IP Library › Patent Application 16986790
Patent Application
App. No. 16/986,790

AMYLIN ANALOGUES

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Quick Facts
Patent No.
US None
App. No.
16/986,790
Filed
Aug 6, 2020
Art Unit
1658
USPC
514/4.9
Abstract

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.

Claims (683)

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:

(SEQ ID NO: 3)

Arg-Cys-X3-Thr-Ala-Thr-Cys-Ala-Thr-X10-Arg-Leu-

Ala-X14-Phe-Leu-X17-Arg-X19-X20-Phe-Gly(Me)-Ala-

Ile(Me)-Leu-Ser-Ser-Thr-X31-Val-Gly-Ser-X35-Thr-

X37

(I);

wherein

X3 is selected from the group consisting of Asn, Gly, Pro and Gln;

X10 is selected from the group consisting of Gln, Asp and Glu;

X14 is selected from the group consisting of Asp, His, Asn and Aad;

X17 is selected from the group consisting of His, Asn, Gln, Glu, Thr, Val, Lys and Aad;

X19-X20 is selected from the group consisting of Ser-Ser, Val-Val, Ser-Val and Val-Ser, or is absent;

X31 is selected from the group consisting of Asp, Glu and Asn;

X35 is selected from the group consisting of Asp, Glu, Asn, Ser, Phe, Orn, Aad, Gly and Thr; and

X37 is selected from the group consisting of Pro, Apr and Hyp;

and wherein the compound has at least one residue selected from:

X3 is Gln;

X14 is His, Asn or Aad;

X17 is Asn, Gln, Glu, Thr or Aad;

X19-X20 is Val-Ser or Ser-Val; and

X35 is Ser, Phe, Orn, Aad, Gly or Thr;

or a pharmaceutically acceptable salt thereof.

2 - 4 . (canceled)

5 . An amylin analogue according to claim 1 wherein Z is an amino acid sequence of formula II:

(SEQ ID NO: 4)

Arg-Cys-X3-Thr-Ala-Thr-Cys-Ala-Thr-X10-Arg-Leu-

Ala-X14-Phe-Leu-X17-Arg-X19-X20-Phe-Gly(Me)-Ala-

Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-X35-Thr-

X37

(II);

wherein

X3 is selected from the group consisting of Asn, Gly and Gln;

X10 is selected from the group consisting of Gln, Asp and Glu;

X14 is selected from the group consisting of Asp, His and Aad;

X17 is selected from the group consisting of His, Asn, Gln, Glu, Lys and Aad;

X19-X20 is Ser-Ser or is absent;

X35 is selected from the group consisting of Asp, Glu, Asn, Ser, Orn, Aad, Gly and Thr; and

X37 is selected from the group consisting of Pro and Hyp;

and wherein the compound has at least one residue selected from:

X3 is Gln;

X14 is His or Aad;

X17 is Asn, Gln, Glu or Aad; and

X35 is Ser, Phe, Orn, Aad, Gly or Thr.

6 . (canceled)

7 . An amylin analogue according to claim 1 wherein Z is an amino acid sequence of formula III:

(SEQ ID NO: 5)

Arg-Cys-X3-Thr-Ala-Thr-Cys-Ala-Thr-X10-Arg-Leu-

Ala-X14-Phe-Leu-X17-Arg-X19-X20-Phe-Gly(Me)-Ala-

Ile(Me)-Leu-Ser-Ser-Thr-Glu-Val-Gly-Ser-X35-

Thr-X37

(III);

wherein

X3 is selected from the group consisting of Asn, Gly and Gln;

X10 is selected from the group consisting of Gln, Asp and Glu;

X14 is selected from the group consisting of Asp, His and Aad;

X17 is selected from the group consisting of His and Gln;

X19-X20 is Ser-Ser or is absent;

X35 is selected from the group consisting of Asp, Glu, Asn, Aad and Gly; and

X37 is selected from the group consisting of Pro and Hyp;

and wherein the compound has at least one residue selected from:

X3 is Gln;

X14 is His or Aad;

X17 is Gln; and

X35 is Aad.

