Amylin Analogues

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.

Description

[0001] The present invention relates to amylin analogues that are amylin receptor agonists, and to their medical use in the treatment and/or prevention of a variety of diseases, conditions or disorders, including treatment and/or prevention of excess food intake, obesity and excess body weight, metabolic diseases, and other conditions and disorders described herein. In particular, the present invention relates to stable amylin analogues that have a long duration of action and are well suited for use in the form of a liquid formulation.

BACKGROUND OF THE INVENTION

[0002] Amylin is one of a family of peptide hormones that includes amylin, calcitonin, calcitonin gene-related peptide, adrenomedullin and intermedin (intermedin also being known as AFP-6), and has been implicated in various metabolic diseases and disorders. Human amylin was first isolated, purified and characterized as the major component of amyloid deposits in the islets of pancreases from type 2 diabetes patients.

[0003] Native human amylin is a 37-amino acid peptide having the formula

TABLE-US-00001 (SEQ ID NO: 1) H-KC( )NTATC( )ATQRLANFLVHSSNNFGAILSSINVGSNTY-NH.sub.2

wherein H- at the N-terminus designates a hydrogen atom, corresponding to the presence of a free amino group on the N-terminal amino acid residue [i.e. the lysine (K) residue at sequence position number 1 in the sequence shown above]; wherein --NH.sub.2 at the C-terminus indicates that the C-terminal carboxyl group is in the amide form; and wherein the parentheses ( ) associated with the two cysteine (C, Cys) residues at sequence positions 2 and 7 indicate the presence of an intramolecular disulfide bridge between the two Cys residues in question.

[0004] Amylin may be beneficial in treating metabolic disorders such as diabetes and/or obesity. Amylin is believed to regulate gastric emptying, and to suppress glucagon secretion and food intake, thereby regulating the rate of glucose release to the circulation. Amylin appears to complement the actions of insulin. Compared to healthy adults, type 1 diabetes patients have no circulating amylin, and type 2 diabetes patients exhibit reduced postprandial amylin concentrations. In human trials an amylin analogue known as pramlintide, described in WO 93/10146 and having the sequence Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-S- er-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 2), which also possesses a disulphide bridge between the Cys residues at positions 2 and 7, has been shown to reduce body weight or reduce weight gain. An alternative amylin analogue incorporating N-methylated residues and having a reduced tendency to fibrillation, designated IAPP-GI, has been described by Yan et al. (PNAS, 103(7), 2046-2051, 2006). IAPP-GI appears to have lower activity than native amylin, however. Further analogues of amylin or pramlintide are described in WO2013/156594, WO2012/168430, WO2012/168431 and WO2012/168432, as well as WO2006/042745.

[0005] Obesity is believed to be a major causal factor in development of type 2 diabetes, which constitutes a growing and worldwide major health problem. Diseases or disorders that may develop as a consequence of untreated diabetes include cardiovascular and peripheral artery disease, micro- and macrovascular complications, stroke, and certain forms of cancer, particularly hematopoietic cancers.

[0006] There is a need in the art for further amylin analogues. For example, amylin analogues that show a reduced tendency for fibrillation and/or high chemical stability at or around pH 7 might allow for a formulation at or near physiological pH. Amylin analogues having high levels of agonist activity at the amylin receptor and/or appropriately long plasma elimination half lives, may also enable longer intervals between dosing than is currently possible (e.g. once weekly, or even less frequently) and hence improve patient compliance.

SUMMARY OF THE INVENTION

[0007] The present invention relates to compounds which are analogues of human amylin.

[0008] In a first aspect, the invention provides an amylin analogue which is a compound having the formula:

R.sup.1--Z--R.sup.2

wherein R.sup.1 is hydrogen, C.sub.1-4 acyl, benzoyl or C.sub.1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R.sup.2 is OH or NHR.sup.3, wherein R.sup.3 is hydrogen or C.sub.1-3-alkyl; and Z is an amino acid sequence of formula 1:

TABLE-US-00002 (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;

[0009] or a pharmaceutically acceptable salt or solvate thereof.

[0010] Throughout this specification, amino acid positions of the amylin analogues are numbered according to the corresponding position in human amylin having the sequence shown above. The sequence of Formula I (and other formulae herein) contains a two amino acid deletion corresponding to the two residues Asn21 and Asn22 of human amylin. Thus, for ease of comparison with the amylin sequence, the Phe residue immediately C-terminal (downstream) of position X20 is designated as position 23, since it aligns with Phe23 of human amylin. Thus, the numbering of any given residue in Formula I above, and in other formulae elsewhere in this specification, reflects the corresponding residue in human amylin when optimally aligned therewith and does not necessarily reflect its linear position in the particular sequence.

[0011] (It will be apparent that any of the relevant formulae presented in this specification could be written to include residues X21-X22 at the appropriate positions, wherein X21 and X22 are absent.)

[0012] It has surprisingly been found that simultaneous deletion of the residues at positions X21 and X22 (and even additionally at positions X19 and X20) leads to active and stable amylin analogues. Further, without wishing to be bound by any particular theory, it is believed that the deletion of these residues may enhance the chemical stability of the molecules, especially at neutral and/or alkaline pH. Fibrillation and precipitation of the compounds may also be reduced. Thus the compounds may have superior properties for formulation as compared to existing amylin analogues.

[0013] Furthermore, the compounds described here show similar or even increased activity compared to wild type amylin (e.g. agonist activity at the hAMYR3 and/or hAMYR1 and/or hCTR2 receptors), despite being methylated at the same positions as IAPP-GI (which has lower activity than wild type amylin).

[0014] In some embodiments of formula I it may be desirable that:

X31 is Glu;

[0015] X19-X20 is Ser-Ser or is absent; and/or

X37 is Hyp or Pro.

[0016] It may be desirable that the amylin analogue contains at least one of His14, Asn14, Aad14, Gln17 and Thr17.

[0017] If X14 is Asp, then it may be desirable that X17 is Asn, Gln, Glu, Thr or Aad. X17 is Gln may be particularly preferred.

[0018] In some circumstances, it may be desirable that X35 is not a hydrophobic residue, e.g. Phe. Such residues may increase tendency towards fibrillation in some formulations.

[0019] Z may be an amino acid sequence of formula II:

TABLE-US-00003 (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.

[0020] In some embodiments of formula II, X17 may be selected from His and Gln.

Z may be an amino acid sequence of formula III:

TABLE-US-00004 (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.

[0021] In any of the formulae described above, it may be desirable that:

X10 is selected from Gln and Glu; and/or X35 is selected from Asp, Glu, Asn and Aad, e.g. X35 is selected from Asp and Asn.

[0022] Additionally or alternatively, it may be that X3 is selected from Asn and Gly and/or X17 is Gn. The presence of Gin at position X17 is believed to correlate with good levels of chemical and physical stability.

[0023] Additionally or alternatively, X35 is Asn and/or X37 is Hyp.

[0024] In some embodiments of the formulae described above:

X3 is Gin;

[0025] X10 is selected from Glu and Asp; X14 is selected from His and Aad; X35 is selected from Gly and Asn; and X37 is selected from Pro and Hyp.

[0026] In other embodiments of the formulae described above:

X3 is Gly;

[0027] X10 is selected from Glu and Asp; X14 is selected from His and Aad; X35 is selected from Gly and Asn; and X37 is selected from Pro and Hyp.

[0028] Combinations of specific residues which may be present in any of the amylin analogues described include:

Gly3+Glu10;

Asn3+Glu10;

Gln3+Glu10;

Asn3+Gln10; or

Gln3+Asp10.

[0029] In some embodiments, X14 is selected from His and Aad, and/or X17 is Gln.

[0030] For example, the combination of Aad14 and Gln17 appears to provide good activity.

[0031] Additionally or alternatively, X17 may be Gln, X31 may be Glu and X37 may be Hyp, i.e. the analogue may contain the combination Gln17+Glu31+Hyp37.

[0032] In some embodiments, X19-X20 is Ser-Ser. In other embodiments X19-X20 is absent.

[0033] Certain residue combinations which may be favourable for chemical stability include:

X3 is Gly, X10 is Glu and X14 is His;

[0034] X3 is selected from Asn and Gln, X10 is Glu and X14 is His; X3 is Gly, X10 is Glu and X14 is selected from Aad and Asp;

X10 is Asp and X14 is Aad;

[0035] X14 is selected from Aad and His, X31 is Glu and X37 is selected from Pro and Hyp; and

X14 is Aad, X31 is Glu and X37 is Hyp.

[0036] Of these combinations, the following may additionally (or alternatively) have a favourable effect on activity:

X3 is Gly, X10 is Glu and X14 is selected from Aad and Asp; X14 is selected from Aad and His, X31 is Glu and X37 is selected from Pro and Hyp;

X14 is Aad, X31 is Glu and X37 is Hyp.

[0037] For example, the compound may comprise the residues:

Gly3+Glu10+His14

Asn3+Glu10+His14;

Gln3+Glu10+His14;

Gly3+Glu10+Aad14;

Gly3+Glu10+Asp14;

Asp10+Aad14;

His14+Glu31+Pro37

His14+Glu31+Hyp37

Aad14+Glu31+Pro37; and

Aad14+Glu31+Hyp37.

[0038] Yet further combinations of desirable residues include:

Gly3+Glu31;

Gly3+Ser19+Ser20+Glu31

Gly3+Glu10+Glu31+Asn35+Hyp37; and

Gly3+Glu10+Ser19+Ser20+Glu31+Asn35+Hyp37.

[0039] Any of the above-described residues and combinations of residues may be combined except where inconsistent with one another.

[0040] The invention also provides an amylin analogue which is a compound having the formula:

R.sup.1--Z--R.sup.2

wherein R.sup.1 is hydrogen, C.sub.1-4 acyl, benzoyl or C.sub.1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R.sup.2 is OH or NHR.sup.3, wherein R.sup.3 is hydrogen or C.sub.1-3-alkyl; and Z is an amino acid sequence selected from the group consisting of:

TABLE-US-00005 (SEQ ID NO: 99) RCNTATCATQRLADFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS ETP; (SEQ ID NO: 100) RCNTATCATQRLADFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSTNVG SNT-Apr; and (SEQ ID NO: 101) RCNTATCATQRLAHFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSTNVG SNT-Apr;

or a pharmaceutically acceptable salt or solvate thereof.

[0041] Thus, the amylin analogue may have the formula:

R.sup.1--Z--R.sup.2

wherein R.sup.1 is hydrogen, C.sub.1-4 acyl, benzoyl or C.sub.1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R.sup.2 is OH or NHR.sup.3, wherein R.sup.3 is hydrogen or C.sub.1-3-alkyl; and Z is an amino acid sequence selected from the group consisting of:

TABLE-US-00006 (SEQ ID NO: 6) RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 7) RCNTATCATQRLANFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 8) RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 9) RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 10) RCGTATCATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 11) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 12) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSF T-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)-LSSTEVGSG T-Hyp (SEQ ID NO: 16) RCNTATCATQRLAHFLHRF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP (SEQ ID NO: 17) RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP (SEQ ID NO: 18) RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP (SEQ ID NO: 19) RCGTATCATERLANFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 20) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 21) RCGTATCATERLAHFLKRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 22) RCNTATCATQRLAHFLHRSVF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 23) RCNTATCATQRLAHFLHRVSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 24) RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 25) RCPTATCATDRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSD TP (SEQ ID NO: 26) RCNTATCATQRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 27) RCPTATCATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSN TP (SEQ ID NO: 28) RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 29) RCPTATCATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSD TP (SEQ ID NO: 30) RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 31) RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 32) RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 33) RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 34) RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSF T-Hyp (SEQ ID NO: 35) RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSF T-Hyp (SEQ ID NO: 36) RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS TP (SEQ ID NO: 37) RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS TP (SEQ ID NO: 38) RCGTATCATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS TP (SEQ ID NO: 39) RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS TP (SEQ ID NO: 40) RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS TP (SEQ ID NO: 41) RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSF TP (SEQ ID NO: 42) RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSF TP (SEQ ID NO: 43) RCGTATCATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 44) RCGTATCATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSF T-Hyp (SEQ ID NO: 45) RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTE VGSST-Hyp (SEQ ID NO: 46) RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTE VGS-Orn-T-Hyp (SEQ ID NO: 47) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Apr (SEQ ID NO: 48) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS TP (SEQ ID NO: 49) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS- Orn-TP (SEQ ID NO: 50) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGST T-Hyp (SEQ ID NO: 51) RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 52) RCNTATCATQRLAHFL-Aad-RSSF-Gly(Me)-A-Ile(Me)-LSSTE VGSNT-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)-LSSTEVGSG T-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)-LSSTEVGSN T-Hyp

(SEQ ID NO: 57) RCGTATCATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE VGSNT-Hyp (SEQ ID NO: 58) RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 59) RCQTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 60) RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 61) RCPTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSN T-Hyp (SEQ ID NO: 62) RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSD T-Hyp (SEQ ID NO: 63) RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP (SEQ ID NO: 64) RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP (SEQ ID NO: 65) RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 66) RCPTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 67) RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP (SEQ ID NO: 68) RCNTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP (SEQ ID NO: 69) RCPTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP (SEQ ID NO: 70) RCNTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 71) RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 72) RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 73) RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSG T-Hyp (SEQ ID NO: 74) RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSG T-Hyp (SEQ ID NO: 75) RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGST T-Hyp (SEQ ID NO: 76) RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGST T-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)-LSSTEVGSN TP (SEQ ID NO: 81) RCNTATCATQRLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT- Hyp (SEQ ID NO: 82) RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSG TP (SEQ ID NO: 83) RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSG T-Hyp (SEQ ID NO: 84) RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGST TP (SEQ ID NO: 85) RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGST T-Hyp (SEQ ID NO: 86) RCNTATCATQRLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS TP (SEQ ID NO: 87) RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS TP (SEQ ID NO: 88) RCNTATCATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE VGSNT-Hyp (SEQ ID NO: 89) RCNTATCATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE VGSST-Hyp (SEQ ID NO: 90) RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 91) RCQTATCATDRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE VGSNT-Hyp (SEQ ID NO: 92) RCQTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSG T-Hyp (SEQ ID NO: 93) RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSG T-Hyp (SEQ ID NO: 94) RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP (SEQ ID NO: 95) RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE VGSNTP (SEQ ID NO: 96) RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE VGSGTP (SEQ ID NO: 97) RCQTATCATDRLA-Aad-FLQRF-Gly(Me)-A-Ile(Me)-LSSTEVG SNT-Hyp (SEQ ID NO: 98) RCQTATCATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP

or a pharmaceutically acceptable salt or solvate thereof.

[0042] In some embodiments, R.sup.1 is M or M-L-, and/or R.sup.2 is NH.sub.2.

