AMYLIN ANALOGUES
The present invention relates to amylin analogues and to their use in the treatment or prevention of a variety of diseases, conditions or disorders, including obesity, excess food intake and associated metabolic diseases such as diabetes. The analogues have good physical and chemical stability, good solubility, and a long duration of action, and are well suited for use in the form of a liquid formulation.
1 . An amylin analogue which is a compound having the formula:
R 1 —Z—R 2
wherein
R 1 is hydrogen, C 1-4 acyl, benzoyl or C 1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;
R 2 is OH or NHR 3 , wherein R 3 is hydrogen or C 1-3 -alkyl; and
Z is an amino acid sequence of formula I:
(I)
(SEQ ID NO: 3)
X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-
Phe-Leu-X17-Arg-X19-X20-Phe-Gly(Me)-Ala-Ile(Me)-
X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37
wherein
X1 is selected from the group consisting of Arg, Lys and Glu;
X3 is selected from the group consisting of Gly, Gln and Pro;
X4 is selected from the group consisting of Thr and Glu;
X5 is selected from the group consisting of Ala and Leu;
X6 is selected from the group consisting of Thr and Ser;
X10 is selected from the group consisting of Glu and Gln;
X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;
X17 is selected from the group consisting of Gln, His and Thr;
X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;
X27 is selected from the group consisting of Leu and Pro;
X32 is selected from the group consisting of Val and Thr;
X35 is selected from the group consisting of Asn and Ser;
X37 is selected from the group consisting of Hyp and Pro; and
X2 and X7 are amino acid residues whose side chains together form a lactam bridge;
or a pharmaceutically acceptable salt thereof.
2 . An amylin analogue according to claim 1 wherein X1 is selected from Arg and Lys.
3 . An amylin analogue according to claim 1 wherein:
(i) X3 is Gly, X4 is Thr, X5 is Ala and/or X6 is Thr;
(ii) X3 is Gly, X4 is Thr, X5 is Ala and X6 is Thr;
(iii) X14 is selected from His, Asp and Aad;
(iv) X17 is Gln;
(v) X19-X20 is selected from Ser-Ser and Thr-Thr, or is absent; or
(vi) X32 is Val, X35 is Asn and/or X37 is Hyp.
4 - 8 . (canceled)
9 . An amylin analogue according to claim 1 wherein Z is an amino acid sequence of formula II:
(II)
(SEQ ID NO: 4)
X1-X2-Gly-Thr-Ala-Thr-X7-Ala-Thr-X10-Arg-Leu-Ala-
X14-Phe-Leu-Gln-Arg-X19-X20-Phe-Gly(Me)-Ala-Ile
(Me)-X27-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp
wherein
X1 is selected from Arg and Lys;
X10 is selected from the group consisting of Glu and Gln;
X14 is selected from the group consisting of Aad, Asp and His;
X19-X20 is selected from Ser-Ser and Thr-Thr or is absent;
X27 is selected from the group consisting of Leu and Pro; and
X2 and X7 are amino acid residues whose side chains together form a lactam bridge.
10 . (canceled)
11 . An amylin analogue according to claim 1 wherein one of the residues at position X2 and X7 is selected from Asp, Glu and Aad, and the other is selected from Dap, Dab, Orn, Lys and hLys.
12 . (canceled)
13 . An amylin analogue according to claim 11 wherein:
X2 is Asp and X7 is Lys;
X2 is Asp and X7 is Orn;
X2 is Asp and X7 is Dab;
X2 is Asp and X7 is hLys;
X2 is Dap and X7 is Aad;
X2 is Glu and X7 is Dab; or
X2 is Dab and X7 is Glu.
14 . An amylin analogue according to claim 13 wherein:
X2 is Asp and X7 is Lys; or
X2 is Asp and X7 is Orn.
15 . An amylin analogue according to claim 1 wherein X14 is selected from Asp and Aad.
