa Xaa Ile Xaa Xaa Xaa1 5 10 15Xaa Xaa
Ala Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 407941PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(b) of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluMOD_RES(3)..(3)AibVARIANT(8)..(8)Xaa is Thr or
SerVARIANT(14)..(14)Xaa is Ala, Tyr or AibVARIANT(15)..(15)Xaa is
LeuVARIANT(16)..(16)Xaa is Asp or GluVARIANT(18)..(18)Xaa is Ile or
LysVARIANT(21)..(21)Xaa is Lys or ArgVARIANT(22)..(22)Xaa is Ala or
GluVARIANT(24)..(24)Xaa is Val or IleVARIANT(25)..(25)Xaa is Asn or
GluVARIANT(28)..(28)Xaa is Leu or ValVARIANT(30)..(30)Xaa is Aib or
GlyVARIANT(31)..(31)Xaa is Lys, Gly or absentVARIANT(32)..(41)Y1,
which may be present or absent. If present, up to 2 residues may be
present or absent, and Y1 is SEQ ID NO 74, SEQ ID NO 75, SEQ ID NO
76, or SEQ ID NO 77. 79Xaa Tyr Ala Glu Gly Thr Phe Xaa Ser Asp Tyr
Ser Ile Xaa Xaa Xaa1 5 10 15Lys Xaa Ala Gln Xaa Xaa Phe Xaa Xaa Trp
Leu Xaa Ala Xaa Xaa Xaa 20 25 30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 408043PRTArtificial sequenceSynthetic sequence GIP Analogue
General Formula I(a) of PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-,
Ac or pGluVARIANT(2)..(2)Xaa is His or TyrVARIANT(3)..(3)Xaa is
Ala, Aib or GlyVARIANT(4)..(4)Xaa is Glu or AspVARIANT(8)..(8)Xaa
is Thr, Ser or IleVARIANT(10)..(10)Xaa is Asp or
GluVARIANT(11)..(11)Xaa is Tyr, Leu or SerVARIANT(12)..(12)Xaa is
Ser or LeuVARIANT(14)..(14)Xaa is Ala, Tyr or
AibVARIANT(15)..(15)Xaa is Met, Leu or SerVARIANT(16)..(16)Xaa is
Asp or GluVARIANT(17)..(17)Xaa is Lys, Gly, Ser or
GluVARIANT(18)..(18)Xaa is Ile, Lys, Gln, Arg or
GluVARIANT(20)..(20)Xaa is Gln, Ala, Glu or LysVARIANT(21)..(21)Xaa
is Gln, Lys or ArgVARIANT(22)..(22)Xaa is Asp, Ala or
GluVARIANT(23)..(23)Xaa is Phe or 1NalVARIANT(24)..(24)Xaa is Val,
Ile or LeuVARIANT(25)..(25)Xaa is Asn, Glu, Arg or
LysVARIANT(28)..(28)Xaa is Leu, Val, Ile, Lys, Glu or
SerVARIANT(29)..(29)Xaa is Ala, Ser, Arg or AibVARIANT(30)..(30)Xaa
is Gln, Aib, Glu, Lys or TyrVARIANT(31)..(31)Xaa is Lys, Gly, Pro
or absentVARIANT(32)..(32)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(33)..(33)Xaa is Lys, Ser or
absentVARIANT(34)..(34)Xaa is Lys, Ser, Glu or
absentVARIANT(35)..(35)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(36)..(36)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(37)..(37)Xaa is Trp, Pro, Lys or
absentVARIANT(38)..(38)Xaa is Lys, Pro, Glu or
absentVARIANT(39)..(39)Xaa is His, Pro, Ser, Lys or
absentVARIANT(40)..(40)Xaa is Asn, Ser or
absentVARIANT(41)..(41)Xaa is Ile or absentVARIANT(42)..(42)Xaa is
Thr or absentVARIANT(43)..(43)Xaa is Gln or absent 80Xaa Xaa Xaa
Xaa Gly Thr Phe Xaa Ser Xaa Xaa Xaa Ile Xaa Xaa Xaa1 5 10 15Xaa Xaa