[0043] Specific amylin analogues of the invention include:

TABLE-US-00007 (SEQ ID NO: 102) [19CD]-isoGlu-RCNTATCATQRLADFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 103) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 104) [19CD]-isoGlu-RCNTATCATQRLANFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 105) [19CD]-isoGlu-RCNTATCATQRLADFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSINVGSNT-Apr-NH.- sub.2 (SEQ ID NO: 106) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSINVGSNT-Apr-NH.- sub.2 (SEQ ID NO: 107) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 108) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 109) [19CD]-isoGlu-RCGTATCATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 110) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.su- b.2 (SEQ ID NO: 111) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.su- b.2 (SEQ ID NO: 112) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-N- H.sub.2 (SEQ ID NO: 113) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-N- H.sub.2 (SEQ ID NO: 114) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.su- b.2 (SEQ ID NO: 115) [19CD]-isoGlu-RCNTATCATQRLAHFLHRF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 116) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 117) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 118) [19CD]-isoGlu-RCGTATCATERLANFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 119) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 120) [19CD]-isoGlu-RCGTATCATERLAHFLKRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 121) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSVF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 122) [19CD]-isoGlu-RCNTATCATQRLAHFLHRVSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 123) [19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 124) [19CD]-isoGlu-RCPTATCATDRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSDTP-NH.sub.2 (SEQ ID NO: 125) [19CD]-isoGlu-RCNTATCATQRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 126) [19CD]-isoGlu-RCPTATCATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSNTP-NH.sub.2 (SEQ ID NO: 127) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 128) [19CD]-isoGlu-RCPTATCATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSDTP-NH.sub.2 (SEQ ID NO: 129) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.su- b.2 (SEQ ID NO: 130) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.su- b.2 (SEQ ID NO: 131) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.su- b.2 (SEQ ID NO: 132) [19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.su- b.2 (SEQ ID NO: 133) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.su- b.2 (SEQ ID NO: 134) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.su- b.2 (SEQ ID NO: 135) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (SEQ ID NO: 136) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (SEQ ID NO: 137) [19CD]-isoGlu-RCGTATCATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (SEQ ID NO: 138) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (SEQ ID NO: 139) [19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (SEQ ID NO: 140) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFTP-NH.sub.2 (SEQ ID NO: 141) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFTP-NH.sub.2 (SEQ ID NO: 142) [19CD]-isoGlu-RCGTATCATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.su- b.2 (SEQ ID NO: 143) [19CD]-isoGlu-RCGTATCATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.su- b.2 (SEQ ID NO: 144) [19CD]-isoGlu-RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-N- H.sub.2 (SEQ ID NO: 145) [19CD]-isoGlu-RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-H- yp-NH.sub.2 (SEQ ID NO: 146) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Apr-NH.su- b.2 (SEQ ID NO: 147) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (SEQ ID NO: 148) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-TP-NH.s- ub.2 (SEQ ID NO: 149) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.su- b.2 (SEQ ID NO: 150) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 151) [19CD]-isoGlu-RCNTATCATQRLAHFL-Aad-RSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-N- H.sub.2 (SEQ ID NO: 152) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-N- H.sub.2 (SEQ ID NO: 153) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.su- b.2 (SEQ ID NO: 154) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-N- H.sub.2 (SEQ ID NO: 155) [19CD]-isoGlu-RCGTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 156) [19CD]-isoGlu-RCGTATCATERLA-Aad-FLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (SEQ ID NO: 157) [19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 158) [19CD]-isoGlu-RCQTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 159) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 160) [19CD]-isoGlu-RCPTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 161) [19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSDT-Hyp-NH.su- b.2 (SEQ ID NO: 162) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 163) [19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 164) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2

(SEQ ID NO: 165) [19CD]-isoGlu-RCPTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 166) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 167) [19CD]-isoGlu-RCNTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 168) [19CD]-isoGlu-RCPTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 169) [19CD]-isoGlu-RCNTATCATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 170) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.su- b.2 (SEQ ID NO: 171) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.su- b.2 (SEQ ID NO: 172) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.su- b.2 (SEQ ID NO: 173) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.su- b.2 (SEQ ID NO: 174) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.su- b.2 (SEQ ID NO: 175) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.su- b.2 (SEQ ID NO: 176) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-N- H.sub.2 (SEQ ID NO: 177) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-N- H.sub.2 (SEQ ID NO: 178) [19CD]-isoGlu-RCGTATCATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.- 2 (SEQ ID NO: 179) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 180) [19CD]-isoGlu-RCNTATCATQRLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.- 2 (SEQ ID NO: 181) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGTP-NH.sub.2 (SEQ ID NO: 182) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.su- b.2 (SEQ ID NO: 183) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTTP-NH.sub.2 (SEQ ID NO: 184) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.su- b.2 (SEQ ID NO: 185) [19CD]-isoGlu-RCNTATCATQRLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (SEQ ID NO: 186) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (SEQ ID NO: 187) [19CD]-isoGlu-RCNTATCATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-N- H.sub.2 (SEQ ID NO: 188) [19CD]-isoGlu-RCNTATCATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-N- H.sub.2 (SEQ ID NO: 189) [19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.su- b.2 (SEQ ID NO: 190) [19CD]-isoGlu-RCQTATCATDRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-N- H.sub.2 (SEQ ID NO: 191) [19CD]-isoGlu-RCQTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.su- b.2 (SEQ ID NO: 192) [19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.su- b.2 (SEQ ID NO: 193) [19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (SEQ ID NO: 194) [19CD]-isoGlu-RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.s- ub.2 (SEQ ID NO: 195) [19CD]-isoGlu-RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGTP-NH.s- ub.2 (SEQ ID NO: 196) [19CD]-isoGlu-RCQTATCATDRLA-Aad-FLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.- sub.2 (SEQ ID NO: 197) [19CD]-isoGlu-RCQTATCATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2

wherein [19CD] represents [19-carboxynonadecanoyl]; and pharmaceutically acceptable salts and solvates thereof.

[0044] Any of the sequences or compounds described above may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7 of the amino acid sequence (numbered from N- to C-terminus, and corresponding to the cysteine residues present at positions 2 and 7 of human amylin). In general, it may be desirable that compounds possess such a disulphide bridge at the time of administration to a subject, but it will be understood that the invention extends to compounds having the specified amino acid sequences before formation of the disulphide. The presence of the disulphide may be indicated by parentheses ( ) following each relevant cysteine residue in the sequence. All of the generic and specific formulae provided above should be construed accordingly to include this possibility. Thus, for example, Formulae I, II and III may be shown as follows:

TABLE-US-00008 (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; (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; and (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;

while the specific compounds listed above may be designated as follows:

TABLE-US-00009 (SEQ ID NO: 102) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 1) (SEQ ID NO: 103) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd.2) (SEQ ID NO: 104) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLANFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 3) (SEQ ID NO: 105) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSINVGSNT-Apr-NH.sub.2 (Compd. 4) (SEQ ID NO: 106) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSINVGSNT-Apr-NH.sub.2 (Compd. 5) (SEQ ID NO: 107) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 6) (SEQ ID NO: 108) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 7) (SEQ ID NO: 109) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 8) (SEQ ID NO: 110) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 9) (SEQ ID NO: 111) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (Compd. 10) (SEQ ID NO: 112) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-Hyp- (Compd. 11) (SEQ ID NO: 113) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (Compd. 12) (SEQ ID NO: 114) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 13) (SEQ ID NO: 115) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 14) (SEQ ID NO: 116) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 15) (SEQ ID NO: 117) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 16). (SEQ ID NO: 118) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLANFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 17) (SEQ ID NO: 119) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 18) (SEQ ID NO: 120) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLKRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 19) (SEQ ID NO: 121) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRSVF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 20) (SEQ ID NO: 122) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRVSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 21) (SEQ ID NO: 123) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 22) (SEQ ID NO: 124) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATDRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSDTP-NH.sub.2 (Compd. 23) (SEQ ID NO: 125) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 24) (SEQ ID NO: 126) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSNTP-NH.sub.2 (Compd. 25) (SEQ ID NO: 127) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 26) (SEQ ID NO: 128) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSDTP-NH.sub.2 (Compd. 27) (SEQ ID NO: 129) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 28) (SEQ ID NO: 130) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 29) (SEQ ID NO: 131) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 30) (SEQ ID NO: 132) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 31) (SEQ ID NO: 133) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (Compd. 32) (SEQ ID NO: 134) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (Compd. 33) (SEQ ID NO: 135) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 34) (SEQ ID NO: 136) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 35) (SEQ ID NO: 137) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 36) (SEQ ID NO: 138) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 37) (SEQ ID NO: 139) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 38) (SEQ ID NO: 140) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFTP-NH.sub.2 (Compd. 39) (SEQ ID NO: 141) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFTP-NH.sub.2 (Compd. 40) (SEQ ID NO: 142) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 41) (SEQ ID NO: 143) [19CD]-isoGlu-R-C( )-GTAT-C(

)-ATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (Compd. 42) (SEQ ID NO: 144) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST- Hyp-NH.sub.2 (Compd. 43) (SEQ ID NO: 145) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2 (Compd. 44) (SEQ ID NO: 146) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Apr-NH.sub.2 (Compd. 45) (SEQ ID NO: 147) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 46) (SEQ ID NO: 148) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-TP-NH.sub.2 (Compd. 47) (SEQ ID NO: 149) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2 (Compd. 48) (SEQ ID NO: 150) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 49) (SEQ ID NO: 151) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFL-Aad-RSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 50) (SEQ ID NO: 152) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2 (Compd. 51) (SEQ ID NO: 153) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 52) (SEQ ID NO: 154) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (Compd. 53) (SEQ ID NO: 155) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 54) (SEQ ID NO: 156) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 55) (SEQ ID NO: 157) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 56) (SEQ ID NO: 158) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 57) (SEQ ID NO: 159) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 58) (SEQ ID NO: 160) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSNT-Hyp-NH.sub.2 (Compd. 59) (SEQ ID NO: 161) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSDT-Hyp-NH.sub.2 (Compd. 60) (SEQ ID NO: 162) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 61) (SEQ ID NO: 163) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 62) (SEQ ID NO: 164) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 63) (SEQ ID NO: 165) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 64) (SEQ ID NO: 166) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 65) (SEQ ID NO: 167) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 66) (SEQ ID NO: 168) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 67) (SEQ ID NO: 169) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 68) (SEQ ID NO: 170) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 69) (SEQ ID NO: 171) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 70) (SEQ ID NO: 172) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 71) (SEQ ID NO: 173) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 72) (SEQ ID NO: 174) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2 (Compd. 73) (SEQ ID NO: 175) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2 (Compd. 74) (SEQ ID NO: 176) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (Compd. 75) (SEQ ID NO: 177) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (Compd. 76) (SEQ ID NO: 178) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 77) (SEQ ID NO: 179) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 78) (SEQ ID NO: 180) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 79) (SEQ ID NO: 181) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGTP-NH.sub.2 (Compd. 80) (SEQ ID NO: 182) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 81) (SEQ ID NO: 183) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTTP-NH.sub.2 (Compd. 82) (SEQ ID NO: 184) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2 (Compd. 83)

(SEQ ID NO: 185) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 84) (SEQ ID NO: 186) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 85) (SEQ ID NO: 187) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 86) (SEQ ID NO: 188) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 87) (SEQ ID NO: 189) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 88) (SEQ ID NO: 190) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 89) (SEQ ID NO: 191) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 90) (SEQ ID NO: 192) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 91) (SEQ ID NO: 193) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 92) (SEQ ID NO: 194) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 93) (SEQ ID NO: 195) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGTP-NH.sub.2 (Compd. 94) (SEQ ID NO: 196) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLA-Aad-FLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 95) (SEQ ID NO: 197) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 96)

wherein [19CD] represents [19-carboxynonadecanoyl]; and pharmaceutically acceptable salts and solvates thereof.

[0045] In certain embodiments, the amylin analogue of the invention is not a compound having the formula:

R.sup.1--Z--R.sup.2

wherein R.sup.1 is hydrogen, C.sub.1-4 acyl, benzoyl or C.sub.1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R.sup.2 is OH or NHR.sup.3, wherein R.sup.3 is hydrogen or C.sub.1-3-alkyl; and Z is an amino acid sequence selected from the group consisting of:

TABLE-US-00010 (SEQ ID NO: 99) RCNTATCATQRLADFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 6) RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 7) RCNTATCATQRLANFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSE TP (SEQ ID NO: 100) RCNTATCATQRLADFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSTNVG SNT-Apr (SEQ ID NO: 101) RCNTATCATQRLAHFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSTNVG SNT-Apr (SEQ ID NO: 8) RCGTATCATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 9) RCGTATCATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 10) RCGTATCATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN T-Hyp (SEQ ID NO: 11) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSS T-Hyp (SEQ ID NO: 12) RCGTATCATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSF T-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)-LSSTEVGSG T-Hyp (SEQ ID NO: 16) RCNTATCATQRLAHFLHRF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP (SEQ ID NO: 17) RCGTATCATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP and (SEQ ID NO: 18) RCNTATCATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSN TP

or a pharmaceutically acceptable salt or solvate thereof.

[0046] For example, in such embodiments, the compound is not:

TABLE-US-00011 (SEQ ID NO: 102) [19CD]-isoGlu-RCNTATCATQRLADFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 103) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 104) [19CD]-isoGlu-RCNTATCATQRLANFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 105) [19CD]-isoGlu-RCNTATCATQRLADFLHRSSNNF-Gly(Me)- A-Ile(Me)-LSSINVGSNT-Apr-NH.sub.2 (SEQ ID NO: 106) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSNNF-Gly(Me)- A-Ile(Me)-LSSINVGSNT-Apr-NH.sub.2 (SEQ ID NO: 107) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (SEQ ID NO: 108) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (SEQ ID NO: 109) [19CD]-isoGlu-RCGTATCATERLAHFLERSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (SEQ ID NO: 110) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (SEQ ID NO: 111) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (SEQ ID NO: 112) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2 (SEQ ID NO: 113) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (SEQ ID NO: 114) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (SEQ ID NO: 115) [19CD]-isoGlu-RCNTATCATQRLAHFLHRF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2 (SEQ ID NO: 116) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2 or (SEQ ID NO: 117) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2;

(wherein [19CD] represents [19-carboxynonadecanoyl]) and pharmaceutically acceptable salts and solvates thereof; or any such compounds comprising an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7 of the amino acid sequence.

[0047] The invention further provides a composition comprising an amylin analogue as described above. The composition may be a pharmaceutical composition, and may comprise a pharmaceutically acceptable carrier, excipient or vehicle.

[0048] The invention further provides a method for the synthesis of an amylin analogue as described above. The method may comprise the steps of synthesising the peptide by solid-phase or liquid-phase methodology, and optionally isolating and/or purifying the final product. The method may further comprise the step of forming a disulphide bond between the thiol groups of the cysteine side chains at positions 2 and 7.

[0049] The present invention further provides an amylin analogue of the invention for use in a method of medical treatment.

[0050] The amylin analogues are useful, inter alia, in the reduction of food intake, promotion of weight loss, and inhibition or reduction of weight gain. As a result, they may be used for treatment of a variety of conditions, diseases, or disorders in a subject, including, but not limited to, obesity and various obesity-related conditions, diseases, or disorders, such as diabetes (e.g. type 2 diabetes), hypertension, dyslipidemia, sleep apnea and cardiovascular disease. The subject may be affected by obesity accompanied by at least one weight-related co-morbid condition, such as diabetes (e.g. type 2 diabetes), hypertension, dyslipidemia, sleep apnea and cardiovascular disease. It will be understood that the amylin analogues may thus be administered to subjects affected by conditions characterised by inadequate control of appetite or otherwise over-feeding, such as binge-eating disorder and Prader-Willi syndrome. It will be clear that the analogues can be used for treatment of combinations of the conditions described.

[0051] Thus, the invention provides an amylin analogue of the invention for use in a method of treating, inhibiting or reducing weight gain, promoting weight loss and/or reducing excess body weight. Treatment may be achieved, for example, by control of appetite, feeding, food intake, calorie intake and/or energy expenditure.

[0052] The invention also provides an amylin analogue of the invention for use in a method of treating obesity as well as associated diseases, disorders and health conditions, including, but not limited to, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease and obesity-induced sleep apnea and respiratory problems, degeneration of cartilage, osteoarthritis, and reproductive health complications of obesity or overweight such as infertility. The subject may be affected by obesity accompanied by at least one weight-related co-morbid condition, such as diabetes (e.g. type 2 diabetes), hypertension, dyslipidemia, sleep apnea and cardiovascular disease.

[0053] The invention also provides an amylin analogue of the invention for use in 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"; including non-alcoholic fatty liver disease (NAFLD), which itself includes non-alcoholic steatohepatitis (NASH)), 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.

[0054] The invention also provides an amylin analogue of the invention for use in a method of lowering circulating LDL levels and/or increasing HDL/LDL ratio.

[0055] Effects of amylin analogues on these conditions may be mediated in whole or in part via an effect on body weight, or may be independent thereof.