16 . An amylin analogue according to claim 1 wherein Z is an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 5)
RD()GTAT-Dap()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 6)
RD()GTAT-Dab()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 7)
RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 8)
RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp
(SEQ ID NO: 9)
RD()GTAT-Orn()-ATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 10)
RD()GTAT-Orn()-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP
(SEQ ID NO: 11)
RD()GTAT-Orn()-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 12)
RD()GTAT-Orn()-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp
(SEQ ID NO: 13)
RD()GTAT-Orn()-ATERLARFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 14)
ED()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 15)
RD()GEATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 16)
RD()GTLTK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 17)
RD()GTASK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 18)
RD()GTATK()ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp
(SEQ ID NO: 19)
RD()GTATK()ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 20)
RD()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp
(SEQ ID NO: 21)
RD()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 22)
RD()GTAT-hLys()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 23)
RD()GTAT-Orn()-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 24)
RD()GTAT-Orn()-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp
(SEQ ID NO: 25)
RD()GTAT-Orn()-ATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp
(SEQ ID NO: 26)
RD()GTAT-Orn()-ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 27)
RD()GTAT-Orn()-ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp
(SEQ ID NO: 28)
RD()GTAT-Orn()-ATERLA-Aad-FLQRATF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 29)
RD()GTAT-Orn()-ATERLA-Aad-FLQRAAF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 30)
RD()GTAT-Orn()-ATERLA-Aad-FLQRGTF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 31)
RD()QTAT-Orn()-ATERLA-Aad-FLQRGTF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 32)
RD()PTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 33)
ED()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp
(SEQ ID NO: 34)
RD()GTATK()ATERLA-Aad-FLQRAAF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 35)
RD()GTATK()ATERLA-Aad-FLQRGGF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 36)
RD()GTATK()ATERLA-Aad-FLQRANF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 37)
RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp
(SEQ ID NO: 38)
RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 39)
RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTETGSNT-Hyp
(SEQ ID NO: 40)
ED()GTATK()ATERLA-Aad-FLQRSSFGly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 41)
RD()GTATK()ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 42)
KD()GTATK()ATQRLA-Aad-FLQRSSF-Gly(Me)-AIle(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 43)
RD()GTATK()ATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 44)
RD()GTATK()ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 45)
RD()GTATK()ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTETGSNT-Hyp
(SEQ ID NO: 46)
KD()GTATK()ATQRLANFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 47)
KD()GTATK()ATQRLANFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTETGSNT-Hyp
(SEQ ID NO: 48)
R-Dap()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 49)
R-Dab()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 50)
R-Orn()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 51)
R-Dap()-GTAT-Aad()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 52)
R-Dab()-GTATE()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 53)
R-Aad()-GTAT-Dap()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
(SEQ ID NO: 54)
RE()GTAT-Dab()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp
or a pharmaceutically acceptable salt thereof.
17 . An amylin analogue according to claim 1 wherein R 1 is M or M-L-.
18 . An amylin analogue according to claim 17 wherein M is a lipophilic substituent comprising a hydrocarbon chain having from 10 to 24 C atoms.
19 . An amylin analogue according to claim 18 wherein the lipophilic substituent comprises a carboxylic acid group at the end of the hydrocarbon chain.
20 . An amylin analogue according to claim 19 wherein the lipophilic substituent is a 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl or 19-carboxy-nonadecanoyl moiety.
21 . An amylin analogue according to claim 17 wherein the linker L comprises a residue of Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, ε-Lys, Asp, β-Asp, Ser, Thr, Gaba, Aib, β-Ala (i.e., 3-aminopropanoyl), 4-aminobutanoyl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl or 8Ado (i.e., 8-amino-3,6-dioxaoctanoyl).
22 . An amylin analogue according to claim 21 wherein L is a residue of Glu, γ-Glu, ε-Lys, β-Ala, 4-aminobutanoyl, 8-aminooctanoyl or 8Ado.
23 . An amylin analogue according to claim 22 wherein R 1 is [19CD]-isoGlu.
24 . An amylin analogue according to claim 1 wherein R 2 is NH 2 .