Ala Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408141PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(a) of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(3)..(3)Xaa is Aib or GlyVARIANT(8)..(8)Xaa is Thr, Ile
or SerVARIANT(11)..(11)Xaa is Tyr, Leu or SerVARIANT(12)..(12)Xaa
is Ser or LeuVARIANT(14)..(14)Xaa is Ala, Tyr or
AibVARIANT(15)..(15)Xaa is LeuVARIANT(16)..(16)Xaa is Asp or
GluVARIANT(17)..(17)Xaa is Ser, Glu or LysVARIANT(18)..(18)Xaa is
Ile or LysVARIANT(20)..(20)Xaa is Gln, Lys, Ala or
GluVARIANT(21)..(21)Xaa is Lys or ArgVARIANT(22)..(22)Xaa is Ala or
GluVARIANT(24)..(24)Xaa is Val or IleVARIANT(25)..(25)Xaa is Asn or
GluVARIANT(28)..(28)Xaa is Leu, Glu, Ser, Lys or
ValVARIANT(29)..(29)Xaa is Aib, Ala, Ser or ArgVARIANT(30)..(30)Xaa
is Aib, Glu or LysVARIANT(31)..(31)Xaa is Lys, Gly or
absentVARIANT(32)..(41)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 81Xaa Tyr
Xaa Glu Gly Thr Phe Xaa Ser Asp Xaa Xaa Ile Xaa Xaa Xaa1 5 10 15Xaa
Xaa Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408243PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula I of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(2)..(2)Xaa is His or TyrVARIANT(3)..(3)Xaa is Ala, Aib
or GlyVARIANT(4)..(4)Xaa is Glu or AspVARIANT(8)..(8)Xaa is Thr,
Ser or IleVARIANT(10)..(10)Xaa is Asp or GluVARIANT(11)..(11)Xaa is
Tyr, Leu or SerVARIANT(12)..(12)Xaa is Ser or
LeuVARIANT(14)..(14)Xaa is Ala, Tyr or AibVARIANT(15)..(15)Xaa is
Met, Leu or SerVARIANT(16)..(16)Xaa is Asp or
GluVARIANT(17)..(17)Xaa is Lys, Gly, Ser or GluVARIANT(18)..(18)Xaa
is Ile, Lys, Gln, Arg or GluVARIANT(20)..(20)Xaa is Gln, Ala, Glu
or LysVARIANT(21)..(21)Xaa is Gln, Lys or ArgVARIANT(22)..(22)Xaa
is Asp, Ala or GluVARIANT(23)..(23)Xaa is Phe or
1NalVARIANT(24)..(24)Xaa is Val, Ile or LeuVARIANT(25)..(25)Xaa is
Asn, Glu, Arg or LysVARIANT(28)..(28)Xaa is Leu, Val, Ile, Lys, Glu
or SerVARIANT(29)..(29)Xaa is Ala, Ser, Arg or
AibVARIANT(30)..(30)Xaa is Gln, Aib, Glu, Lys, Gly or
TyrVARIANT(31)..(31)Xaa is Lys, Gly, Pro or
absentVARIANT(32)..(32)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(33)..(33)Xaa is Lys, Ser or
absentVARIANT(34)..(34)Xaa is Lys, Ser, Glu or
absentVARIANT(35)..(35)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(36)..(36)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(37)..(37)Xaa is Trp, Pro, Lys or
absentVARIANT(38)..(38)Xaa is Lys, Pro, Glu or
absentVARIANT(39)..(39)Xaa is His, Pro, Ser, Lys or
absentVARIANT(40)..(40)Xaa is Asn, Ser or
absentVARIANT(41)..(41)Xaa is Ile or absentVARIANT(42)..(42)Xaa is
Thr or absentVARIANT(43)..(43)Xaa is Gln or absent 82Xaa Xaa Xaa
Xaa Gly Thr Phe Xaa Ser Xaa Xaa Xaa Ile Xaa Xaa Xaa1 5 10 15Xaa Xaa
Ala Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408341PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(3)..(3)Xaa is Aib or GlyVARIANT(8)..(8)Xaa is Thr, Ile