[0056] The invention further provides use of an amylin analogue of the invention in the manufacture of a medicament for treating, inhibiting or reducing weight gain, promoting weight loss and/or reducing excess body weight.

[0057] The invention also provides use of an amylin analogue of the invention in the manufacture of a medicament for treating obesity as well as associated diseases, disorders and health conditions, including, but not limited to, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease and obesity-induced sleep apnea and respiratory problems, degeneration of cartilage, osteoarthritis, and reproductive health complications of obesity or overweight such as infertility. The subject may be affected by obesity accompanied by at least one weight-related co-morbid condition, such as diabetes (e.g. type 2 diabetes), hypertension, dyslipidemia, sleep apnea and cardiovascular disease.

[0058] The invention also provides use of an amylin analogue of the invention in the manufacture of a medicament for the 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"; including non-alcoholic fatty liver disease (NAFLD), which itself includes non-alcoholic steatohepatitis (NASH)), 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.

[0059] The invention also provides use of an amylin analogue of the invention in the manufacture of a medicament for lowering circulating LDL levels and/or increasing HDL/LDL ratio.

[0060] The invention further provides a method of treating, inhibiting or reducing weight gain, promoting weight loss and/or reducing excess body weight in a subject, comprising administering a therapeutically effective amount of an amylin analogue of the invention to the subject.

[0061] The invention also provides a method of treating obesity as well as associated diseases, disorders and health conditions, including, but not limited to, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease and obesity-induced sleep apnea and respiratory problems, degeneration of cartilage, osteoarthritis, and reproductive health complications of obesity or overweight such as infertility in a subject, comprising administering a therapeutically effective amount of an amylin analogue of the invention to the subject. The subject may be affected by obesity accompanied by at least one weight-related co-morbid condition, such as diabetes (e.g. type 2 diabetes), hypertension, dyslipidemia, sleep apnea and cardiovascular disease.

[0062] The invention also provides 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"; including non-alcoholic fatty liver disease (NAFLD), which itself includes non-alcoholic steatohepatitis (NASH)), 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, comprising administering a therapeutically effective amount of an amylin analogue of the invention to the subject.

[0063] The invention further provides a method of lowering circulating LDL levels and/or increasing HDL/LDL ratio in a subject, comprising administering a therapeutically effective amount of an amylin analogue of the invention to the subject.

[0064] The invention further provides the use of an amylin analogue as described above in a method of cosmetic (i.e. non-therapeutic) weight loss. It will be understood that references to therapeutic uses of amylin analogues and methods comprising administration of amylin analogues may equally be taken to encompass uses and administration of such compositions.

[0065] Further aspects and embodiments of the present invention will become apparent from the disclosure below.

DETAILED DESCRIPTION OF THE INVENTION

[0066] Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature employed herein in connection with techniques of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, is that well known and commonly used in the art.

[0067] 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.

[0068] 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 component, or of a stated group of integers or components, but not the exclusion of any other integer or component or group of integers or components.

[0069] The singular forms "a," "an," and "the" include the plurals unless the context clearly dictates otherwise.

[0070] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0071] The terms "patient", "subject," and "individual" may be used interchangeably and may refer to either a human or a non-human animal. Subjects are typically mammals, including humans, non-human primates (including great apes, Old World monkeys and New World monkeys), livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats).

[0072] As used herein, the term "pharmaceutically acceptable salt" is intended to indicate a salt which is not harmful to a patient or subject to which the salt in question is administered. It may suitably be a salt chosen, e.g., among acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts. Examples of basic salts include salts where the cation is selected among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type N(R.sub.1)(R.sup.2)(R.sup.3)(R.sup.4).sup.+, where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently will typically designate hydrogen, optionally substituted C.sub.1-6-alkyl or optionally substituted C.sub.2-6-alkenyl. Examples of relevant C.sub.1-6-alkyl groups include methyl, ethyl, 1-propyl and 2-propyl groups. Examples of C.sub.2-6-alkenyl groups of possible relevance include ethenyl, 1-propenyl and 2-propenyl. Other examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., USA, 1985 (and more recent editions thereof), in the "Encyclopaedia of Pharmaceutical Technology", 3.sup.rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977).

[0073] 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 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.

[0074] The term "agonist" as employed in the context of the invention refers to a substance that activates the receptor type in question, typically by binding to it (i.e. as a ligand).

[0075] Each embodiment of the invention described herein may be taken alone or in combination with one or more other embodiments of the invention.

[0076] Throughout the present specification, unless naturally occurring amino acids are referred to by their full name (e.g. alanine, arginine, etc.), they are designated by their conventional three-letter or single-letter abbreviations (e.g. Ala or A for alanine, Arg or R for arginine, etc.). In the case of certain less common or non-naturally occurring amino acids (i.e. amino acids other than the 20 encoded by the standard mammalian genetic code), unless they are referred to by their full name (e.g. sarcosine, ornithine, etc.), frequently employed three- or four-character codes are employed for residues thereof, including Orn (ornithine, i.e. 2,5-diaminopentanoic acid), Aib (.alpha.-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dap (2,3-diaminopropanoic acid), Har (homoarginine), .gamma.-Glu (.gamma.-glutamic acid), Gaba (.gamma.-aminobutanoic acid), .beta.-Ala (i.e. 3-aminopropanoic acid), 8Ado (8-amino-3,6-dioxaoctanoic acid).

[0077] Unless otherwise indicated, reference is made to the L-isomeric forms of the amino acids in question.

[0078] Additional abbreviations include the following: [0079] Gly(Me): N-methylglycine [also known as sarcosine (Sar)] [0080] Ile(Me): N-methylisoleucine [0081] Aad: 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2-aminohexanedioic acid], also known as homo-glutamic acid [0082] Apr: 4-aminoproline, e.g. (2S,4R)-4-aminoproline [0083] [also denoted (4R)-4-amino-L-proline] [0084] Hyp: 4-hydroxyproline, e.g. (2S,4R)-4-hydroxyproline [0085] [also denoted (4R)-4-hydroxy-L-proline]

[0086] The term "therapeutically effective amount" as used herein in the context of the above-described methods of treatment or other therapeutic interventions according to the invention refers to an amount that is sufficient to cure, ameliorate, alleviate or partially arrest the clinical manifestations of the particular disease, disorder or condition that is the object of the treatment or other therapeutic intervention in question e.g. as measured by established clinical endpoints or other biomarkers (established or experimental). A therapeutically relevant amount may be determined empirically by one skilled in the art based on the indication being treated or prevented and the subject to whom the therapeutically relevant amount is being administered. For example, the skilled worker may measure one or more of the clinically relevant indicators of bioactivity described herein, e.g. plasma lipid levels, blood glucose levels or insulin release. The skilled worker may determine a clinically relevant amount through in vitro or in vivo measurements. Other exemplary measures include weight gain, weight loss, and change in blood pressure.

[0087] An amount adequate to accomplish any or all of these effects is defined as a therapeutically effective amount. The administered amount and the method of administration can be tailored to achieve optimal efficacy. An amount effective for a given purpose will depend, inter alia, on the severity of the disease, disorder or condition that is the object of the particular treatment or other therapeutic intervention, on the body weight and general condition of the subject in question, on diet, on possible concurrent medication, and on other factors well known to those skilled in the medical arts. Determination of an appropriate dosage size and dosing regimen most appropriate for administration of a peptide or pharmaceutically acceptable salt or solvate thereof according to the invention to a human may be guided by the results obtained by the present invention, and may be confirmed in properly designed clinical trials. 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 well known to the skilled person.

[0088] The terms "treatment" and grammatical variants thereof (e.g. "treated", "treating", "treat") as employed in the present context refer to an approach for obtaining beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e. not worsening) of 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" can also mean prolonging survival relative to expected survival time if not receiving treatment. A subject (e.g. a human) in need of treatment may thus be a subject already afflicted with the disease or disorder in question. The term "treatment" includes inhibition or reduction of an increase in severity of a pathological state or symptoms (e.g. weight gain or hyperglycemia) relative to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant disease, disorder or condition.

[0089] The terms "prevention" and grammatical variants thereof (e.g., "prevented", "preventing", "prevent") as employed in the present context refer to an approach for hindering or preventing the development of, or altering the pathology of, a condition, disease or disorder. Accordingly, "prevention" may refer to prophylactic or preventive measures. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, prevention or slowing of symptoms, progression or development of a disease, whether detectable or undetectable. A subject (e.g. a human) in need of "prevention" may thus be a subject not yet afflicted with the disease or disorder in question. The term "prevention" thus includes inhibiting or slowing the onset of disease relative to the absence of treatment, and is not necessarily meant to imply permanent prevention of the relevant disease, disorder or condition.

Synthesis of Amylin Analogues

[0090] The invention further provides a method of synthesis of an amylin analogue of the invention. The amylin analogues (which may also be referred to as compounds or peptides) may suitably be manufactured by standard synthetic methods. Thus, the peptides may be synthesized by, e.g., methods comprising synthesizing the peptide by standard solid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and optionally isolating and purifying the final peptide product. 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 (2.sup.nd edition, 2002) and the synthesis examples herein. The method may further comprise the step of forming a disulfide bond between the thiol groups of the cysteine side chains at positions 2 and 7, e.g. by oxidative cyclisation. In the case of solid phase synthesis, cyclisation may be performed in situ on the solid phase (e.g. resin), i.e. before removal of the peptide from the solid phase.

C.sub.1-4 Acyl Groups

[0091] C.sub.1-4 acyl groups that may be present as a group R.sup.1 in the context of compounds of the present invention include formyl (i.e. methanoyl), acetyl (i.e. ethanoyl), propanoyl, 1-butanoyl and 2-methylpropanoyl groups.

C.sub.1-4 Alkyl Groups

[0092] C.sub.1-4 alkyl groups that may be present as a group R.sup.1 in the context of compounds of the present invention include, but are not limited to, C.sub.1-3 alkyl groups, such as methyl, ethyl, 1-propyl or 2-propyl.

C.sub.1-3 Alkyl Groups

[0093] C.sub.1-3 alkyl groups that may be present as a group R.sup.3 in the context of compounds of the present invention include methyl, ethyl, 1-propyl and 2-propyl.

Half-Life Extending Moieties M

[0094] As described herein, the N-terminal moiety R.sup.1 in a compound of the invention may be a half-life extending moiety (sometimes referred to in the literature as, inter alia, a duration enhancing moiety or albumin binding moiety), optionally linked (covalently attached) to the peptide moiety Z via a linker moiety L. Among suitable half-life extending moieties are certain types of lipophilic substituents. Without wishing to be bound by any particular theory, it is thought that such lipophilic substituents (and other classes of half-life extending moieties) bind albumin in the blood stream, thereby shielding the compound of the invention from renal filtration as well as enzymatic degradation and thus possibly enhancing the half-life of the compound in vivo. The lipophilic substituent may also modulate the potency of the compound as an agonist to the amylin (calcitonin) receptor.

[0095] The lipophilic substituent may be attached to the N-terminal amino acid residue or to the linker L via an ester, a sulfonyl ester, a thioester, an amide, an amine or a sulfonamide. Accordingly it will be understood that preferably the lipophilic substituent includes an acyl group, a sulfonyl group, an N atom, an O atom or an S atom which forms part of the ester, sulfonyl ester, thioester, amide, amine or sulfonamide. Preferably, an acyl group in the lipophilic substituent forms part of an amide or ester with the amino acid residue or the linker.

[0096] The lipophilic substituent may comprise a hydrocarbon chain having from 10 to 24 C atoms, e.g. from 14 to 22 C atoms, e.g. from 16 to 20 C atoms. Preferably it has at least 14 C atoms, and preferably has 20 C atoms or fewer. For example, the hydrocarbon chain may contain 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The hydrocarbon chain may be linear or branched, and may be saturated or unsaturated. Furthermore, it can include a functional group at the end of the lipophilic chain, e.g. a carboxylic acid group 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 N-terminal amino acid residue of the peptide moiety Z or to the linker L, for example an acyl group, a sulfonyl group, an N atom, an O atom or an S atom.

[0097] Most preferably, the hydrocarbon chain is substituted with an acyl group, and accordingly the hydrocarbon chain may be part of an alkanoyl group, for example a dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl or eicosanoyl group. Examples of functionalized hydrocarbon chains are 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl and 19-carboxy-nonadecanoyl.

[0098] As mentioned above, a lipophilic substituent M may be linked to the N-terminal amino acid residue of Z via a linker L. In embodiments, the linker moiety L may itself comprise one, two, three or more linked sub-moieties L.sup.1, L.sup.2, L.sup.3, . . . etc. When the linker L comprises only one such moiety, it is attached to the lipophilic substituent and to the N-terminal amino acid residue of Z. The linker may then be attached to the lipophilic substituent and to the N-terminal amino acid residue of Z independently by means of an ester, a sulfonyl ester, a thioester, an amide, an amine or a sulfonamide bond. Accordingly, it may include two moieties independently selected from acyl, sulfonyl, an N atom, an O atom and an S atom. The linker may consist of a linear or branched C.sub.1-10 hydrocarbon chain or more preferably a linear C.sub.1-5 hydrocarbon chain. Furthermore the linker can be substituted with one or more substituents selected from C.sub.1-6 alkyl, amino C.sub.1-6 alkyl, hydroxy C.sub.1-6 alkyl and carboxy C.sub.1-6 alkyl.

[0099] In some embodiments the linker may be, for example, a residue of any naturally occurring or non-naturally occurring amino acid. For example, the linker may be a residue of Gly, Pro, Ala, Val, Leu, lie, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, .alpha.-Glu, .gamma.-Glu, .epsilon.-Lys, Asp, .beta.-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 8Ado (i.e. 8-amino-3,6-dioxaoctanoyl).

[0100] References to .gamma.-Glu, .epsilon.-Lys, and .beta.-Asp indicate residues of amino acids which participate in bonds via their side chain carboxyl or amine functional groups. Thus .gamma.-Glu, and .beta.-Asp participate in bonds via their amino and side chain carboxyl groups, while .epsilon.-Lys participates via its carboxyl and side chain amino groups.

[0101] In certain embodiments, the linker is a residue of Glu, .gamma.-Glu, E-Lys, .beta.-Ala, 4-aminobutanoyl, 8-aminooctanoyl or 8Ado. In the context of the present invention, .gamma.-Glu and isoGlu are used interchangeably.

[0102] An example of a lipophilic substituent comprising a lipophilic moiety M and linker L is shown in the formula below:

##STR00001##

[0103] Here, the backbone nitrogen of an Arg residue is covalently attached to a .gamma.-Glu linker (L) via an amide linkage. A 19-carboxy-nonadecanoyl group is covalently attached to the .gamma.-Glu linker via an amide linkage. This combination of lipophilic moiety and linker, attached to an Arg residue, may be referred to by the shorthand notation [19CD]-isoGlu-R, e.g. when shown in formulae of specific compounds.

[0104] 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).

[0105] The hydrocarbon chain in a lipophilic substituent may be further substituted. For example, it may be further substituted with up to three substituents selected from NH.sub.2, OH and COOH. If the hydrocarbon chain is further substituted, it is preferably further substituted with only one substituent. Alternatively or additionally, the hydrocarbon chain may include a cycloalkane or heterocycloalkane moiety, for example as shown below:

##STR00002##

[0106] In some embodiments, the cycloalkane or heterocycloalkane moiety is a six-membered ring, e.g. a piperidine ring.

[0107] In alternative embodiments of the present invention, the N-terminal amino acid of Z in a compound of the invention may be linked (covalently attached) to a biotinylic substituent, optionally via a linker moiety L. Without wishing to be bound by any particular theory, it is likewise believed that such biotinylic substituents bind to albumin in the blood stream, thereby shielding the compound of the invention from enzymatic degradation and thus possibly enhancing the half-life of the compound in vivo. A linker, when present, may provide spacing between the peptide moiety Z and the biotinylic substituent.