25 . An amylin analogue according to claim 1 which is:
(Compound 1)
(SEQ ID NO: 55)
[19CD]-isoGlu-RD()GTAT-Dap()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 2)
(SEQ ID NO: 56)
[19CD]-isoGlu-RD()GTAT-Dab()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 3)
(SEQ ID NO: 57)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 4)
(SEQ ID NO: 58)
[19CD]-isoGlu-isoGlu-RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-
Ile(Me)-LSSTEVGSNT-Hyp-NH 2
(Compound 5)
(SEQ ID NO: 59)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
PSSTEVGSNT-Hyp-NH 2
(Compound 6)
(SEQ ID NO: 60)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 7)
(SEQ ID NO: 61)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNTP-NH 2
(Compound 8)
(SEQ ID NO: 62)
[19CD]-isoGlu-RD()GTAT-Orn()-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 9)
(SEQ ID NO: 63)
[19CD]-isoGlu-RD()GTAT-Orn()-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
PSSTEVGSNT-Hyp-NH 2
(Compound 10)
(SEQ ID NO: 64)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLARFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 11)
(SEQ ID NO: 65)
[19CD]-isoGlu-ED()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 12)
(SEQ ID NO: 66)
[19CD]-isoGlu-RD()GEATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 13)
(SEQ ID NO: 67)
[19CD]-isoGlu-RD()GTLTK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 14)
(SEQ ID NO: 68)
[19CD]-isoGlu-RD()GTASK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 15)
(SEQ ID NO: 69)
[19CD]-isoGlu-RD()GTATK()ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTE-
VGSNT-Hyp-NH 2
(Compound 16)
(SEQ ID NO: 70)
[19CD]-isoGlu-RD()GTATK()ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 17)
(SEQ ID NO: 71)
[19CD]-isoGlu-RD()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTE-
VGSNT-Hyp-NH 2
(Compound 18)
(SEQ ID NO: 72)
[19CD]-isoGlu-RD()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 19)
(SEQ ID NO: 73)
[19CD]-isoGlu-RD()GTAT-hLys()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 20)
(SEQ ID NO: 74)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 21)
(SEQ ID NO: 75)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-
PSSTEVGSNT-Hyp-NH 2
(Compound 22)
(SEQ ID NO: 76)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSST-Hyp-NH 2
(Compound 23)
(SEQ ID NO: 77)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 24)
(SEQ ID NO: 78)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-
PSSTEVGSNT-Hyp-NH 2
(Compound 25)
(SEQ ID NO: 79)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRATF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 26)
(SEQ ID NO: 80)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRAAF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 27)
(SEQ ID NO: 81)
[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRGTF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 28)
(SEQ ID NO: 82)
[19CD]-isoGlu-RD()QTAT-Orn()-ATERLA-Aad-FLQRGTF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 29)
(SEQ ID NO: 83)
[19CD]-isoGlu-RD()PTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 30)
(SEQ ID NO: 84)
[19CD]-isoGlu-ED()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-
PSSTEVGSNT-Hyp-NH 2
(Compound 31)
(SEQ ID NO: 85)
[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRAAF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 32)
(SEQ ID NO: 86)
[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRGGF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 33)
(SEQ ID NO: 87)
[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRANF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 34)
(SEQ ID NO: 88)
[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-
PSSTEVGSNT-Hyp-NH 2
(Compound 35)
(SEQ ID NO: 89)
[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 36)
(SEQ ID NO: 90)
[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTETGSNT-Hyp-NH 2
(Compound 37)
(SEQ ID NO: 91)
[19CD]-isoGlu-ED()GTATK()ATERLA-Aad-FLQRSSFGly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 38)
(SEQ ID NO: 92)
[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLORTTF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 39)
(SEQ ID NO: 93)
[19CD]-isoGlu-KD()GTATK()ATQRLA-Aad-FLQRSSF-Gly(Me)-AIle(Me)-
LSSTEVGSNTHyp-NH 2
(Compound 40)
(SEQ ID NO: 94)
[19CD]-isoGlu-RD()GTATK()ATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 41)
(SEQ ID NO: 95)
[19CD]-isoGlu-RD()GTATK()ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 42)
(SEQ ID NO: 96)
[19CD]-isoGlu-RD()GTATK()ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTETGSNT-Hyp-NH 2
(Compound 43)
(SEQ ID NO: 97)
[19CD]-isoGlu-KD()GTATK()ATQRLANFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-
VGSNT-Hyp-NH 2
(Compound 44)
(SEQ ID NO: 98)
[19CD]-isoGlu-KD()GTATK()ATQRLANFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTETGSNT-Hyp-NH 2
(Compound 45)
(SEQ ID NO: 99)
[19CD]-isoGlu-R-Dap()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 46)
(SEQ ID NO: 100)
[19CD]-isoGlu-R-Dab()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 47)
(SEQ ID NO: 101)
[19CD]-isoGlu-R-Orn()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 48)
(SEQ ID NO: 102)
[19CD]-isoGlu-R-Dap()-GTAT-Aad()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 49)
(SEQ ID NO: 103)
[19CD]-isoGlu-R-Dab()-GTATE()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 50)
(SEQ ID NO: 104)
[19CD]-isoGlu-R-Aad()-GTAT-Dap()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
(Compound 51)
(SEQ ID NO: 105)
[19CD]-isoGlu-RE()GTAT-Dab()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-
LSSTEVGSNT-Hyp-NH 2
or a pharmaceutically acceptable salt thereof.
26 . A pharmaceutical composition comprising an amylin analogue according to claim 1 in combination with a pharmaceutically acceptable carrier, excipient or vehicle.
27 . A method for the synthesis of an amylin analogue according to claim 1 comprising synthesizing the analogue by solid-phase or liquid-phase peptide synthesis methodology, optionally isolating and/or purifying the final product, and optionally further comprising the step of forming an amide bond between the side chains at positions 2 and 7.
28 - 32 . (canceled)