8 - 17 . (canceled)

18 . An amylin analogue according to claim 1 wherein Z is:

(SEQ ID NO: 6)

RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP,

(SEQ ID NO: 7)

RCNTATCATQRLANFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP,

(SEQ ID NO: 8)

RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 9)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 10)

RCGTATCATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 11)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 12)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSFT-Hyp,

(SEQ ID NO: 13)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGS-Orn-T-Hyp,

(SEQ ID NO: 14)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGS-Aad-T-Hyp,

(SEQ ID NO: 15)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGT-Hyp,

(SEQ ID NO: 16)

RCNTATCATQRLAHFLHRF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP,

(SEQ ID NO: 17)

RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 18)

RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 19)

RCGTATCATERLANFLVRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 20)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 21)

RCGTATCATERLAHFLKRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 22)

RCNTATCATQRLAHFLHRSVF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP,

(SEQ ID NO: 23)

RCNTATCATQRLAHFLHRVSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP,

(SEQ ID NO: 24)

RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP,

(SEQ ID NO: 25)

RCPTATCATDRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-

LSSTDVGSDTP,

(SEQ ID NO: 26)

RCNTATCATQRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP,

(SEQ ID NO: 27)

RCPTATCATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTDVGSNTP,

(SEQ ID NO: 28)

RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP,

(SEQ ID NO: 29)

RCPTATCATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTDVGSDTP,

(SEQ ID NO: 30)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 31)

RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 32)

RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 33)

RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 34)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSFT-Hyp,

(SEQ ID NO: 35)

RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSFT-Hyp,

(SEQ ID NO: 36)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSSTP,

(SEQ ID NO: 37)

RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSSTP,

(SEQ ID NO: 38)

RCGTATCATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSSTP,

(SEQ ID NO: 39)

RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSSTP,

(SEQ ID NO: 40)

RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSSTP,

(SEQ ID NO: 41)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSFTP,

(SEQ ID NO: 42)

RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSFTP,

(SEQ ID NO: 43)

RCGTATCATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 44)

RCGTATCATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSFT-Hyp,

(SEQ ID NO: 45)

RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 46)

RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGS-Orn-T-Hyp,

(SEQ ID NO: 47)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Apr,

(SEQ ID NO: 48)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSSTP,

(SEQ ID NO: 49)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGS-Orn-TP,

(SEQ ID NO: 50)

RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSTT-Hyp,

(SEQ ID NO: 51)

RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 52)

RCNTATCATQRLAHFL-Aad-RSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 53)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGS-Orn-T-Hyp,

(SEQ ID NO: 54)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGT-Hyp,

(SEQ ID NO: 55)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGS-Aad-T-Hyp,

(SEQ ID NO: 56)

RCGTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 57)

RCGTATCATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 58)

RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 59)

RCQTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 60)

RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 61)

RCPTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTDVGSNT-Hyp,

(SEQ ID NO: 62)

RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSDT-Hyp,

(SEQ ID NO: 63)

RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 64)

RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 65)

RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 66)

RCPTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 67)

RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 68)

RCNTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 69)

RCPTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 70)

RCNTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 71)

RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 72)

RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 73)

RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGT-Hyp,

(SEQ ID NO: 74)

RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGT-Hyp,

(SEQ ID NO: 75)

RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSTT-Hyp,

(SEQ ID NO: 76)

RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSTT-Hyp,

(SEQ ID NO: 77)

RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGS-Aad-T-Hyp,

(SEQ ID NO: 78)

RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGS-Aad-T-Hyp,

(SEQ ID NO: 79)

RCGTATCATERLAHFLQRF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 80)

RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 81)

RCNTATCATQRLAHFLQRF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGT-Hyp,

(SEQ ID NO: 82)

RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGTP,

(SEQ ID NO: 83)

RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGT-Hyp,

(SEQ ID NO: 84)

RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSTTP,

(SEQ ID NO: 85)

RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSTT-Hyp,

(SEQ ID NO: 86)

RCNTATCATQRLAHFLERSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSSTP,

(SEQ ID NO: 87)

RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSSTP,

(SEQ ID NO: 88)

RCNTATCATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 89)

RCNTATCATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSST-Hyp,

(SEQ ID NO: 90)

RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 91)

RCQTATCATDRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

(SEQ ID NO: 92)

RCQTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGT-Hyp,

(SEQ ID NO: 93)

RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGT-Hyp,

(SEQ ID NO: 94)

RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 95)

RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNTP,

(SEQ ID NO: 96)

RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSGTP,

(SEQ ID NO: 97)

RCQTATCATDRLA-Aad-FLQRF-Gly(Me)-A-Ile(Me)-

LSSTEVGSNT-Hyp,

or

(SEQ ID NO: 98)

RCQTATCATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP.