[0108] The biotinylic substituent may be attached to the N-terminal amino acid residue or to the linker via an maleimide ester bond, a sulfonyl ester bond, a thioester bond, an amide bond, an amine bond or a sulfonamide bond. Accordingly it will be understood that the biotinylic substituent preferably comprises an maleimido group, an acyl group, a sulfonyl group, an N atom, an O atom or an S atom which forms part of the ester, sulfonyl ester, thioester, amide, amine or sulfonamide bond in question.

[0109] Examples of biotinylic substituents may include

##STR00003##

[0110] Biotin is known as Vitamin H or Coenzyme R, and is a water-soluble B-complex vitamin (vitamin B7). It has been shown to increase oral uptake of certain drugs.

Efficacy of Compounds

[0111] The compounds of the invention are amylin receptor agonists, i.e. they are capable of binding to, and inducing signalling by, one or more receptors or receptor complexes regarded as physiological receptors for human amylin. These include the human calcitonin receptor hCTR2, as well as complexes comprising the human calcitonin receptor hCTR2 and at least one of the human receptor activity modifying proteins designated hRAMP1, hRAMP2 and hRAMP3. Complexes between hCTR2 and hRAMP1, hRAMP2 and hRAMP3 are designated hAMYR1, hAMYR2 and hAMYR3 (i.e. human amylin receptors 1, 2 and 3) respectively.

[0112] Without wishing to be bound by theory, a compound may be considered an amylin receptor agonist if it has agonist activity at one or more of hAMYR1, hAMYR2 and hAMYR3, e.g. against hAMYR1 and/or hAMYR3, e.g. at hAMYR3.

[0113] Typically an amylin receptor agonist will also have agonist activity at hCTR2 when expressed in the absence of hRAMP1, hRAMP2 and hRAMP3. Typically, the agonist will have activity at hCTR2 (when expressed in the absence of hRAMP1, hRAMP2 and hRAMP3) which is less than 10-fold higher than its activity at any one of hAMYR1, hAMYR2 and hAMYR3 (i.e. its activity at all of these receptors) in a comparable assay. Agonist activity at hCTR2 may be less than 5-fold higher than agonist activity at hAMYR1, hAMYR2 and hAMYR3, substantially equal to (e.g. +/-10%) agonist activity at hAMYR1, hAMYR2 and hAMYR3, or less than agonist activity at hAMYR1, hAMYR2 and hAMYR3. In this regard, it may be sufficient just to compare activity between hCTR2 and hAMYR3.

[0114] The ability to induce cAMP formation (i.e. to induce adenylate cyclase activity) as a result of binding to the relevant receptor or receptor complex is typically regarded as indicative of agonist activity. Other intracellular signaling pathways or events may also be used as read-outs for amylin receptor agonist activity. These may include calcium release, .beta.-arrestin recruitment, receptor internalization, kinase activation or inactivation, lipase activation, inositol phosphate release, diacylglycerol release or nuclear transcription factor translocation.

[0115] A suitable comparable assay format would utilize cells which express hCTR2 and which differ only in their expression of hRAMP1, 2 and 3. For example, a "base" cell line which does not express any of hCTR2, hRAMP1, hRAMP2 and hRAMP3 may be engineered to generate cells which express (i) hCTR2, and (ii) one of hAMYR1, hAMYR2 and hAMYR3 (i.e. hCTR2 plus one of hRAMP1, hRAMP2 and hRAMP3), e.g. hAMYR3. The base cells will typically be mammalian cells and may be primate cells. They may be non-human primate cells. Preferably the base cell does not express any of CTR2, RAMP1, RAMP2 or RAMP3 (whether human, or native to the base cell if the base cell is non-human). The base cells may be fibroblast cells. Suitable non-human fibroblast base cells include COS7 cells, from African green monkey, which do not express native CTR2 or RAMPs.

[0116] Comparative activity may be measured by any suitable means, such as via determination of EC.sub.50 values as described below. It will be apparent that the same biological read-out must be for both receptor types.

[0117] Compounds of the present invention may exhibit a number of advantageous properties in relation to human amylin and existing analogues thereof, such as pramlinitide, IAPP-GI, and analogues described in WO2012/168430, WO2012/168431 and WO2012/168432. As compared to human amylin or any of those analogues, compounds of the invention may, for example, exhibit improved efficacy (e.g., in the form of improved in vitro activity or potency at one or more of the receptors hCTR2, hAMRY1, hAMRy2 or hAMYR3. Additionally or alternatively, compounds of the invention may exhibit improved solubility in aqueous media, especially at pH values in the range from 4 to 7.5, or at a range of pH values across that range. Moreover, compounds of the present invention may additionally or alternatively exhibit reduced tendency to undergo fibrillation in pharmaceutically relevant aqueous media, especially at pH values in the range from 4 to 7, or at a range of pH values across that range. Furthermore, compounds of the present invention may additionally or alternatively exhibit improved chemical stability (i.e. reduced tendency to undergo chemical degradation) in aqueous media, especially at pH values in the range from 4 to 9, or at a range of pH values across that range.

[0118] Compounds of the invention may thus be well suited for formulation in acidic media (e.g. pH 4) and in neutral or near-neutral media (e.g. pH 7 or 7.4). In contrast to pramlintide, for example, which generally exhibits poor chemical stability and rapid fibrillation in pharmaceutically relevant aqueous media at neutral pH, compounds of the invention may be thus well suited for co-formulation with, for example, insulin, various insulin analogues and/or other therapeutic (e.g. anti-diabetic or anti-obesity) agents that require a neutral or near-neutral formulation pH.

[0119] In general it is preferred to use a biological assay which measures intracellular signalling caused by binding of the compound to the relevant receptor, as discussed above. Activation of the calcitonin/amylin receptor by compounds of the invention (which behave as agonists of the receptor) induces cAMP formation and activation of other intracellular signaling pathways and events. Thus, production of cAMP or any other suitable parameter in suitable cells expressing the receptor can be used to monitor agonist activity towards the receptor.

[0120] The skilled person will be aware of suitable assay formats, and examples are provided below. For example, the assays may make use of the human calcitonin receptor (hCTR2) having primary accession number GI: 4502547 (NP_001733.1) or the hAMYR3 receptor (see Example 2, below). Where sequences of precursor proteins are referred to, it should be understood that assays may make use of the mature protein, lacking the signal sequence.

[0121] 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 [hCTR2] lower than the EC.sub.50 [hCTR2] of native amylin, or lower than that of pramlintide, in a particular assay may be considered to have higher potency or activity at the receptor than amylin, or higher than that of pramlintide, respectively.

[0122] In some embodiments of compounds of the present invention, the EC.sub.50 towards hCTR2 is below 1.4 nM.

[0123] In some embodiments of compounds of the present invention, the EC.sub.50 towards hCTR2 is below 0.8 nM.

[0124] In some embodiments of compounds of the present invention, the EC.sub.50 towards hCTR2 is below 0.4 nM.

[0125] In some embodiments of compounds of the present invention, the EC.sub.50 towards hCTR2 is below 0.2 nM.

[0126] In some embodiments of compounds of the present invention, the EC.sub.50 towards hCTR2 is below 0.1 nM.

[0127] An EC.sub.50 towards hCTR2 of approximately 0.2 (+/-10%) or below may be desirable. The EC.sub.50 at hCTR2 may be an indication of the effect of a compound on food intake, weight gain and/or weight loss. Compounds with lower EC.sub.50 values at hCTR2 may have a greater effect on these parameters.

[0128] In some embodiments of compounds of the present invention, the EC.sub.50 towards hAMYR3 is below 1 nM.

[0129] In some embodiments of compounds of the present invention, the EC.sub.50 towards hAMYR3 is below 0.5 nM.

[0130] In some embodiments of compounds of the present invention, the EC.sub.50 towards hAMYR3 is below 0.4 nM.

[0131] In some embodiments of compounds of the present invention, the EC.sub.50 towards hAMYR3 is below 0.3 nM.

[0132] In some embodiments of compounds of the present invention, the EC.sub.50 towards hAMYR3 is below 0.2 nM.

[0133] For example, the EC.sub.50 at hCTR2 (when expressed in the absence of hRAMP1, hRAMP2 and hRAMP3) may be less than 10-fold lower than the EC.sub.50 at any or all of hAMYR1, hAMYR2 and hAMYR3, e.g. at hAMYR3.

[0134] The EC.sub.50 at hCTR2 (when expressed in the absence of hRAMP1, hRAMP2 and hRAMP3) may be less than 5-fold lower than the EC.sub.50 at any or all of hAMYR1, hAMYR2 and hAMYR3, e.g. at hAMYR3.

[0135] The EC.sub.50 at hCTR2 (when expressed in the absence of hRAMP1, hRAMP2 and hRAMP3) may be substantially equal to (e.g. +/-50%) the EC.sub.50 at any or all of hAMYR1, hAMYR2 and hAMYR3, e.g. at hAMYR3.

[0136] The EC.sub.50 at hCTR2 (when expressed in the absence of hRAMP1, hRAMP2 and hRAMP3) may be higher than the EC.sub.50 at any or all of hAMYR1, hAMYR2 and hAMYR3, e.g. at hAMYR3.

[0137] Such assays may be performed under the conditions described in Examples 2 and 3.

[0138] Additionally or alternatively, compounds of the invention may show excellent solubility. For example, they may show solubility of greater than or equal to 1 mg/ml at pH 4, pH 5, pH 6, pH 7 and/or pH 7.5, e.g. at 25.degree. C., e.g. under the conditions described in Example 4.

[0139] Additionally or alternatively, compounds of the invention may show excellent resistance to fibrillation. For example, they may show no detectable fibrillation after 96 hours at pH 4.0 and/or pH 7.0, e.g. at 40.degree. C., e.g. under the conditions described in Example 5.

[0140] Additionally or alternatively, compounds of the invention may show excellent chemical stability, i.e. resistance to degradation in solution. For example, they may retain at least 70% purity, at least 75% purity, at least 80% purity, at least 85% purity, at least 90% purity, or at least 95% purity after incubation at pH 4, pH 7.5, and/or pH 9 at 40.degree. C. for 7 days, e.g. under the conditions described in Example 6.

Therapeutic Uses

[0141] The compounds of the invention are useful, inter alia, in the reduction of food intake, promotion of weight loss, and inhibition or reduction of weight gain. They may therefore provide an attractive treatment option for, inter alia, obesity and metabolic diseases caused, characterised by, or associated with, excess body weight.

[0142] Thus, the compounds may be used in a method of treating, inhibiting or reducing weight gain, promoting weight loss, reducing food intake, and/or reducing excess body weight. Treatment may be achieved, for example, by control of appetite, feeding, food intake, calorie intake and/or energy expenditure.

[0143] The compounds may be used in a method of treating obesity as well as associated diseases, disorders and health conditions, including, but not limited to, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease and obesity-induced sleep apnea and respiratory problems, degeneration of cartilage, osteoarthritis, and reproductive health complications of obesity or overweight such as infertility.

[0144] The compounds may also be used in in 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"; including non-alcoholic fatty liver disease (NAFLD), which itself includes non-alcoholic steatohepatitis (NASH)), 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.

[0145] The compounds may also be useful in lowering circulating LDL levels and/or increasing HDL/LDL ratio.

[0146] The effects of the compounds described above may be mediated in whole or in part via an effect on body weight, or may be independent thereof.

[0147] Metabolic syndrome is characterized by a group of metabolic risk factors in one person. They include 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), insulin resistance and glucose intolerance, prothrombotic state (e.g. high fibrinogen or plasminogen activator inhibitor-1 in the blood), and proinflammatory state (e.g., elevated C-reactive protein in the blood).

[0148] Individuals with metabolic syndrome are at increased risk of coronary heart disease and other diseases related to other manifestations of arteriosclerosis (e.g. stroke and peripheral vascular disease). The dominant underlying risk factor for this syndrome appears to be abdominal obesity.

Pharmaceutical Compositions

[0149] The invention also extends to compositions, such as pharmaceutical compositions, comprising amylin analogues. As with all aspects of the invention, it is to be understood that reference to an amylin analogue encompasses reference to pharmaceutically acceptable salts and solvates.

[0150] The amylin analogues of the present invention may be formulated as pharmaceutical compositions which are suited for administration with or without storage, and which typically comprise a therapeutically effective amount of at least one peptide of the invention, together with a pharmaceutically acceptable carrier, excipient or vehicle.

[0151] 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", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., USA, 1985. For example, sterile saline and phosphate-buffered saline at slightly acidic or physiological pH may be used. Suitable pH-buffering agents may, e.g., be phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine or acetate (e.g. as sodium acetate), or mixtures thereof. The term further encompasses any carrier agents listed in the US Pharmacopeia for use in animals, including humans.

[0152] A pharmaceutical composition 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 or components. The unit dosage form may be presented as a packaged preparation, the package containing discrete quantities of the preparation, for example, packaged tablets, capsules or powders in vials or ampoules. The unit dosage form may also be, e.g., a capsule, cachet or tablet in itself, or it may be an appropriate number of any of these packaged forms. A unit dosage form may also be provided in single-dose injectable form, for example in the form of a pen device containing a liquid-phase (typically aqueous) composition. Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for e.g. oral, intravitreal, rectal, vaginal, nasal, topical, enteral or parenteral (including subcutaneous (sc), intramuscular (im), intravenous (iv), intradermal and transdermal) administration or administration by inhalation. 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 pharmaceutical formulation.

[0153] Subcutaneous or transdermal modes of administration may in some cases be suitable for peptides of the invention.

[0154] Further embodiments relate to devices, dosage forms and packages used to deliver the pharmaceutical formulations of the present invention. Thus, at least one peptide in a stable or preserved formulation or solution described herein can be administered to a patient in accordance with the present invention via a variety of delivery methods, including by sc or im injection, or by transdermal, pulmonary or transmucosal administration, or by implant, or by use of an osmotic pump, cartridge, micro-pump or other means recognized by a person of skill in the art.

[0155] Still further embodiments relate to oral formulations and oral administration. Formulations for oral administration may rely on the co-administration of adjuvants (e.g. resorcinols and/or nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to artificially increase the permeability of the intestinal walls, and/or the co-administration of enzymatic inhibitors (e.g. pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) or trasylol) to inhibit enzymatic degradation. The active constituent compound of a solid-type dosage form for oral administration can be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, or glyceride. These dosage forms can also contain other type(s) of additives, e.g. an inactive diluting agent, a lubricant (such as magnesium stearate), a paraben, a preserving agent (such as sorbic acid, ascorbic acid or alpha-tocopherol), an antioxidant (such as cysteine), a disintegrant, binder, thickener, buffering agent, pH-adjusting agent, sweetening agent, flavoring agent or perfuming agent.

Dosages

[0156] A typical dosage of an amylin analogue as employed in the context of the present invention may be in the range from about 0.0001 to about 100 mg/kg body weight per day, such as from about 0.0005 to about 50 mg/kg body weight per day, such as from about 0.001 to about 10 mg/kg body weight per day, e.g. from about 0.01 to about 1 mg/kg body weight per day, administered in one or more doses, such as from one to three doses. The exact dosage employed will depend, inter alia, on: the nature and severity of the disease or disorder to be treated, on the sex, age, body weight and general condition of the subject to be treated, on possible other, concomitant, disease or disorder that is undergoing or is to undergo treatment, as well as on other factors that will be known to a medical practitioner of skill in the art.