or SerVARIANT(11)..(11)Xaa is Tyr, Leu or SerVARIANT(12)..(12)Xaa
is Ser or LeuVARIANT(14)..(14)Xaa is Ala, Tyr or
AibVARIANT(15)..(15)Xaa is LeuVARIANT(16)..(16)Xaa is Asp or
GluVARIANT(17)..(17)Xaa is Ser, Glu or LysVARIANT(18)..(18)Xaa is
Ile or LysVARIANT(20)..(20)Xaa is Gln, Lys, Ala or
GluVARIANT(21)..(21)Xaa is Lys or ArgVARIANT(22)..(22)Xaa is Ala or
GluVARIANT(24)..(24)Xaa is Val or IleVARIANT(25)..(25)Xaa is Asn or
GluVARIANT(28)..(28)Xaa is Leu, Glu, Ser, Lys or
ValVARIANT(29)..(29)Xaa is Aib, Ala, Ser or ArgVARIANT(30)..(30)Xaa
is Aib, Glu, Gly or LysVARIANT(31)..(31)Xaa is Lys, Gly or
absentVARIANT(32)..(41)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 83Xaa Tyr
Xaa Glu Gly Thr Phe Xaa Ser Asp Xaa Xaa Ile Xaa Xaa Xaa1 5 10 15Xaa
Xaa Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408443PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula I' of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(3)..(3)Xaa is Ala, Aib or GlyVARIANT(4)..(4)Xaa is Glu
or AspVARIANT(8)..(8)Xaa is Thr, Ser or IleVARIANT(10)..(10)Xaa is
Asp or GluVARIANT(11)..(11)Xaa is Tyr, Leu or
SerVARIANT(12)..(12)Xaa is Ser or LeuVARIANT(13)..(13)Xaa is Ile or
LysVARIANT(14)..(14)Xaa is Ala, Tyr or AibVARIANT(15)..(15)Xaa is
Met, Leu or SerVARIANT(16)..(16)Xaa is Asp or
GluVARIANT(17)..(17)Xaa is Lys, Gly, Ser or GluVARIANT(20)..(20)Xaa
is Gln, Ala, Glu or LysVARIANT(21)..(21)Xaa is Gln, Lys, Arg or
HisVARIANT(22)..(22)Xaa is Asp, Ala or GluVARIANT(23)..(23)Xaa is
Phe or 1NalVARIANT(24)..(24)Xaa is Val, Ile or
LeuVARIANT(25)..(25)Xaa is Asn, Glu, Arg or LysVARIANT(28)..(28)Xaa
is Leu, Val, Ile, Lys, Glu or SerVARIANT(29)..(29)Xaa is Ala, Ser,
Arg or AibVARIANT(30)..(30)Xaa is Gln, Aib, Lys, Gly or
AlaVARIANT(31)..(31)Xaa is Lys, Gly, Pro or
absentVARIANT(32)..(32)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(33)..(33)Xaa is Lys, Ser or
absentVARIANT(34)..(34)Xaa is Lys, Ser, Glu or
absentVARIANT(35)..(35)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(36)..(36)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(37)..(37)Xaa is Trp, Pro, Lys or
absentVARIANT(38)..(38)Xaa is Lys, Pro, Glu or
absentVARIANT(39)..(39)Xaa is His, Pro, Ser, Lys or
absentVARIANT(40)..(40)Xaa is Asn, Ser or
absentVARIANT(41)..(41)Xaa is Ile or absentVARIANT(42)..(42)Xaa is
Thr or absentVARIANT(43)..(43)Xaa is Gln or absent 84Xaa Tyr Xaa
Xaa Gly Thr Phe Xaa Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Xaa Lys
Ala Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408543PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula I(a)' of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(3)..(3)Xaa is Ala, Aib or GlyVARIANT(4)..(4)Xaa is Glu
or AspVARIANT(8)..(8)Xaa is Thr, Ser or IleVARIANT(10)..(10)Xaa is
Asp or GluVARIANT(11)..(11)Xaa is Tyr, Leu or