19 . 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 selected from the group consisting of:

(SEQ ID NO: 99)

RCNTATCATQRLADFLHRSSF-Gly(Me)-A-Ile(Me)-

LSSTEVGSETP;

(SEQ ID NO: 100)

RCNTATCATQRLADFLHRSSNNF-Gly(Me)-A-Ile(Me)-

LSSTNVGSNT-Apr;

and

(SEQ ID NO: 101)

RCNTATCATQRLAHFLHRSSNNF-Gly(Me)-A-Ile(Me)-

LSSTNVGSNT-Apr;

or a pharmaceutically acceptable salt or thereof.

20 . An amylin analogue according to claim 1 wherein R 1 is M- or M-L-.

21 . An amylin analogue according to claim 20 , wherein M is an alkanoyl group.

22 . An amylin analogue according to claim 21 , wherein M is selected from 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl and 19-carboxy-nonadecanoyl.

23 . An amylin analogue according to claim 1 wherein R 1 is M-L- and L is a residue of an amino acid selected from the group consisting 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, 4-aminobutanoyl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl and 8Ado.

24 . An amylin analogue according to claim 23 wherein L is a γ-Glu residue.

25 . An amylin analogue according to claim 1 wherein R 2 is NH 2 .

26 . An amylin analogue according to claim 1 which is selected from the group consisting of:

(SEQ ID NO: 103)

[19CD]-isoGlu-RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ,

(SEQ ID NO: 104)

[19CD]-isoGlu-RCNTATCATQRLANFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ,

(SEQ ID NO: 107)

[19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 108)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 109)

[19CD]-isoGlu-RCGTATCATERLAHFLERSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 110)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 111)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSFT-Hyp-NH 2 ,

(SEQ ID NO: 112)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH 2 ,

(SEQ ID NO: 113)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH 2 ,

(SEQ ID NO: 114)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGT-Hyp-NH 2 ,

(SEQ ID NO: 115)

[19CD]-isoGlu-RCNTATCATQRLAHFLHRF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ,

(SEQ ID NO: 116)

[19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 117)

[19CD]-isoGlu-RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 118)

[19CD]-isoGlu-RCGTATCATERLANFLVRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 119)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 120)

[19CD]-isoGlu-RCGTATCATERLAHFLKRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 121)

[19CD]-isoGlu-RCNTATCATQRLAHFLHRSVF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ,

(SEQ ID NO: 122)

[19CD]-isoGlu-RCNTATCATQRLAHFLHRVSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ,

(SEQ ID NO: 123)

[19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ,

(SEQ ID NO: 124)

[19CD]-isoGlu-RCPTATCATDRLAHFLVRSSF-Gly(Me)-A-

Ile(Me)-LSSTDVGSDTP-NH 2 ,

(SEQ ID NO: 125)

[19CD]-isoGlu-RCNTATCATQRLAHFLVRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ,

(SEQ ID NO: 126)

[19CD]-isoGlu-RCPTATCATDRLAHFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTDVGSNTP-NH 2 ,

(SEQ ID NO: 127)

[19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ,

(SEQ ID NO: 128)

[19CD]-isoGlu-RCPTATCATDRLAHFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTDVGSDTP-NH 2 ,

(SEQ ID NO: 129)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 130)

[19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 131)

[19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 132)

[19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 133)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSFT-Hyp-NH 2 ,

(SEQ ID NO: 134)

[19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSFT-Hyp-NH 2 ,

(SEQ ID NO: 135)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSSTP-NH 2 ,

(SEQ ID NO: 136)

[19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSSTP-NH 2 ,

(SEQ ID NO: 137)

[19CD]-isoGlu-RCGTATCATERLAHFLERSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSSTP-NH 2 ,

(SEQ ID NO: 138)

[19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSSTP-NH 2 ,

(SEQ ID NO: 139)

[19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSSTP-NH 2 ,

(SEQ ID NO: 140)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSFTP-NH 2 ,

(SEQ ID NO: 141)

[19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSFTP-NH 2 ,

(SEQ ID NO: 142)

[19CD]-isoGlu-RCGTATCATERLADFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 143)

[19CD]-isoGlu-RCGTATCATERLADFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSFT-Hyp-NH 2 ,

(SEQ ID NO: 144)

[19CD]-isoGlu-RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)-

A-Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 145)