[0157] An amylin analogue of the invention may be administered continuously (e.g. by intravenous administration or another continuous drug administration method), or may be administered to a subject at intervals, typically at regular time intervals, depending on the desired dosage and the pharmaceutical composition selected by the skilled practitioner for the particular subject. Regular administration dosing intervals include, e.g., once daily, twice daily, once every two, three, four, five or six days, once or twice weekly, once or twice monthly, and the like. Such regular peptide administration regimens may, in certain circumstances such as, e.g., during chronic long-term administration, be advantageously interrupted for a period of time so that the medicated subject reduces the level of, or stops taking, the medication, often referred to as taking a "drug holiday." Drug holidays are useful for, e.g., maintaining or regaining sensitivity to a drug especially during long-term chronic treatment, or to reduce unwanted side-effects of long-term chronic treatment of the subject with the drug. The timing of a drug holiday depends on the timing of the regular dosing regimen and the purpose for taking the drug holiday (e.g., to regain drug sensitivity and/or to reduce unwanted side effects of continuous, long-term administration). In some embodiments, the drug holiday may be a reduction in the dosage of the drug (e.g. to below the therapeutically effective amount for a certain interval of time). In other embodiments, administration of the drug is stopped for a certain interval of time before administration is started again using the same or a different dosing regimen (e.g. at a lower or higher dose and/or frequency of administration). A drug holiday of the invention may thus be selected from a wide range of time-periods and dosage regimens. An exemplary drug holiday is two or more days, one or more weeks, or one or more months, up to about 24 months of drug holiday. So, for example, a regular daily dosing regimen with a peptide of the invention may, for example, be interrupted by a drug holiday of a week, or two weeks, or four weeks, after which time the preceding, regular dosage regimen (e.g. a daily or a weekly dosing regimen) is resumed. A variety of other drug holiday regimens are envisioned to be useful for administering peptides of the invention.

[0158] Thus, the peptide may be delivered via an administration regime which comprises two or more administration phases separated by respective drug holiday phases.

[0159] During each administration phase, the peptide is administered to the recipient subject in a therapeutically effective amount according to a pre-determined administration pattern. The administration pattern may comprise continuous administration of the drug to the recipient subject over the duration of the administration phase. Alternatively, the administration pattern may comprise administration of a plurality of doses of the peptide to the recipient subject, wherein said doses are spaced by dosing intervals.

[0160] A dosing pattern may comprise at least two doses per administration phase, at least five doses per administration phase, at least 10 doses per administration phase, at least 20 doses per administration phase, at least 30 doses per administration phase, or more.

[0161] Said dosing intervals may be regular dosing intervals, which may be as set out above, including once daily, twice daily, once every two, three, four, five or six days, once or twice weekly, once or twice monthly, or a regular and even less frequent dosing interval, depending on the particular dosage formulation, bioavailability, and pharmacokinetic profile of the peptide.

[0162] An administration phase may have a duration of at least two days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at least 6 months, or more.

[0163] Where an administration pattern comprises a plurality of doses, the duration of a possible following drug holiday phase is longer than the dosing interval used in that administration pattern. Where the dosing interval is irregular, the duration of a drug holiday phase may be greater than the mean interval between doses over the course of the administration phase. Alternatively the duration of the drug holiday may be longer than the longest interval between consecutive doses during the administration phase.

[0164] The duration of a possible drug holiday phase may be at least twice that of the relevant dosing interval (or mean thereof), at least 3 times, at least 4 times, at least 5 times, at least 10 times, or at least 20 times that of the relevant dosing interval or mean thereof.

[0165] Within these constraints, a drug holiday phase may have a duration of at least two days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at least 6 months, or more, depending on the administration pattern during the previous administration phase.

[0166] An administration regime entailing the use of drug holiday comprises at least 2 administration phases. Consecutive administration phases are separated by respective drug holiday phases. Thus the administration regime may comprise at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30 administration phases, or more, each separated by respective drug holiday phases.

[0167] Consecutive administration phases may utilise the same administration pattern, although this may not always be desirable or necessary. However, if other drugs or active agents are administered in combination with a peptide of the invention, then typically the same combination of drugs or active agents is given in consecutive administration phases. In certain embodiments, the recipient subject is a human.

Combination Therapy

[0168] An amylin analogue of the invention may be administered as part of a combination therapy together with another active agent for the treatment of the disease or disorder in question, e.g. an anti-diabetic agent, an anti-obesity agent, an agent for treatment of metabolic syndrome, an anti-dyslipidemia agent, an anti-hypertensive agent, a proton pump inhibitor, or an anti-inflammatory agent. In such cases, the two active agents may be given together or separately, e.g. as constituents in the same pharmaceutical composition or formulation, or as separate formulations.

[0169] Thus a peptide of the invention may have some benefit if administered in combination with an anti-diabetic agent of known type, including, but not limited to, metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, a GLP-1 receptor agonist (including GLP-1 or a GLP-1 analogue, an exendin-4 or an exendin-4 analogue, any other GLP-1 receptor agonist including liraglutide (Saxenda.TM., Victoza.TM.), Dulaglutide or Albiglutide or a glucagon-GLP-1 dual agonist, e.g. as described in WO2008/101017, WO2008/152403, WO2010/070252, WO2010/070253, WO2010/070255, WO2010/070251, WO2011/006497, WO2011/160630, WO2011/160633, WO2013/092703, WO2014/041195), an SGLT2 inhibitor (i.e. an inhibitor of sodium-glucose transport, e.g. a gliflozin such as empagliflozin, canagliflozin, dapagliflozin or ipragliflozin), a GPR40 agonist (FFAR1/FFA1 agonist, e.g. fasiglifam), or an insulin or an insulin analogue. Examples of appropriate insulin analogues include, but are not limited to, Lantus.TM., Novorapid.TM., Humalog.TM., Novomix.TM., Actraphane.TM. HM, Levemir.TM. Degludec.TM. and Apidra.TM.. Other relevant anti-diabetic agents in this connection include GLP-1 receptor agonists, such as exenatide (Byetta.TM. and Bydureon.TM. exendin-4) and Byetta LAR.TM., lixisenatide (Lyxumia.TM.) and liraglutide (Victoza.TM.).

[0170] Moreover, a peptide of the invention may be used in combination with an anti-obesity agent of known type, including, but not limited to, peptide YY or an analogue thereof, neuropeptide Y (NPY) or an analogue thereof, a cannabinoid receptor 1 antagonist, a lipase inhibitor, Human prolslet Peptide (HIP), a melanocortin receptor 4 agonist, a GLP-1 receptor agonist (including GLP-1 or a GLP-1 analogue, an exendin-4 or an exendin-4 analogue, any other GLP-1 receptor agonist including liraglutide (Saxenda.TM., Victoza.TM.), Dulaglutide or Albiglutide or a glucagon-GLP-1 dual agonist, e.g. as described in WO2008/101017, WO2008/152403, WO2010/070252, WO2010/070253, WO2010/070255, WO2010/070251, WO2011/006497, WO2011/160630, WO2011/160633, WO2013/092703, WO2014/041195), Orlistat.TM. Sibutramine.TM., phentermine, a melanin concentrating hormone receptor 1 antagonist, CCK, amylin, pramlintide and leptin, as well as analogues thereof.

[0171] A peptide of the invention may further be used in combination with an anti-hypertension agent of a known type, including, but not limited to, an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker and a calcium channel blocker.

[0172] A peptide of the invention may still further be used in combination with an anti-dyslipidemia agent of known type, including, but not limited to, a statin, a fibrate, a niacin, a PSCK9 (Proprotein convertase subtilisin/kexin type 9) inhibitor, and a cholesterol absorption inhibitor.

[0173] A peptide of the invention may also be used in combination with a proton pump inhibitor (i.e. a pharmaceutical agent possessing pharmacological activity as an inhibitor of H.sup.+/K.sup.+-ATPase) of known type, including, but not limited to, an agent of the benzimidazole derivative type or of the imidazopyridine derivative type, such as Omeprazole.TM., Lansoprazole.TM., Dexlansoprazole.TM., Esomeprazole.TM., Pantoprazole.TM., Rabeprazole.TM., Zolpidem.TM., Alpidem.TM., Saripidem.TM. or Necopidem.TM..

[0174] In addition, with regard to anti-inflammatory treatment, a peptide of the invention may be beneficial if administered in combination with an anti-inflammatory agent of known type, including, but not limited to:

steroids and corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; non-steroidal anti-inflammatory agents (NSAIDs), such as propionic acid derivatives (e.g. alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen); acetic acid derivatives (e.g. indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac); fenamic acid derivatives (e.g. flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid); biphenylcarboxylic acid derivatives (e.g. diflunisal and flufenisal); oxicams (e.g. isoxicam, piroxicam, sudoxicam and tenoxicam); salicylates (e.g. acetylsalicylic acid and sulfasalazine); and pyrazolones (e.g. apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); COX II inhibitors, such as rofecoxib and celecoxib; preparations of interferon beta (e.g. interferon beta-1a or interferon beta-1b); and certain other compounds, such as 5-aminosalicylic acid and prodrugs and pharmaceutically acceptable salts thereof.

[0175] Metformin has also been demonstrated to have anti-inflammatory properties (see, e.g., Haffner et al., Diabetes 54: 1566-1572 (2005)) and as such may also be useful in combination with compounds (peptides) of the invention.

Devices and Kits

[0176] In some embodiments, the invention relates to a device comprising an amylin analogue or pharmaceutical composition of the invention, for delivery of the analogue to a subject. Via such devices, amylin analogues can be administered to a patient via a variety of delivery methods, including: intravenous, subcutaneous, intramuscular or intraperitoneal injection; oral administration; transdermal administration; pulmonary or transmucosal administration; administration by implant, osmotic pump, cartridge or micro pump; or by other means recognized by a person of skill in the art.

[0177] In some embodiments, the invention relates to a kit comprising an amylin analogue of the invention or a pharmaceutical composition of the invention. In certain embodiments, the kit further comprises packaging and/or instructions for use.

[0178] The device or kit may be useful for combination therapy as described above. Thus the device or kit may further comprise a further active agent, e.g. an anti-diabetic agent, an anti-obesity agent, an agent for treatment of metabolic syndrome, an anti-dyslipidemia agent, an anti-hypertensive agent, a proton pump inhibitor, or an anti-inflammatory agent as described above, or a pharmaceutical composition comprising such an active agent.

EXAMPLES

[0179] The following examples demonstrate certain specific embodiments of the present invention. The following examples were carried out using standard techniques that are well known and routine to those of skill in the art, except where otherwise described in detail. It is to be understood that these examples are for illustrative purposes only and do not purport to be wholly definitive as to conditions or scope of the invention. As such, they should not be construed as limiting the scope of the present invention in any way.

[0180] Abbreviations employed in the examples include: [0181] Acm: acetaminomethyl [0182] COMU.TM.: (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeni- umhexafluorophosphate [0183] DCM: dichloromethane [0184] DMF: N,N-dimethylformamide [0185] HATU: 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate [0186] DIPEA: diisopropylethylamine [0187] DODT: 3,6-dioxa-1,8-octanedithiol [0188] EtOH: ethanol [0189] Et.sub.2O: diethyl ether [0190] TFA: trifluoroacetic acid [0191] TIS: triisopropylsilane [0192] MeCN: acetonitrile [0193] HPLC: high performance liquid chromatography [0194] RP-HPLC: reverse phase high performance liquid chromatography [0195] MS: mass spectrometry [0196] ESI-MS: electron spray ionization mass spectrometry [0197] IBMX: 3-isobutyl-1-methylxanthine [0198] BSA: bovine serum albumin [0199] cAMP: cyclic adenosine monophosphate [0200] DMEM: Dulbecco's Modified Eagle Medium [0201] FCS: fetal calf serum [0202] HEPES: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid [0203] p-ERK: phosphorylated extracellular regulated kinase [0204] PBS: phosphate-buffered saline [0205] Boc: tert-butoxycarbonyl [0206] Fmoc: 9-fluorenylmethoxycarbonyl [0207] Trt: trityl (i.e. triphenylmethyl) [0208] NEP: N-ethylpyrrolidone [0209] NMP N-methylpyrrolidone [0210] v/v: volume/volume [0211] w/v: weight/volume

[0212] The following examples are provided to illustrate certain embodiments of the invention and are not intended to limit the scope of the invention.

Measurement of Physiological Parameters

[0213] Unless otherwise specified, whole-blood glucose levels were determined on tail-vein blood samples by the Biosen (EKF Diagnostic, Germany) enzyme-based electrode method. Blood samples were analyzed for glycated hemoglobin (HbA1c) using a Cobas c111 analyzer (Roche Diagnostics, Mannheim, Germany). Plasma insulin levels were measured using a Meso Scale Discovery (MSD) system (Rockville, Md., USA). Liver fat content was determined by magnetic resonance (MR) scanning using an Echo systems MR scanner. Fat depots were measured by weighing of excised fat.

Example 1: Synthesis of Compounds

[0214] The following compounds were synthesised:

TABLE-US-00012 (SEQ ID NO: 102) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 1) (SEQ ID NO: 103) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd.2) (SEQ ID NO: 104) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLANFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 3) (SEQ ID NO: 105) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSINVGSNT-Apr-NH.sub.2 (Compd. 4) (SEQ ID NO: 106) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRSSNNF-Gly(Me)-A-Ile(Me)-LSSINVGSNT-Apr-NH.sub.2 (Compd. 5) (SEQ ID NO: 107) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 6) (SEQ ID NO: 108) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 7) (SEQ ID NO: 109) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 8) (SEQ ID NO: 110) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 9) (SEQ ID NO: 111) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (Compd. 10) (SEQ ID NO: 112) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2 (Compd. 11) (SEQ ID NO: 113) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (Compd. 12) (SEQ ID NO: 114) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 13) (SEQ ID NO: 115) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 14) (SEQ ID NO: 116) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 15) (SEQ ID NO: 117) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 16). (SEQ ID NO: 118) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLANFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 17) (SEQ ID NO: 119) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 18) (SEQ ID NO: 120) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLKRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 19) (SEQ ID NO: 121) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRSVF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 20) (SEQ ID NO: 122) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLHRVSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 21) (SEQ ID NO: 123) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 22) (SEQ ID NO: 124) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATDRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSDTP-NH.sub.2 (Compd. 23) (SEQ ID NO: 125) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 24) (SEQ ID NO: 126) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSNTP-NH.sub.2 (Compd. 25) (SEQ ID NO: 127) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSETP-NH.sub.2 (Compd. 26) (SEQ ID NO: 128) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATDRLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSDTP-NH.sub.2 (Compd. 27) (SEQ ID NO: 129) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 28) (SEQ ID NO: 130) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 29) SEQ ID NO: 131) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 30) (SEQ ID NO: 132) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 31) (SEQ ID NO: 133) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (Compd. 32) (SEQ ID NO: 134) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (Compd. 33) (SEQ ID NO: 135) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 34) (SEQ ID NO: 136) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 35) (SEQ ID NO: 137) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 36) (SEQ ID NO: 138) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 37) (SEQ ID NO: 139) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLVRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 38) (SEQ ID NO: 140) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFTP-NH.sub.2 (Compd. 39) (SEQ ID NO: 141) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLNRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFTP-NH.sub.2 (Compd. 40) (SEQ ID NO: 142) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 41) (SEQ ID NO: 143) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLADFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2 (Compd. 42)

(SEQ ID NO: 144) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 43) (SEQ ID NO: 145) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2 (Compd. 44) (SEQ ID NO: 146) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Apr-NH.sub.2 (Compd. 45) (SEQ ID NO: 147) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 46) (SEQ ID NO: 148) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-TP-NH.sub.2 (Compd. 47) (SEQ ID NO: 149) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2 (Compd. 48) (SEQ ID NO: 150) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 49) (SEQ ID NO: 151) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFL-Aad-RSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 50) (SEQ ID NO: 152) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2 (Compd. 51) (SEQ ID NO: 153) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 52) (SEQ ID NO: 154) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (Compd. 53) (SEQ ID NO: 155) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 54) (SEQ ID NO: 156) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 55) (SEQ ID NO: 157) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 56) (SEQ ID NO: 158) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 57) (SEQ ID NO: 159) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 58) (SEQ ID NO: 160) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTDVGSNT-Hyp-NH.sub.2 (Compd. 59) (SEQ ID NO: 161) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSDT-Hyp-NH.sub.2 (Compd. 60) (SEQ ID NO: 162) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 61) (SEQ ID NO: 163) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 62) (SEQ ID NO: 164) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 63) (SEQ ID NO: 165) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 64) (SEQ ID NO: 166) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 65) (SEQ ID NO: 167) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 66) (SEQ ID NO: 168) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 67) (SEQ ID NO: 169) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATERLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 68) (SEQ ID NO: 170) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 69) (SEQ ID NO: 171) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 70) (SEQ ID NO: 172) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 71) (SEQ ID NO: 173) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 72) (SEQ ID NO: 174) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2 (Compd. 73) (SEQ ID NO: 175) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2 (Compd. 74) (SEQ ID NO: 176) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (Compd. 75) (SEQ ID NO: 177) [19CD]-isoGlu-R-C( )-PTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2 (Compd. 76) (SEQ ID NO: 178) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 77) (SEQ ID NO: 179) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 78) (SEQ ID NO: 180) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 79) (SEQ ID NO: 181) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGTP-NH.sub.2 (Compd. 80) (SEQ ID NO: 182) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 81) (SEQ ID NO: 183) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTTP-NH.sub.2 (Compd. 82) (SEQ ID NO: 184) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2 (Compd. 83) (SEQ ID NO: 185) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLERSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2

(Compd. 84) (SEQ ID NO: 186) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSSTP-NH.sub.2 (Compd. 85) (SEQ ID NO: 187) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 86) (SEQ ID NO: 188) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2 (Compd. 87) (SEQ ID NO: 189) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 88) (SEQ ID NO: 190) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 89) (SEQ ID NO: 191) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 90) (SEQ ID NO: 192) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2 (Compd. 91) (SEQ ID NO: 193) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 92) (SEQ ID NO: 194) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 93) (SEQ ID NO: 195) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSGTP-NH.sub.2 (Compd. 94) (SEQ ID NO: 196) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLA-Aad-FLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 95) (SEQ ID NO: 197) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP-NH.sub.2 (Compd. 96)

([19CD]-isoGlu represents a [19-carboxynonadecanoyl] group linked to the free alpha-amino group of the N-arginine residue via an iso-glutamic acid linker.)