SerVARIANT(12)..(12)Xaa is Ser or LeuVARIANT(13)..(13)Xaa is Ile or
LysVARIANT(14)..(14)Xaa is Ala, Tyr or AibVARIANT(15)..(15)Xaa is
Leu or SerVARIANT(16)..(16)Xaa is Asp or GluVARIANT(17)..(17)Xaa is
Lys, Gly, Ser or GluVARIANT(20)..(20)Xaa is Gln, Ala, Glu or
LysVARIANT(21)..(21)Xaa is Gln, Lys, Arg or HisVARIANT(22)..(22)Xaa
is Asp, Ala or GluVARIANT(23)..(23)Xaa is Phe or
1NalVARIANT(24)..(24)Xaa is
Val, Ile or LeuVARIANT(25)..(25)Xaa is Asn, Glu, Arg or
LysVARIANT(28)..(28)Xaa is Leu, Val, Ile, Lys, Glu or
SerVARIANT(29)..(29)Xaa is Ala, Ser, Arg or AibVARIANT(30)..(30)Xaa
is Gln, Aib, Lys, Gly or AlaVARIANT(31)..(31)Xaa is Lys, Gly, Pro
or absentVARIANT(32)..(32)Xaa is Gly, Pro, Ser, Glu or
absentVARIANT(33)..(33)Xaa is Lys, Ser or
absentVARIANT(34)..(34)Xaa is Lys, Ser, Glu or
absentVARIANT(35)..(35)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(36)..(36)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(37)..(37)Xaa is Trp, Pro, Lys or
absentVARIANT(38)..(38)Xaa is Lys, Pro, Glu or
absentVARIANT(39)..(39)Xaa is His, Pro, Ser, Lys or
absentVARIANT(40)..(40)Xaa is Asn, Ser or
absentVARIANT(41)..(41)Xaa is Ile or absentVARIANT(42)..(42)Xaa is
Thr or absentVARIANT(43)..(43)Xaa is Gln or absent 85Xaa Tyr Xaa
Xaa Gly Thr Phe Xaa Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Xaa Lys
Ala Xaa Xaa Xaa Xaa Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408643PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula I(b)' of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(3)..(3)Xaa is Ala, Aib or GlyVARIANT(4)..(4)Xaa is Glu
or AspVARIANT(8)..(8)Xaa is Thr or SerVARIANT(10)..(10)Xaa is Asp
or GluVARIANT(11)..(11)Xaa is Tyr or LeuVARIANT(12)..(12)Xaa is Ser
or LeuVARIANT(13)..(13)Xaa is Ile or LysVARIANT(14)..(14)Xaa is
Ala, Tyr or AibVARIANT(15)..(15)Xaa is Leu or
SerVARIANT(16)..(16)Xaa is Asp or GluVARIANT(17)..(17)Xaa is Lys,
Ser or GluVARIANT(20)..(20)Xaa is Gln, Ala, Glu or
LysVARIANT(21)..(21)Xaa is Gln, Lys, Arg or HisVARIANT(22)..(22)Xaa
is Asp, Ala or GluVARIANT(24)..(24)Xaa is Val, Ile or
LeuVARIANT(25)..(25)Xaa is Asn, Glu, Arg or LysVARIANT(28)..(28)Xaa
is Leu, Glu, Val or IleVARIANT(29)..(29)Xaa is Ala, Ser, Arg or
AibVARIANT(30)..(30)Xaa is Gln, Gly, Aib or AlaVARIANT(31)..(31)Xaa
is Lys, Gly, Pro or absentVARIANT(32)..(32)Xaa is Gly, Pro, Ser,
Glu or absentVARIANT(33)..(33)Xaa is Lys, Ser or
absentVARIANT(34)..(34)Xaa is Lys, Ser, Glu or
absentVARIANT(35)..(35)Xaa is Asn, Gly, Ala, Lys or
absentVARIANT(36)..(36)Xaa is Asp, Ala, Pro, Glu or
absentVARIANT(37)..(37)Xaa is Trp, Pro, Lys or
absentVARIANT(38)..(38)Xaa is Lys, Pro, Glu or
absentVARIANT(39)..(39)Xaa is His, Pro, Ser, Lys or
absentVARIANT(40)..(40)Xaa is Asn, Ser or
absentVARIANT(41)..(41)Xaa is Ile or absentVARIANT(42)..(42)Xaa is