[19CD]-isoGlu-RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)-

A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH 2 ,

(SEQ ID NO: 146)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Apr-NH 2 ,

(SEQ ID NO: 147)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSSTP-NH 2 ,

(SEQ ID NO: 148)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGS-Orn-TP-NH 2 ,

(SEQ ID NO: 149)

[19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSTT-Hyp-NH 2 ,

(SEQ ID NO: 150)

[19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 151)

[19CD]-isoGlu-RCNTATCATQRLAHFL-Aad-RSSF-Gly(Me)-

A-Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 152)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH 2 ,

(SEQ ID NO: 153)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGT-Hyp-NH 2 ,

(SEQ ID NO: 154)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH 2 ,

(SEQ ID NO: 155)

[19CD]-isoGlu-RCGTATCATERLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 156)

[19CD]-isoGlu-RCGTATCATERLA-Aad-FLQRSSF-Gly(Me)-

A-Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 157)

[19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 158)

[19CD]-isoGlu-RCQTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 159)

[19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 160)

[19CD]-isoGlu-RCPTATCATDRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTDVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 161)

[19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSDT-Hyp-NH 2 ,

(SEQ ID NO: 162)

[19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 163)

[19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 164)

[19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 165)

[19CD]-isoGlu-RCPTATCATQRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 166)

[19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 167)

[19CD]-isoGlu-RCNTATCATERLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 168)

[19CD]-isoGlu-RCPTATCATERLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 169)

[19CD]-isoGlu-RCNTATCATERLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 170)

[19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 171)

[19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 172)

[19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGT-Hyp-NH 2 ,

(SEQ ID NO: 173)

[19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGT-Hyp-NH 2 ,

(SEQ ID NO: 174)

[19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSTT-Hyp-NH 2 ,

(SEQ ID NO: 175)

[19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSTT-Hyp-NH 2 ,

(SEQ ID NO: 176)

[19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH 2 ,

(SEQ ID NO: 177)

[19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH 2 ,

(SEQ ID NO: 178)

[19CD]-isoGlu-RCGTATCATERLAHFLQRF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 179)

[19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 180)

[19CD]-isoGlu-RCNTATCATQRLAHFLQRF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGT-Hyp-NH 2 ,

(SEQ ID NO: 181)

[19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGTP-NH 2 ,

(SEQ ID NO: 182)

[19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGT-Hyp-NH 2 ,

(SEQ ID NO: 183)

[19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSTTP-NH 2 ,

(SEQ ID NO: 184)

[19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSTT-Hyp-NH 2 ,

(SEQ ID NO: 185)

[19CD]-isoGlu-RCNTATCATQRLAHFLERSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSSTP-NH 2 ,

(SEQ ID NO: 186)

[19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSSTP-NH 2 ,

(SEQ ID NO: 187)

[19CD]-isoGlu-RCNTATCATQRLA-Aad-FLQRSSF-

Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 188)

[19CD]-isoGlu-RCNTATCATQRLA-Aad-FLQRSSF-Gly(Me)-

A-Ile(Me)-LSSTEVGSST-Hyp-NH 2 ,

(SEQ ID NO: 189)

[19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 190)

[19CD]-isoGlu-RCQTATCATDRLA-Aad-FLQRSSF-Gly(Me)-

A-Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 191)

[19CD]-isoGlu-RCQTATCATERLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGT-Hyp-NH 2 ,

(SEQ ID NO: 192)

[19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSGT-Hyp-NH 2 ,

(SEQ ID NO: 193)

[19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 194)

[19CD]-isoGlu-RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)-

A-Ile(Me)-LSSTEVGSNTP-NH 2 ,

(SEQ ID NO: 195)

[19CD]-isoGlu-RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)-

A-Ile(Me)-LSSTEVGSGTP-NH 2 ,

(SEQ ID NO: 196)

[19CD]-isoGlu-RCQTATCATDRLA-Aad-FLQRF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNT-Hyp-NH 2 ,

(SEQ ID NO: 197)

[19CD]-isoGlu-RCQTATCATERLAHFLQRF-Gly(Me)-A-

Ile(Me)-LSSTEVGSNTP-NH 2 ,

wherein [19CD] represents [19-carboxynonadecanoyl];

or a pharmaceutically acceptable salt thereof.

27 . An amylin analogue according to claim 1 , comprising an intramolecular disulfide bridge formed between the cysteine residues present at positions 2 and 7 of the amino acid sequence.