[0215] Also synthesized, for use as controls, were:

TABLE-US-00013 Pramlintide: (SEQ ID NO: 198) H-K( )NTATC( )ATQRLANFLVHSSNNFGPILPPINVGSNTY-NH.sub.2

NN96: N-.alpha.-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyryl]-[A- rg1, Glu14, His17, Pro37]-pramlintide-NH.sub.2 (NN96 is disclosed in WO 2012/168430 and has the amino acid sequence:

TABLE-US-00014 (SEQ ID NO: 199) RC( )NTATC( )ATQRLAEFLHHSSNNFGPILPPTNVGSNTP) (SEQ ID NO: 200) [19CD]-isoGlu-R-C( )-NTAT-C( )-ATQRLAEFLHHSSFGPILP FINVGSNTP-NH.sub.2 (Compd. 97) (SEQ ID NO: 201) [19CD]-isoGlu-R-C( )-GTAT-C( )-ATERLA-Aad- FLQRSSNNF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 98) (SEQ ID NO: 202) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATERLAHFLQRSSNNF- Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 99) (SEQ ID NO: 203) [19CD]-isoGlu-R-C( )-QTAT-C( )-ATDRLA-Aad- FLQRSSNNF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2 (Compd. 100)

[0216] Compound 97 has the same sequence as NN96 except for a deletion of the Asn residues at positions 21 and 22.

[0217] Compounds 98, 99 and 100 have the same sequences as compound 55, compound 57 and compound 89 respectively, except for Asn residues inserted at positions 21 and 22.

[0218] Parentheses "( )" indicate intramolecular disulphide bridges between the side chains of cysteine residues at positions 2 and 7 of the relevant amino acid sequences.

[0219] Unless otherwise specified, reagents and solvents employed in the following were available commercially in standard laboratory reagent or analytical grade, and were used without further purification.

[0220] Suitable general procedures for synthesis include the following:

General Procedures for Solid-Phase Synthesis of Peptides

[0221] A CEM Liberty Peptide Synthesizer was employed, using standard Fmoc chemistry. TentaGel.TM. S Ram resin (1 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. Pseudoprolines [i.e. dipeptides employed to minimize aggregation during peptide synthesis, such as Fmoc-Phe-Thr(.psi.-Me,Me-Pro)-OH and Fmoc-Asp-Ser(.psi.-Me,Me-Pro)-OH and Fmoc-Ser-Ser(.psi.-Me,Me-Pro)-OH] were used where appropriate, and non-naturally occurring amino acids and other suitable building blocks were employed without any changes to the general procedure.

[0222] The following optical isomers of particular amino acids (including non-naturally occurring amino acids) were employed in the synthesis of the compounds:

Apr: (2S,4R)-4-aminoproline [also denoted (4R)-4-amino-L-proline]; Hyp: (2S,4R)-4-hydroxyproline [also denoted (4R)-4-hydroxy-L-proline]. Aad: (2S)-2-aminoadipic acid

Coupling:

[0223] 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). Alternatively the coupling was done without heating and the reaction time extended to 60 min in this case.

[0224] In the case of difficult couplings (e.g. coupling of a residue immediately after an N-methylated amino acid residue or other sterically hindered amino acid residue as recognized by a person of skill in the art) the coupling was repeated one or more times.

Deprotection:

[0225] Piperidine/DMF (1:4, i.e. 1 part piperidine to 4 parts DMF by volume; 10 ml) was added to the resin for initial deprotection, and the mixture was microwave-heated (40.degree. C.; 30 sec.). The reaction vessel was drained and a second portion of piperidine/DMF (1:4; 10 ml) was added and heated (75.degree. C.; 3 min) again. The resin was then washed with DMF (6.times.10 ml).

Oxidative Cyclisation

[0226] Intramolecular ring formation (disulfide bridge formation) between the Cys residues in positions 2 and 7 (initially coupled in the form of Acm-protected cysteines) was performed with the peptide still attached to the resin, using 163 mg thallium(III) trifluoroacetate [TI(TFA).sub.3] in 5 mL NMP in a simultaneous Acm-deprotection and disulfide-formation step.

Cleavage:

[0227] 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/H.sub.2O (90:5:5; 40 ml; 2 h; room temp.) or alternatively with TFA/DODT (95:5; 40 ml; 2 h; room temp.). Most of the TFA was removed under reduced pressure, and the crude peptide was precipitated and washed three times with Et.sub.2O and dried to constant weight at room temperature.

Purification and Characterisation:

[0228] The crude peptide was purified by preparative reverse phase HPLC using a PerSeptive Biosystems VISION Workstation or a Gilson system (Pumps: "Pump 305", "331 Pump", "332 Pump", "402 Syringe Pump"; column changer "Valvemate.RTM. II" UV detector "UV/Vis-155"; and the fraction collector "GX 281" equipped with a suitable column and a fraction collector, and run with a gradient of buffer A (0.1% aqueous TFA) and buffer B (0.1% TFA, 90% MeCN, water). Fractions were analysed by analytical HPLC and MS, and relevant fractions were pooled and lyophilised. The final product was characterized by HPLC and MS.

[0229] One of skill in the art will appreciate that standard methods of peptide synthesis may be used to generate the compounds of the invention.

Example 2: Generation of Cell Lines Expressing (i) Human Calcitonin Receptor (hCTR2), and (ii) Human Amylin Receptor 3 (hAMYR3) Consisting of hCTR2 Co-Expressed with Human Receptor Activity Modifying Protein 3 (hRAMP3)

[0230] The cell line COS7, originating from African Green Monkey kidney fibroblast cells, was used for establishment of the stable cell lines described below. The COS7 cellular background was used due to it being RAMP naive, and as such it provides the best available system for testing of the monomeric hCTR and different heterodimeric amylin receptor subtypes functionally generated by introduction of the individual RAMPs.

Calcitonin Receptor Cell Line:

[0231] A cell line expressing the human calcitonin receptor (hCTR2) was generated in the COS7 cellular background as stable clones. In brief, hCTR2 (GI: 4502547) was amplified by PCR using primers encoding terminal restriction sites for subcloning. The 5'-end primers additionally encoded a near Kozak consensus sequence to ensure efficient translation. The fidelity of the DNA encoding the receptor was confirmed by DNA sequencing. The PCR products encoding the receptor were subcloned into a mammalian expression vector containing a neomycin (G418) resistance marker. The mammalian expression vector encoding the receptor was transfected into COS7 cells by a standard liposome transfection method. 48 hours post-transfection, cells were seeded for limited dilution cloning and selected with 1 mg/ml G418 in the culture medium. After 3 weeks, surviving colonies of hCTR2-expressing cells were picked, propagated and tested in the amylin efficacy assay as described in Example 3 below. One hCTR2-expressing clone was chosen for compound profiling.

Amylin Receptor Cell Line:

[0232] A cell line expressing the human amylin receptor 3 (hAMYR3) was generated in the COS7 cellular background as stable clones. In brief, hCTR2 (GI:4502547) and hRAMP3 (GI:118572586) were amplified by PCR using primers encoding terminal restriction sites for subcloning. The 5'-end primers additionally encoded a near Kozak consensus sequence to ensure efficient translation. The fidelity of the DNA encoding the receptor was confirmed by DNA sequencing. The PCR products encoding the receptor were subcloned into a proprietary tri-cistronic mammalian expression vector with RAMP3, hCTR2 and neomycin (G418) resistance marker. The mammalian expression vector encoding the receptor was transfected into COS7 cells by a standard liposome transfection method. 48 hours post-transfection, cells were seeded for limited dilution cloning and selected with 1 mg/ml G418 in the culture medium. After 3 weeks, surviving colonies of hAMY3R-expressing cells were picked, propagated and tested in the amylin efficacy assay as described in Example 3 below. The functional generation of the amylin receptor phenotype was verified in the efficacy assay by a left-shifted efficacy response to amylin relative to monomeric calcitonin receptor, and one hAMYR3-expressing clone was chosen for compound profiling.

Example 3: hCTR2 and hAMYR3 Assays

[0233] In vitro activity of test peptides at the hCTR2 and hAMYR3 receptors was assessed by measuring the induction of cAMP following stimulation of the receptor using the AlphaScreen.RTM. cAMP Assay kit from Perkin-Elmer.

[0234] Briefly, COS7 cells expressing hCTR2 (see Example 2, above) were seeded at 30-40,000 cells per well in 96-well microtiter plates coated with 0.01% poly-L-lysine, and grown for 1 day in culture in 100 .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 200 .mu.l Tyrode buffer [Tyrode's Salts (9.6 g/I), 10 mM HEPES, pH 7.4]. Cells were incubated in 100 .mu.l Tyrode buffer containing increasing concentrations of test peptides, 100 M IBMX and 0.1% casein for 15 min at 37.degree. C. The reaction was stopped by carefully decanting off the compound/buffer medium and replacing it with lysis/detection buffer (80 .mu.l 0.1% w/v BSA, 5 mM HEPES, 0.3% v/v Tween-20 in deionized water). After incubation at room temperature for 10 min., the cAMP content of the resulting cell lysate was estimated according to the AlphaScreen.RTM. cAMP Assay manufacturer's instructions. EC.sub.50 values were estimated by computer-aided curve fitting using the 4-parameter logistic (4PL) non-linear model.

[0235] The in vitro activity results (expressed as EC.sub.50 values) are summarized in Table 1, below.

Example 4: Assessment of Solubility

[0236] A stock solution of the test peptide (2 mg/ml; determined from the weighed amount of peptide) in demineralized water adjusted to pH 2.5 with HCl was prepared, and aliquots were diluted 1:1 in 100 mM acetate buffer (pH 4.0 and pH 5.0), 100 mM histidine buffer (pH 6.0 and pH 7.0) and 100 mM phosphate buffer (pH 6.0, pH 7.0 and pH7.5), respectively, and loaded in a standard flat-bottom, non-sterile 96-well UV Microplate. The absorbance of samples (single samples, n=1) at 280 and 325 nm was measured in an absorbance-based plate reader, which was preheated to ambient temperature (typically 25.degree. C.). The turbidity absorbance criterion for a peptide solubility of .gtoreq.1 mg/ml was an absorbance at 325 nm of s 0.02 absorbance units (which is 5 to 6 times the standard deviation of 8 buffer samples in a plate).

[0237] Measurements were made on Compounds 1-17, 19, 27-38, 49-69 and 71-87. With the exception of Compound 10 at pH 6.0. Compound 31 at pH 7.0 and 7.5, and Compound 38 at pH 6.0 and 7.5, all of the tested compounds exhibited solubility .gtoreq.1 mg/ml in all the test buffers.

Example 5: Assessment of Physical Stability

[0238] Aggregation in the form of fibril formation was detected using the amyloid-specific dye Thioflavin T (ThT), which is frequently employed to demonstrate the presence of fibrils in solution (see, e.g., Groenning, M., J. Chem. Biol. 3(1) (2010), pp. 1-18; Groenning et al., J. Struct. Biol. 158 (2007) pp. 358-369; and Levine, H., III, Protein Sci. 2 (1993) pp. 404-410) Test peptides (2 mg/ml) were dissolved in demineralized water adjusted to pH 2.5 with HCl, at ambient temperature (typically 25.degree. C.). Solutions containing (i) 1 mg/ml of test peptide, 40 .mu.M ThT and 50 mM phosphate (Ph) buffer (pH 7.0), (ii) 1 mg/ml of test peptide, 40 .mu.M ThT and 50 mM histidine (His) buffer (pH 7.0), and (iii) 1 mg/ml of test peptide, 40 .mu.M ThT and 50 mM acetate (Ac) buffer (pH 4.0), were loaded in a 96-well black fluorescence plate (clear bottom) in triplicate. Data were collected at fixed intervals of 10 min, each preceded by 300 s of automixing (agitation), over a period of 96 hours at 40.degree. C. Physical stability, expressed as lag-time of fibril formation (in hours), was defined as the intersection between two linear regressions representing the initial stable phase and the growth phase. Data are summarized in Table 1 below.

Example 6: Assessment of Chemical Stability

[0239] Samples of each test peptide were dissolved in MilliQ.TM. water, and the pH of the solution was adjusted to pH 4, pH 6, pH 7.5 or pH 9, respectively, using either HCl or NaOH. The final peptide concentration was 0.2 mg/ml. Samples were placed in glass vials and incubated at 40.degree. C. The samples were analyzed by RP-HPLC on a C8 column with gradient elution using an ammonium formate/water eluent system, or on a C18 column with gradient elution using a trifluoroacetic acid/water eluent system. The area-percentage (area-%) of the main peak after incubation time T=t (relative to time T=0) was determined by UV spectroscopy at 220 nm.

[0240] The purity was first determined as follows:

Purity(area-%)=(area of main peak/total area of all peaks).times.100.

[0241] The purity was then normalized between time points by setting purity at time 0 (T=0) to 100 for each pH value for a given peptide, as follows:

Normalised area-% at time t (T=t)=[area-%(T=t)/area-%(T=0)].times.100.

[0242] The chemical stability assessment results (in the form of normalized purity values) are summarized in Table 1 (below). The normalized purity values in Table 1 were determined after 7 days of incubation.