Thr or absentVARIANT(43)..(43)Xaa is Gln or absent 86Xaa Tyr Xaa
Xaa Gly Thr Phe Xaa Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Xaa Lys
Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408741PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II' of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(3)..(3)Xaa is Aib or GlyVARIANT(8)..(8)Xaa is Thr, Ile
or SerVARIANT(11)..(11)Xaa is Tyr or LeuVARIANT(12)..(12)Xaa is Ser
or LeuVARIANT(13)..(13)Xaa is Ile or LysVARIANT(14)..(14)Xaa is
Ala, Tyr or AibVARIANT(16)..(16)Xaa is Asp or
GluVARIANT(17)..(17)Xaa is Ser, Glu or LysVARIANT(20)..(20)Xaa is
Gln or AlaVARIANT(21)..(21)Xaa is Lys, His or
ArgVARIANT(22)..(22)Xaa is Ala, Asp or GluVARIANT(24)..(24)Xaa is
Val or IleVARIANT(25)..(25)Xaa is Asn, Lys or
GluVARIANT(28)..(28)Xaa is Leu, Glu, Val or IleVARIANT(29)..(29)Xaa
is Aib, Ala, Ser or ArgVARIANT(30)..(30)Xaa is Gln, Aib, Ala, Gly
or LysVARIANT(31)..(31)Xaa is Lys, Gly or
absentVARIANT(32)..(41)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 87Xaa Tyr
Xaa Glu Gly Thr Phe Xaa Ser Asp Xaa Xaa Xaa Xaa Leu Xaa1 5 10 15Xaa
Lys Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408841PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(a)' of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluVARIANT(3)..(3)Xaa is Aib or GlyVARIANT(8)..(8)Xaa is Thr, Ile
or SerVARIANT(11)..(11)Xaa is Tyr or LeuVARIANT(12)..(12)Xaa is Ser
or LeuVARIANT(14)..(14)Xaa is Ala, Tyr or AibVARIANT(16)..(16)Xaa
is Asp or GluVARIANT(17)..(17)Xaa is Ser, Glu or
LysVARIANT(20)..(20)Xaa is Gln, Lys, Ala or GluVARIANT(21)..(21)Xaa
is Lys, His or ArgVARIANT(22)..(22)Xaa is Ala, Asp or
GluVARIANT(24)..(24)Xaa is Val or IleVARIANT(25)..(25)Xaa is Asn,
Lys or GluVARIANT(28)..(28)Xaa is Leu, Glu, Val or
IleVARIANT(29)..(29)Xaa is Aib, Ala, Ser or ArgVARIANT(30)..(30)Xaa
is Gln, Aib, Ala, or GlyVARIANT(31)..(31)Xaa is Lys, Gly or
absentVARIANT(32)..(41)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 88Xaa Tyr
Xaa Glu Gly Thr Phe Xaa Ser Asp Xaa Xaa Ile Xaa Leu Xaa1 5 10 15Xaa
Lys Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 408941PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(b)' of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluMOD_RES(3)..(3)AibVARIANT(8)..(8)Xaa is Thr or
SerVARIANT(14)..(14)Xaa is Ala or TyrVARIANT(16)..(16)Xaa is Asp or
GluVARIANT(17)..(17)Xaa is Lys, Glu or SerVARIANT(21)..(21)Xaa is
Lys, His or ArgVARIANT(22)..(22)Xaa is Ala, Asp or
GluVARIANT(24)..(24)Xaa is Val or IleVARIANT(28)..(28)Xaa is Leu,
Glu or ValVARIANT(29)..(29)Xaa is Arg or SerVARIANT(31)..(31)Xaa is
Lys, Gly or absentVARIANT(32)..(41)Y1, which may be present or
absent. If present, up to 2 residues may be present or absent, and
Y1 is SEQ ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77.