28 . A pharmaceutical composition comprising an amylin analogue according to claim 1 , in combination with a pharmaceutically acceptable carrier, excipient or vehicle.

29 . A device comprising an amylin analogue according to claim 1 , for delivery of the amylin analogue to a subject.

30 . A kit comprising an amylin analogue according to claim 1 , and optionally further comprising packaging and instructions for use.

31 . (canceled)

32 . A method for the synthesis of an amylin analogue according to claim 1 .

33 . A method according to claim 32 comprising synthesizing the amylin analogue by solid-phase or liquid-phase methodology, optionally isolating and purifying the final product, and further optionally comprising the step of forming a disulfide bond between the thiol groups of the cysteine side chains at positions 2 and 7.

34 . (canceled)

35 . A method of treating, inhibiting or reducing weight gain, promoting weight loss, reducing food intake, and/or reducing excess body weight in a subject in need, said method comprising administering to said subject a therapeutically effective amount of an amylin analogue according to claim 1 .

36 . A method of treating obesity, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease, obesity-induced sleep apnea and respiratory problems, degeneration of cartilage, osteoarthritis, or reproductive health complications of obesity or overweight such as infertility, in a subject in need, said method comprising administering to said subject a therapeutically effective amount of an amylin analogue according to claim 1 .

37 . (canceled)

38 . A method of prevention or treatment of Alzheimer's disease, diabetes, type 1 diabetes, type 2 diabetes, pre-diabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, metabolic disease including metabolic syndrome, hyperglycemia, hypertension, atherogenic dyslipidemia, hepatic steatosis (“fatty liver”), kidney failure, arteriosclerosis (e.g. atherosclerosis), macrovascular disease, microvascular disease, diabetic heart (including diabetic cardiomyopathy and heart failure as a diabetic complication) coronary heart disease, peripheral artery disease or stroke, and combinations thereof in a subject in need, said method comprising administering to said subject a therapeutically effective amount of an amylin analogue according to claim 1 .

39 . A method of lowering circulating LDL levels and/or increasing HDL/LDL ratio, comprising administering an amylin analogue of claim 1 .

40 - 46 . (canceled)

47 . An amylin analogue according to claim 19 which is selected from the group consisting of:

(SEQ ID NO 102)

[19CD]-isoGlu-RCNTATCATQRLADFLHRSSF-Gly(Me)-A-

Ile(Me)-LSSTEVGSETP-NH 2 ;

(SEQ ID NO 105)

[19CD]-isoGlu-RCNTATCATQRLADFLHRSSNNF-Gly(Me)-A-

Ile(Me)-LSSTNVGSNT-Apr-NH 2 ;

and

(SEQ ID NO 106)

[19CD]-isoGlu-RCNTATCATQRLAHFLHRSSNNF-Gly(Me)-A-

Ile(Me)-LSSTNVGSNT-Apr-NH 2 ;

wherein [19CD] represents [19-carboxynonadecanoyl]:

or a pharmaceutically acceptable salt thereof.

Assignments (7)
RELEASE OF SECURITY INTEREST Recorded May 17, 2023
From: ZOOLANDER SA LLC
To: ZEALAND PHARMA A/S
Reel/Frame 063672/0342 →
RELEASE OF SECURITY INTEREST Recorded May 11, 2023
From: ZOOLANDER SA LLC
To: ZEALAND PHARMA A/S
Reel/Frame 063624/0547 →
PATENT SECURITY AGREEMENT Recorded Dec 27, 2021
From: ZEALAND PHARMA A/S
To: ZOOLANDER SA LLC
Reel/Frame 058593/0261 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2021
From: JUST, RASMUS; GIEHM, LISE; VILLADSEN, JESPER SKODBORG; MUNCH, HENRIK KOFOED; SKARBALIENE, JOLANTA; DERYABINA, MARIA ALEXANDROVNA; MATHIESEN, JESPER MOSOLFF
To: ZEALAND PHARMA A/S
Reel/Frame 054892/0357 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2021
From: DEMMER, OLIVER
To: ZEALAND PHARMA A/S
Reel/Frame 054966/0108 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2021
From: HAMPRECHT, DIETER WOLFGANG
To: BOEHRINGER INGELHEIM INTERNATIONAL GMBH
Reel/Frame 054892/0522 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2021
From: BOEHRINGER INGELHEIM INTERNATIONAL GMBH
To: ZEALAND PHARMA A/S
Reel/Frame 054892/0560 →