TABLE-US-00015 TABLE 1 EC.sub.50 , chemical stability and fibrillation data Normalized purity hCTR2 hAMYR3 after 7 days, 40.degree. C.** Fibrillation.sup..sctn..sctn. Cmpd. EC.sub.50 EC.sub.50 pH pH 4.0 pH 7.0 pH 7.0 No. (nM) (nM) pH 4 pH 6 7.5 pH 9 (Ac) (His) (Phos.) 1 0.079 0.230 FND FND FND 2 0.076 0.120 A A B FND FD FND 3 0.160 0.200 A B B FD FD FD 4 0.210 0.220 B C C FND FND FND 5 0.200 0.180 B C C FND FND FND 6 0.077 0.220 A B B FND FND FND 7 0.087 0.340 A A A A FND FND FND 8 0.180 0.360 A B A A FND FND FND 9 0.099 0.290 A B B B FND FD FD 10 0.160 0.350 A A B B FND FD FD 11 0.130 0.200 A B A B FND FD FD 12 0.120 0.250 A A B B FND FD FD 13 0.120 0.380 A A A A FND FD FD 14 0.150 0.260 A A A A FND FD FND 15 0.044 0.079 A B B B FND FD FND 16 0.073 0.110 A A A B FD FD FND 17 0.13 0.61 18 0.12 0.41 FND FD FD 19 0.16 0.28 A A A C FND FND FND 20 0.19 0.33 FND FD FND 21 0.12 0.23 FND FD FD 22 0.078 0.59 FND FD FND 23 0.094 0.13 24 0.085 0.19 25 0.046 0.094 26 0.057 0.12 27 0.063 0.16 FD FD FD 28 0.11 0.13 A B B B FND FND FND 29 0.09 0.12 A B B 30 0.07 0.12 FND FD FD 31 0.09 0.29 32 0.17 0.23 FND FD FD 33 0.11 0.15 34 0.09 0.12 A B B B FND FND FND 35 0.05 0.11 A A B B FND FND FND 36 0.21 0.36 A A B B FND FND FD 37 0.04 0.07 38 0.06 0.12 39 0.16 0.22 40 0.12 0.19 41 0.15 0.34 B A A A 42 0.12 0.34 43 0.22 0.35 A A A A 44 0.2 0.3 45 0.16 0.31 46 0.1 0.14 47 0.1 0.19 48 0.12 0.26 A A A A FND FND FND 49 0.06 0.15 A A A B FD FND FND 50 0.12 0.19 51 0.08 0.11 A B B B FND FND FND 52 0.07 0.09 A B B B FND FND FND 53 0.14 0.13 A A B B FND FND FND 54 0.08 0.14 A A B B FND FND FND 55 0.11 0.08 A A A B FND FND FND 56 0.06 0.08 A A A B FND FND FND 57 0.08 0.11 A A A A FND FND FND 58 0.05 0.1 A A B B FND FD FND 59 0.03 0.11 A B C B FND FD FD 60 0.08 0.09 A A A B FND FND FND 61 0.12 0.17 62 0.18 0.22 63 0.35 0.37 64 0.11 0.15 65 0.14 0.26 A A A A 66 0.19 0.30 67 0.27 0.65 68 0.32 0.29 69 0.12 0.17 A A B B 70 0.35 0.36 71 0.11 0.18 A A A B FND FD FD 72 0.35 0.27 73 0.12 0.24 74 0.58 0.39 75 0.36 0.26 76 0.44 0.49 77 0.16 0.42 A A B B FND FND FND 78 0.15 0.24 79 0.12 0.23 A A B B FND FD FD 80 0.13 0.28 A A A A 81 0.10 0.23 A A A A 82 0.21 0.53 83 0.13 0.32 84 0.15 0.54 85 0.1 0.14 86 0.1 0.15 A A A A 87 0.2 0.13 88 0.06 A A A A FND FND FND 89 0.16 0.20 A A A B FND FND FND 90 0.20 0.24 A A A A FND FND FND 91 0.08 0.17 A A A A FND FND FND 92 0.10 0.22 A A A A 93 0.43 95 0.18 0.20 A A A A 96 0.33 0.28 A A A A FND FND FND Pramlin- 1.40 0.230 FD FD tide NN96 0.089 0.150 A A B B FND FD FD **A = >90%; B = 70-90%; C = <70%; Blank = not determined. .sup..sctn..sctn.FND = fibrillation not detected; FD = fibrillation detected.

Example 7: Pharmacokinetic (PK) Profiling in Rats

[0243] Compounds 6, 7, 9, 11, 13, 15, 28, 34, 36, 49, 55, 57 and 71 were tested for their pharmacokinetic properties in rats.

[0244] Sprague Dawley male rats were given a single subcutaneous (sc) bolus of each peptide to be tested, as specified below. 30 nmol/kg doses of compound were administered. Blood samples were drawn from the tail vein prior to dosing and at 24, 48, 72, 96 and 168 hours after dosing. Blood samples were taken from two rats at each time point, and only 2 blood samples were drawn from each rat, i.e. 10 rats were used for each compound. The rats were euthanized immediately after the last blood sampling by concussion and cervical dislocation.

[0245] The dosing vehicle used for each test peptide was a mannitol-containing histidine buffer (pH 7.0). Plasma samples were analyzed after precipitation with ethanol by liquid chromatography mass spectrometry (LC-MS/MS). Mean plasma concentrations were used for calculation of the pharmacokinetic parameters using the non-compartmental approach in Phoenix WinNonlin 6.3.

[0246] Plasma terminal elimination half-life (t.sub.1/2) was determined as ln(2)/.lamda.z, where .lamda.z is the magnitude of the slope of the log linear regression of the log concentration versus time profile during the terminal phase. Apparent clearance (CL/F) was determined as dose/AUC.sub.inf (sc), where AUC.sub.inf is the area under the plasma concentration vs. time curve extrapolated to infinity (AUC.sub.inf=AUC.sub.last+C.sub.last/.lamda.z, where C.sub.last is the last observed plasma concentration).

Results

[0247] As shown in Table 2, below, the plasma terminal elimination half-lives for all tested peptides were determined to be in the range of 14.1 hours to 36.7 hours, while the apparent clearance values for all tested peptides were in the range of 0.00406 to 0.0146 liter/hour/kg.

TABLE-US-00016 TABLE 2 Plasma terminal elimination half-lives (t.sub.1/2) and apparent clearance values (Cl/F; I/h/kg) Compound No. CI/F t.sub.1/2 (hours) 6 0.0069 24.2 7 0.0087 25.4 9 0.0096 17.9 11 0.0118 14.1 13 0.0106 15.0 15 0.0116 18.9 28 0.0128 17.1 34 0.0148 17.2 36 0.0117 25.7 49 0.00406 36.7 55 0.0045 26.2 57 0.0078 17.9 71 0.0146 14.7

Example 8: Effect on Acute Food Intake and Body Weight in Normal Sprague Dawley Rats

[0248] Compounds 6, 7, 9, 11, 13, 15, 28, 34, 36, 49, 55, 57, 59, 71 and 79 were tested for their effect on food intake and body weight in rats.

[0249] Sprague Dawley (SD) rats were obtained from Taconic A/S, Denmark. The animals arrived at least 7 days before the study start to allow acclimatization to experimental conditions. From arrival and throughout the study, the rats were housed in groups of 2 (n=2) in a light-, temperature- and humidity-controlled room (reversed 12/12 h light/dark cycle: lights turned off during day-time and on during night-time; temperature 20-22.degree. C.; relative humidity 50-80%). Animals had access ad libitum to food (Altromin.TM. 1324, Brogaarden A/S, Gentofte, Denmark) and water (domestic quality tap water with citric acid added to pH 3.6) during the entire study. Stratification of rats was based on body weight (BW) on a cage-by-cage basis; mean BWs per cage were used as the basis for pairing four cages together in a group (n=8 per group). A vehicle group and positive control group were included in each set of tests. Rats were dosed subcutaneously (sc) once in the morning immediately before turning off the lights, using a body weight-corrected dose (30 nmol/kg) of test peptide. Dosing volume was 5 ml/kg. Food intake was recorded manually at t=-24 and 0 hours (pre-dose) and at t=24, 48, 72 and 96 hours after dosing. Body weight was measured daily.

[0250] Statistical analyses were performed using GraphPad.TM. Prism version 5. The measured parameters were compared using one-way ANOVA followed by Dunnett's multiple comparison tests. Differences were considered statistically significant at p<0.05.

Results

[0251] As shown in Table 3, below, 48 hours after dosing, each of the tested compounds had given rise to a clear, statistically significant inhibition of food intake (vehicle-corrected, in %). This reduction in food intake was reflected by a decrease in body weight (vehicle-corrected, in %) observed on day 4 post-dosing (after 96 h) in the treated rats. (Not shown.) Normal feeding behavior was subsequently resumed.

TABLE-US-00017 TABLE 3 Acute food intake data FI inhibition after 48 h Compound No. (vehicle corrected) (%) 6 97 .+-. 0.2 7 94 .+-. 1.4 9 91 .+-. 2.5 11 88 .+-. 3.4 13 88 .+-. 2.4 15 93 .+-. 1.6 28 74 .+-. 5.4 34 70 .+-. 6.6 36 20 .+-. 3.4 49 98 .+-. 0.2 55 90 .+-. 2.4 57 77 .+-. 8.7 59 99 .+-. 0.1 71 84 .+-. 5.7 79 71 .+-. 5.6

Example 9: Oral Glucose Tolerance Test (OGTT) in Rats

[0252] Male Sprague Dawley rats [Crl:CD(SD), weight range 260-280 g upon arrival] were housed in groups of 2 (n=2) or 3 (n=3). The animals were maintained on a 12 h/12 h light/dark cycle. Animals had access ad libitum to a standard chow diet and tap water (domestic quality tap water) during the initial one week acclimatization period.

[0253] Fasted rats (fasted for 7 hours) were employed in the test. Rats had previously been randomized into two groups, designated test group and control group, respectively. The total number of animals per group was 10 (n=10).

[0254] A single subcutaneous injection of either vehicle (control group; vehicle: 50 mM histidine buffer, pH 7, with 200 mM mannitol) or Compound 7 in vehicle [test group; dose 30 nmol/kg body weight (2 ml/kg)] was subsequently administered to each animal. All rats then received an oral glucose bolus (2 g/kg) 16 hours after vehicle or compound administration. Blood glucose levels in tail blood samples taken 20 min. before glucose administration (time zero, baseline) and then 15 min., 30 min., 60 min., 90 min., 120 min. and 180 min after glucose administration were determined using a glucometer (GlucoSmart Swing.TM.; MSP Bodmann GmbH, Germany).

[0255] Baseline glucose levels were essentially the same in the test and control groups, but the elevation of glucose levels over the course of the 180 minute measurement time period was significantly lowered in the test group compared to the control group. Table 4 (below) summarizes the blood glucose AUC (area under curve) determined over the period from t=15 min. to t=180 min. from a plot of measured glucose levels as a function of time. The data are presented as mean.+-.S.E.M. The two-sided unpaired Student t-test was used for statistical comparison of the test group and the control group.

TABLE-US-00018 TABLE 4 Control Test group group (Compound 7) p-value Glucose AUC, t = 15-180 min. 270 .+-. 38 122 .+-. 29 p < 0.0062 (mmol/L); mean .+-. S.E.M.

[0256] It is clear from the results that the tested compound significantly improves glucose tolerance in the test group compared to the control group.

Example 10: Effect of Deletion at Positions 21 and 22

[0257] The chemical stability assessment described in Example 6 was repeated for four pairs of compounds, each differing only by the presence or absence of an Asn-Asn (N--N) doublet at positions 21 and 22.

TABLE-US-00019 TABLE 5 Compound Positions 21-22 pH 4 pH 6 pH 7.5 pH 9 NN96 N-N A A B B 97 .DELTA. A A A A 55 .DELTA. A A A B 98 N-N A A B B 57 .DELTA. A A A B 99 N-N A A B B 89 .DELTA. A A A A 100 N-N A A A B [Designations "A", "B" and "C" are the same as in Table 1. ".DELTA." signifies a deletion at positions 21 and 22.]

[0258] It can be seen that deletion of the Asn-Asn doublet at positions 21 and 22 tends to increase chemical stability in the neutral to alkaline pH range.

[0259] Activity at the human calcitonin (hCTR2) and amylin (hAMYR3) was also determined, as described in Example 3. As shown in Table 6, the deletion tends to increase the activity at both receptors, especially in compounds containing methylated amino acid residues.

TABLE-US-00020 TABLE 6 hCTR2 EC.sub.50 hAMYR3 EC.sub.50 Compound (nM) (nM) NN96 0.089 0.150 97 0.10 0.13 55 0.11 0.08 98 7.2 0.38 57 0.08 0.11 99 3.8 0.59 89 0.16 0.20 100 2.2 0.53

Sequence CWU 1

1

203137PRTHomo sapiensDISULFID(2)..(7) 1Lys Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asn Phe Leu1 5 10 15Val His Ser Ser Asn Asn Phe Gly Ala Ile Leu Ser Ser Thr Asn Val 20 25 30Gly Ser Asn Thr Tyr 35237PRTArtificial sequenceSynthetic Amylin analogueDISULFID(2)..(7) 2Lys Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asn Phe Leu1 5 10 15Val His Ser Ser Asn Asn Phe Gly Pro Ile Leu Pro Pro Thr Asn Val 20 25 30Gly Ser Asn Thr Tyr 35337PRTArtificial sequenceAmino acid sequence Z of Formula I in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793VARIANT(1)..(37)The compound has at least one residue selected from Xaa3 is Gln; Xaa14 is His, Asn or Aad; Xaa17 is Asn, Gln, Glu, Thr or Aad; Xaa19-Xaa20 is Val-Ser or Ser-Val; & Xaa35 is Ser, Phe, Orn, Aad, Gly or ThrDISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7VARIANT(3)..(3)Xaa is selected from the group consisting of Asn, Gly, Pro and GlnVARIANT(10)..(10)Xaa is selected from the group consisting of Gln, Asp and GluVARIANT(14)..(14)Xaa is selected from the group consisting of Asp, His, Asn and AadVARIANT(17)..(17)Xaa is selected from the group consisting of His, Asn, Gln, Glu, Thr, Val, Lys and AadVARIANT(19)..(20)Xaa-Xaa is selected from the group consisting of Ser-Ser, Val-Val, Ser-Val and Val-Ser, or is absentSITE(21)..(22)Xaa21-Xaa22 are absentMOD_RES(24)..(24)MeGlyMOD_RES(26)..(26)MeIleVARIANT(31)..(31)Xaa is selected from the group consisting of Asp, Glu and AsnVARIANT(35)..(35)Xaa is selected from the group consisting of Asp, Glu, Asn, Ser, Phe, Orn, Aad, Gly and ThrVARIANT(37)..(37)Xaa is selected from the group consisting of Pro, Apr and Hyp 3Arg Cys Xaa Thr Ala Thr Cys Ala Thr Xaa Arg Leu Ala Xaa Phe Leu1 5 10 15Xaa Arg Xaa Xaa Xaa Xaa Phe Gly Ala Ile Leu Ser Ser Thr Xaa Val 20 25 30Gly Ser Xaa Thr Xaa 35437PRTArtificial sequenceAmino acid sequence Z of Formula II in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793VARIANT(1)..(37)The compound has at least one residue selected from Xaa3 is Gln; Xaa14 is His or Aad; Xaa17 is Asn, Gln, Glu or Aad; and Xaa35 is Ser, Orn, Aad, Gly or ThrDISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7VARIANT(3)..(3)Xaa is selected from the group consisting of Asn, Gly and GlnVARIANT(10)..(10)Xaa is selected from the group consisting of Gln, Asp and GluVARIANT(14)..(14)Xaa is selected from the group consisting of Asp, His and AadVARIANT(17)..(17)Xaa is selected from the group consisting of His, Asn, Gln, Glu, Lys and AadVARIANT(19)..(20)Xaa-Xaa is Ser-Ser or is absentSITE(21)..(22)Xaa21-Xaa22 are absentMOD_RES(24)..(24)MeGlyMOD_RES(26)..(26)MeIleVARIANT(35)..(35)Xaa is selected from the group consisting of Asp, Glu, Asn, Ser, Orn, Aad, Gly and ThrVARIANT(37)..(37)Xaa is selected from the group consisting of Pro and Hyp 4Arg Cys Xaa Thr Ala Thr Cys Ala Thr Xaa Arg Leu Ala Xaa Phe Leu1 5 10 15Xaa Arg Xaa Xaa Xaa Xaa Phe Gly Ala Ile Leu Ser Ser Thr Glu Val 20 25 30Gly Ser Xaa Thr Xaa 35537PRTArtificial sequenceAmino acid sequence Z of Formula III in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793VARIANT(1)..(37)The compound has at least one residue selected from Xaa3 is Gln; Xaa14 is His or Aad; Xaa17 is Gln; and Xaa35 is Aad.DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7VARIANT(3)..(3)Xaa is selected from the group consisting of Asn, Gly and GlnVARIANT(10)..(10)Xaa is selected from the group consisting of Gln, Asp and GluVARIANT(14)..(14)Xaa is selected from the group consisting of Asp, His and AadVARIANT(17)..(17)Xaa is selected from the group consisting of His and GlnVARIANT(19)..(20)Xaa-Xaa is Ser-Ser or is absentSITE(21)..(22)Xaa21-Xaa22 are absentMOD_RES(24)..(24)MeGlyMOD_RES(26)..(26)MeIleVARIANT(35)..(35)Xaa is selected from the group consisting of Asp, Glu, Asn, Aad and GlyVARIANT(37)..(37)Xaa is selected from the group consisting of Pro and Hyp 5Arg Cys Xaa Thr Ala Thr Cys Ala Thr Xaa Arg Leu Ala Xaa Phe Leu1 5 10 15Xaa Arg Xaa Xaa Xaa Xaa Phe Gly Ala Ile Leu Ser Ser Thr Glu Val 20 25 30Gly Ser Xaa Thr Xaa 35635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 6Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 35735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 7Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asn Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 35835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 8Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 35935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 9Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 351035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 10Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Glu Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 351135PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 11Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 351235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 12Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Phe Thr Pro 351335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(33)..(33)OrnMOD_RES(- 35)..(35)4Hyp 13Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Arg Thr Pro 351435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(33)..(33)AadMOD_RES(- 35)..(35)4Hyp 14Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 351535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 15Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 351633PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(20)..(20)MeGlyMOD_RES(22)..(22)MeIle 16Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15His Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Glu Thr 20 25 30Pro1735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 17Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 351835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 18Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 351935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 19Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asn Phe Leu1 5 10 15Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 352035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 20Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 352135PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 21Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Lys Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 352235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 22Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Val Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 352335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 23Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15His Arg Val Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 352435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 24Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 352535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and