89Xaa Tyr Ala Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Xaa Leu Xaa1
5 10 15Xaa Lys Ala Gln Xaa Xaa Phe Xaa Glu Trp Leu Xaa Xaa Ala Xaa
Xaa 20 25 30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35
409041PRTArtificial sequenceSynthetic sequence GIP Analogue General
Formula II(c) of PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluMOD_RES(3)..(3)AibVARIANT(8)..(8)Xaa is Thr or
SerVARIANT(14)..(14)Xaa is Ala, Aib or TyrVARIANT(16)..(16)Xaa is
Asp or GluVARIANT(17)..(17)Xaa is Glu, Lys or
SerVARIANT(21)..(21)Xaa is Lys, His or ArgVARIANT(22)..(22)Xaa is
Ala, Asp or GluVARIANT(25)..(25)Xaa is Glu or
AsnVARIANT(28)..(28)Xaa is Leu, Glu or ValVARIANT(30)..(30)Xaa is
Gln or AibVARIANT(31)..(31)Xaa is Lys, Gly or
absentVARIANT(32)..(41)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 90Xaa Tyr
Ala Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Xaa Leu Xaa1 5 10 15Xaa
Lys Ala Gln Xaa Xaa Phe Val Xaa Trp Leu Xaa Ala Xaa Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 409141PRTArtificial
sequenceSynthetic sequence GIP Analogue General Formula II(d) of
PCT/EP2013/059319VARIANT(1)..(1)Xaa is Hy-, Ac or
pGluMOD_RES(3)..(3)AibVARIANT(8)..(8)Xaa is Thr or
SerVARIANT(14)..(14)Xaa is Ala, Aib or TyrVARIANT(16)..(16)Xaa is
Asp or GluVARIANT(17)..(17)Xaa is Glu, Lys or
SerVARIANT(21)..(21)Xaa is Lys, His or ArgVARIANT(28)..(28)Xaa is
Leu, Glu or ValVARIANT(31)..(31)Xaa is Lys, Gly or
absentVARIANT(32)..(41)Y1, which may be present or absent. If
present, up to 2 residues may be present or absent, and Y1 is SEQ
ID NO 74, SEQ ID NO 75, SEQ ID NO 76, or SEQ ID NO 77. 91Xaa Tyr
Ala Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Xaa Leu Xaa1 5 10 15Xaa
Lys Ala Gln Xaa Ala Phe Val Glu Trp Leu Xaa Ala Gln Xaa Xaa 20 25
30Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 409231PRTArtificial
sequenceSynthetic sequence GIP AnalogueSITE(1)..(1)Xaa is
pGluMOD_RES(30)..(30)Aib 92Xaa Tyr Ala Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp1 5 10 15Lys Lys Ala Gln Arg Ala Phe Val Asn
Trp Leu Leu Ala Ala Lys 20 25 309329PRTArtificial SequenceSynthetic
Construct 93Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Glu Lys1 5 10 15Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala
20 259430PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 94Tyr Xaa Glu
Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala
Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gln Lys 20 25
309539PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(13)..(13)Xaa is
2-Aminoisobutyric acid (Aib)SITE(39)..(39)Linked to R2, wherein R2
is -NH2 95Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu
Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Glu Trp Leu Leu Ala Gln
Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser 359630PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 96Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ala Leu Asp Lys1 5 10 15Ile Ala
Gln Arg Ala Phe Val Asn Trp Leu Val Ala Xaa Lys 20 25
309730PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 97Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu
Glu Lys1 5 10 15Ile Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gln
Lys 20 25 309830PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 98Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
309930PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is pGluMISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 99Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa
Lys 20 25 3010030PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 100Tyr Gly Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
3010130PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 101Tyr Xaa Glu Gly Thr Phe Ser Ser Asp Tyr Ser Ile Tyr Leu
Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa
Lys 20 25 3010230PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 102Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Leu Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
3010330PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 103Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Leu Ile Tyr Leu
Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa
Lys 20 25 3010430PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 104Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ala Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
3010530PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 105Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Ser
Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa
Lys 20 25 3010630PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 106Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
3010730PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 107Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ala Leu
Glu Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa
Lys 20 25 3010830PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 108Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
3010930PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 109Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Asp Glu1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa
Lys 20 25 3011030PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 110Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser1 5 10 15Lys Ala
Lys Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
3011130PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 111Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Lys Glu Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
3011230PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 112Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Lys Trp Leu Leu Ala Xaa
Lys 20 25 3011330PRTArtificial Sequencesynthetic
construct'SITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 113Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Val Ala Xaa Lys 20 25
3011430PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 114Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Lys Ala Xaa
Lys 20 25 3011529PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(28)..(28)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(29)..(29)Linked to R2, wherein R2 is -NH2 115Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Xaa Lys 20 2511636PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(33)..(33)Xaa is beta-(1-naphthyl)-alanine
(1Nal)SITE(36)..(36)Linked to R2, wherein R2 is -NH2 116Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys Tyr Gly 20 25 30Xaa
Leu Asp Phe 3511734PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(31)..(31)Xaa is beta-(1-naphthyl)-alanine
(1Nal)SITE(34)..(34)Linked to R2, wherein R2 is -NH2 117Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Tyr Gly Xaa Leu 20 25 30Asp
Phe11830PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 118Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Asp Lys1 5 10 15Lys Ala Glu Lys Ala Phe Val Asn Trp Leu Leu Ala Xaa
Lys 20 25 3011939PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(39)..(39)Linked to R2, wherein R2 is -NH2 119Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Gly Pro Ser 20 25 30Ser
Gly Ala Pro Pro Pro Ser 3512038PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(38)..(38)Linked to R2, wherein R2 is -NH2 120Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Gly Pro Ser 20 25 30Ser
Gly Ala Pro Pro Ser 3512130PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 121Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala
Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gln Lys 20 25
3012230PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)15-carboxy-pentadecanoyl-isoGluMISC_FEATURE(29-
)..(29)Xaa is 2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to
R2, wherein R2 is -NH2 122Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp
Leu Leu Ala Xaa Lys 20 25 3012339PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(13)..(13)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(39)..(39)Linked to
R2, wherein R2 is -NH2 123Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Xaa Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Glu Trp
Leu Leu Ala Gln Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser
3512439PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(39)..(39)Linked to
R2, wherein R2 is -NH2 124Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Glu Trp
Leu Leu Ala Gln Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser
3512529PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 125Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Glu1 5 10 15Lys Ala Ala Lys Glu Phe Ile Glu Trp
Leu Glu Ser Ala 20 2512639PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluMISC_FEATURE(29)..(29)Xaa
is 2-Aminoisobutyric acid (Aib)SITE(39)..(39)Linked to R2, wherein
R2 is -NH2 126Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr
Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Leu Ala
Xaa Lys Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser
3512739PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluMISC_FEATURE(29)..(29)Xaa
is 2-Aminoisobutyric acid (Aib)SITE(39)..(39)Linked to R2, wherein
R2 is -NH2 127Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ala
Leu Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Val Ala
Xaa Lys Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser
3512829PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)SITE(29)..(29)Linked to R2, wherein R2
is -NH2 128Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Glu Lys1 5 10 15Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Ser Ala
20 2512929PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(29)..(29)Linked to R2, wherein R2 is -NH2 129Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala
Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 2513029PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(29)..(29)Linked to R2, wherein R2 is -NH2 130Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala
Gln Lys Glu Phe Val Glu Trp Leu Leu Ser Ala 20 2513129PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(29)..(29)Linked to R2, wherein R2 is -NH2 131Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu1 5 10 15Lys Ala
Ala Lys Asp Phe Val Glu Trp Leu Leu Ser Ala 20 2513229PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(29)..(29)Linked to R2, wherein R2 is -NH2 132Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Ser1 5 10 15Lys Ala
Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 2513329PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(29)..(29)Linked to R2, wherein R2 is -NH2 133Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 2513429PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(29)..(29)Linked to R2, wherein R2 is -NH2 134Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala
Ala Lys Glu Phe Val Glu Trp Leu Leu Ser Ala 20 2513529PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(29)..(29)Linked to R2, wherein R2 is -NH2 135Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser1 5 10 15Lys Ala
Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 2513629PRTArtificial
Sequencesynthetic constructSITE(1)..(1)Linked to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 136Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Lys Tyr Leu Asp Ser1 5 10 15Lys Ala Ala His Asp Phe Val Glu Trp
Leu Leu Ser Ala 20 2513729PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 137Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala Ala Lys Glu Phe Val Glu Trp
Leu Leu Ser Ala 20 2513829PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 138Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Ser1 5 10 15Lys Ala Ala His Asp Phe Val Glu Trp
Leu Leu Arg Ala 20 2513929PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 139Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Glu1 5 10 15Lys Ala Ala Lys Asp Phe Val Glu Trp
Leu Glu Ser Ala 20 2514029PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 140Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Lys Tyr Leu Asp Glu1 5 10 15Lys Ala Ala Lys Asp Phe Ile Glu Trp
Leu Glu Ser Ala 20 2514129PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 141Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Glu1 5 10 15Lys Ala Ala Lys Asp Phe Ile Glu Trp
Leu Glu Ser Ala 20 2514229PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 142Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Lys Tyr Leu Asp Ser1 5 10 15Lys Ala Ala His Asp Phe Val Glu Trp
Leu Leu Arg Ala 20 2514329PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 143Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Glu1 5 10 15Lys Ala Ala Lys Asp Phe Val Glu Trp
Leu Leu Ser Ala 20 2514439PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(39)..(39)Linked to
R2, wherein R2 is -NH2 144Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Ser1 5 10 15Lys Ala Ala His Asp Phe Val Glu Trp
Leu Leu Ser Ala Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser
3514539PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(39)..(39)Linked to
R2, wherein R2 is -NH2 145Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Glu Lys1 5 10 15Lys Ala Ala Lys Glu Phe Val Glu Trp
Leu Leu Ser Ala Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser
3514639PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)SITE(39)..(39)Linked to R2, wherein R2
is -NH2 146Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Asp Ser1 5 10 15Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala
Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser
3514729PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is
Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MOD_RES(17)..(17)Hexadecanoyl-isoGluSITE(29)..(29)Linked to
R2, wherein R2 is -NH2 147Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Glu1 5 10 15Lys Ala Ala His Asp Phe Val Glu Trp
Leu Leu Ser Ala 20 2514830PRTArtificial Sequencesynthetic
constructSITE(1)..(1)Linked to R1, wherein R1 is Hydrogen
(Hy-)MISC_FEATURE(2)..(2)Xaa is 2-Aminoisobutyric acid
(Aib)MISC_FEATURE(29)..(29)Xaa is 2-Aminoisobutyric acid
(Aib)SITE(30)..(30)Linked to R2, wherein R2 is -NH2 148Tyr Xaa Glu
Gly Thr Phe Thr Ser Asp Ser Ser Ile Tyr Leu Asp Lys1 5 10 15Lys Ala
Gln Arg Ala Phe Val Asn Trp Leu Leu Ala Xaa Lys 20 25
3014930PRTArtificial Sequencesynthetic constructSITE(1)..(1)Linked
to R1, wherein R1 is Hydrogen (Hy-)MISC_FEATURE(2)..(2)Xaa is
2-Aminoisobutyric acid (Aib)MISC_FEATURE(29)..(29)Xaa is
2-Aminoisobutyric acid (Aib)SITE(30)..(30)Linked to R2, wherein R2
is -NH2 149Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Asp Lys1 5 10 15Lys Ala Gln Arg Ala Phe Val Asn Trp Leu Ser Ala Xaa
Lys 20 25 30
* * * * *