7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 25Arg Cys Pro Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe Leu1 5 10 15Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Asp Val Gly Ser 20 25 30Asp Thr Pro 352635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 26Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 352735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 27Arg Cys Pro Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Asp Val Gly Ser 20 25 30Asn Thr Pro 352835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 28Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 352935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 29Arg Cys Pro Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Asp Val Gly Ser 20 25 30Asp Thr Pro 353035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 30Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 353135PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 31Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 353235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 32Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 353335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 33Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 353435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 34Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Phe Thr Pro 353535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 35Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Phe Thr Pro 353635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 36Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 353735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 37Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 353835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 38Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Glu Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 353935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 39Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 354035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 40Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 354135PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 41Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Phe Thr Pro 354235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 42Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Phe Thr Pro 354335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 43Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 354435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 44Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Phe Thr Pro 354535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(- 35)..(35)4Hyp 45Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 354635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(- 33)..(33)OrnMOD_RES(35)..(35)4Hyp 46Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Arg Thr Pro 354735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleSITE(35)..(35)Xaa is Apr, 4-aminoproline 47Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Xaa 354835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 48Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 354935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(33)..(33)Orn 49Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Arg Thr Pro 355035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 50Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Thr Thr Pro 355135PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 51Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 355235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(17)..(17)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(- 35)..(35)4Hyp 52Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Glu Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 355335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is

a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(33)..(33)OrnMOD_RES(- 35)..(35)4Hyp 53Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Arg Thr Pro 355435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 54Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 355535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(33)..(33)AadMOD_RES(- 35)..(35)4Hyp 55Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 355635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 56Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 355735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(- 35)..(35)4Hyp 57Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 355835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 58Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 355935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 59Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 356035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 60Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 356135PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 61Arg Cys Pro Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Asp Val Gly Ser 20 25 30Asn Thr Pro 356235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 62Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asp Thr Pro 356335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 63Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 356435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 64Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 356535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 65Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 356635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 66Arg Cys Pro Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 356735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 67Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 356835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 68Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 356935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 69Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 357035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 70Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 357135PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 71Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 357235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 72Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 357335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 73Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 357435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 74Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 357535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 75Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Thr Thr Pro 357635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 76Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Thr Thr Pro 357735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(33)..(33)AadMOD_RES(- 35)..(35)4Hyp 77Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 357835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(33)..(33)AadMOD_RES(- 35)..(35)4Hyp 78Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 357933PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(20)..(20)MeGlyMOD_RES(22)..(22)MeIleMOD_RES(33)..(33)4Hyp 79Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Asn Thr 20 25 30Pro8035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine

residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 80Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 358133PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(20)..(20)MeGlyMOD_RES(22)..(22)MeIleMOD_RES(33)..(33)4Hyp 81Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Gly Thr 20 25 30Pro8235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 82Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 358335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 83Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 358435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 84Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Thr Thr Pro 358535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 85Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Thr Thr Pro 358635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 86Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Glu Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 358735PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 87Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 358835PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(- 35)..(35)4Hyp 88Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Glu Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 358935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(- 35)..(35)4Hyp 89Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Glu Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Ser Thr Pro 359035PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 90Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 359135PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(- 35)..(35)4Hyp 91Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala Glu Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 359235PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 92Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 359335PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIleMOD_RES(35)..(35)4Hyp 93Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 359435PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 94Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 359535PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 95Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Asn Thr Pro 359635PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 96Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe Leu1 5 10 15Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Gly Thr Pro 359733PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(14)..(14)AadMOD_RES(20)..(20)MeGlyMOD_RES(22)..(22)MeIleMOD_RES(- 33)..(33)4Hyp 97Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala Glu Phe Leu1 5 10 15Gln Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Asn Thr 20 25 30Pro9833PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(20)..(20)MeGlyMOD_RES(22)..(22)MeIle 98Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe Leu1 5 10 15Gln Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Asn Thr 20 25 30Pro9935PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(22)..(22)MeGlyMOD_RES(24)..(24)MeIle 99Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe Leu1 5 10 15His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser 20 25 30Glu Thr Pro 3510037PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(24)..(24)MeGlyMOD_RES(26)..(26)MeIleSITE(37)..(37)Xaa is Apr, 4-aminoproline 100Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe Leu1 5 10 15His Arg Ser Ser Asn Asn Phe Gly Ala Ile Leu Ser Ser Thr Asn Val 20 25 30Gly Ser Asn Thr Xaa 3510137PRTArtificial sequenceAmino acid sequence Z in synthetic amylin analogue which is a compound having the formula R1-Z-R2 in PCT/EP2016/055793DISULFID(2)..(7)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 2 and 7MOD_RES(24)..(24)MeGlyMOD_RES(26)..(26)MeIleMOD_RES(37)..(37)Xaa is Apr, 4-aminoproline 101Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe Leu1 5 10 15His Arg Ser Ser Asn Asn Phe Gly Ala Ile Leu Ser Ser Thr Asn Val 20 25 30Gly Ser Asn Thr Xaa 3510236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 1.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 102Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3510336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 2.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 103Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3510436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 3.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 104Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asn Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3510538PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 4.MOD_RES(25)..(25)MeGlyMOD_RES(27)..(27)MeIleSITE(38)..(38)Xaa is Apr, 4-aminoproline 105Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe1 5 10 15Leu His Arg Ser Ser Asn Asn Phe Gly Ala Ile Leu Ser Ser Thr Asn 20 25 30Val Gly Ser Asn Thr Xaa 3510638PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd.

5.MOD_RES(25)..(25)MeGlyMOD_RES(27)..(27)MeIleSITE(38)..(38)Xaa is Apr, 4-aminoproline 106Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Asn Asn Phe Gly Ala Ile Leu Ser Ser Thr Asn 20 25 30Val Gly Ser Asn Thr Xaa 3510736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 6.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 107Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3510836PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 7.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 108Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3510936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 8.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 109Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Glu Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3511036PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 9.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 110Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3511136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 10.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 111Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Phe Thr Pro 3511236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 11.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(34)..(34)OrnMOD_RE- S(36)..(36)4Hyp 112Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Arg Thr Pro 3511336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 12.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(34)..(34)AadMOD_RE- S(36)..(36)4Hyp 113Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3511436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 13.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 114Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Gly Thr Pro 3511534PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 14.MOD_RES(21)..(21)MeGlyMOD_RES(23)..(23)MeIle 115Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu His Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Glu 20 25 30Thr Pro11636PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 15.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 116Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3511736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 16.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 117Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3511836PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 17.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 118Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asn Phe1 5 10 15Leu Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3511936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 18.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 119Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3512036PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 19.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 120Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Lys Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3512136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 20.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 121Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Val Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3512236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 21.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 122Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu His Arg Val Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3512336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 22MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 123Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3512436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 23.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 124Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe1 5 10 15Leu Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Asp Val Gly 20 25 30Ser Asp Thr Pro 3512536PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 24.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 125Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3512636PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 25.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 126Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Asp Val Gly 20 25 30Ser Asn Thr Pro 3512736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 26.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 127Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3512836PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine

residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 27.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 128Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Asp Val Gly 20 25 30Ser Asp Thr Pro 3512936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 28.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 129Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3513036PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 29.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 130Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3513136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 30.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 131Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3513236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 31.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 132Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3513336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 32.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 133Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Phe Thr Pro 3513436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 33.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 134Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Phe Thr Pro 3513536PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 34.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 135Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3513636PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 35.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 136Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3513736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 36.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 137Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Glu Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3513836PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 37.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 138Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu His Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3513936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 38.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 139Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Val Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3514036PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 39.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 140Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Phe Thr Pro 3514136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 40.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 141Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Asn Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Phe Thr Pro 3514236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 41.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 142Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3514336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 42.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 143Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Phe Thr Pro 3514436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 43.MOD_RES(15)..(15)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RE- S(36)..(36)4Hyp 144Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3514536PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 44.MOD_RES(15)..(15)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RE- S(34)..(34)OrnMOD_RES(36)..(36)4Hyp 145Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Arg Thr Pro 3514636PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 45.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleSITE(36)..(36)Xaa is Apr, 4-aminoproline 146Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Xaa 3514736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 46.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 147Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3514836PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 47.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(34)..(34)Orn 148Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Arg Thr Pro 3514936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 48.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 149Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Thr Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Thr Thr Pro 3515036PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is

isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 49.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 150Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3515136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 50.MOD_RES(18)..(18)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RE- S(36)..(36)4Hyp 151Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Glu Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3515236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 51.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(34)..(34)OrnMOD_RE- S(36)..(36)4Hyp 152Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Arg Thr Pro 3515336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 52.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 153Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Gly Thr Pro 3515436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 53.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(34)..(34)AadMOD_RE- S(36)..(36)4Hyp 154Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3515536PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 54.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 155Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3515636PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 55.MOD_RES(15)..(15)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RE- S(36)..(36)4Hyp 156Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3515736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 56.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 157Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3515836PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 57.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 158Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3515936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 58.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 159Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3516036PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 59.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 160Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Asp Val Gly 20 25 30Ser Asn Thr Pro 3516136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 60.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 161Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asp Thr Pro 3516236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 61.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 162Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3516336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 62.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 163Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3516436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 63.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 164Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3516536PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 64.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 165Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3516636PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 65.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 166Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3516736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 66.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 167Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3516836PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 67.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 168Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3516936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 68.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 169Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3517036PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 69.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 170Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3517136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine

residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 70.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 171Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3517236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 71.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 172Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Gly Thr Pro 3517336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 72.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 173Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Gly Thr Pro 3517436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 73.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 174Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Thr Thr Pro 3517536PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 74.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 175Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Thr Thr Pro 3517636PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 75.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(34)..(34)AadMOD_RE- S(36)..(36)Hyp 176Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3517736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 76.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(34)..(34)AadMOD_RE- S(36)..(36)Hyp 177Xaa Arg Cys Pro Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Glu Thr Pro 3517834PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 77.MOD_RES(21)..(21)MeGlyMOD_RES(23)..(23)MeIleMOD_RES(34)..(34)4Hyp 178Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Asn 20 25 30Thr Pro17936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 78.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 179Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3518034PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 79.MOD_RES(21)..(21)MeGlyMOD_RES(23)..(23)MeIleMOD_RES(34)..(34)4Hyp 180Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Gly 20 25 30Thr Pro18136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 80.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 181Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Gly Thr Pro 3518236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 81.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 182Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Gly Thr Pro 3518336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 82.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 183Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Thr Thr Pro 3518436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 83.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 184Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asp Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Thr Thr Pro 3518536PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 84.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 185Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Glu Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3518636PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 85.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 186Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3518736PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 86.MOD_RES(15)..(15)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RE- S(36)..(36)4Hyp 187Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3518836PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 87.MOD_RES(15)..(15)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RE- S(36)..(36)Hyp 188Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Ser Thr Pro 3518936PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 88.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)Hyp 189Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3519036PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 89.MOD_RES(15)..(15)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RE- S(36)..(36)Hyp 190Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3519136PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 90.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 191Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Gly Thr Pro 3519236PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 91.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIleMOD_RES(36)..(36)4Hyp 192Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25

30Ser Gly Thr Pro 3519336PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 92.MOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 193Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3519436PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 93.MOD_RES(15)..(15)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 194Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Asn Thr Pro 3519536PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 94.MOD_RES(15)..(15)AadMOD_RES(23)..(23)MeGlyMOD_RES(25)..(25)MeIle 195Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Ser Ser Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly 20 25 30Ser Gly Thr Pro 3519634PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 95.MOD_RES(15)..(15)AadMOD_RES(21)..(21)MeGlyMOD_RES(23)..(23)MeIleMOD_RE- S(34)..(34)Hyp 196Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Asn 20 25 30Thr Pro19734PRTArtificial sequenceSynthetic amylin analogueSITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Sequence may possess an intramolecular disulphide bridge formed between the cysteine residues present at positions 3 and 8, corresponding to the cysteine residues present at positions 2 and 7 of human amylin. Feature is present in Compd. 96.MOD_RES(21)..(21)MeGlyMOD_RES(23)..(23)MeIle 197Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Phe Gly Ala Ile Leu Ser Ser Thr Glu Val Gly Ser Asn 20 25 30Thr Pro19837PRTArtificial sequenceSynthetic control sequence PramlintideDISULFID(2)..(7)Intramolecular disulphide bridge between the side chains of cysteine residues at positions 2 and 7 198Lys Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Asn Phe Leu1 5 10 15Val His Ser Ser Asn Asn Phe Gly Pro Ile Leu Pro Pro Thr Asn Val 20 25 30Gly Ser Asn Thr Tyr 3519937PRTArtificial sequenceSynthetic control sequence NN96, disclosed in WO2012/168430DISULFID(2)..(7)Intramolecular disulphide bridge between the side chains of cysteine residues at positions 2 and 7 199Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Glu Phe Leu1 5 10 15His His Ser Ser Asn Asn Phe Gly Pro Ile Leu Pro Pro Thr Asn Val 20 25 30Gly Ser Asn Thr Pro 3520036PRTArtificial sequenceSynthetic control sequence Compd. 97SITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Intramolecular disulphide bridge between the side chains of cysteine residues at positions 3 and 8 200Xaa Arg Cys Asn Thr Ala Thr Cys Ala Thr Gln Arg Leu Ala Glu Phe1 5 10 15Leu His His Ser Ser Phe Gly Pro Ile Leu Pro Pro Thr Asn Val Gly 20 25 30Ser Asn Thr Pro 3520138PRTArtificial sequenceSynthetic control sequence Compd. 98SITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Intramolecular disulphide bridge between the side chains of cysteine residues at positions 3 and 8MOD_RES(15)..(15)AadMOD_RES(25)..(25)MeGlyMOD_RES(27)..(27)MeIleMOD_RES(- 38)..(38)4Hyp 201Xaa Arg Cys Gly Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Ser Ser Asn Asn Phe Gly Ala Ile Leu Ser Ser Thr Glu 20 25 30Val Gly Ser Asn Thr Pro 3520238PRTArtificial sequenceSynthetic control sequence Compd. 99SITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Intramolecular disulphide bridge between the side chains of cysteine residues at positions 3 and 8MOD_RES(25)..(25)MeGlyMOD_RES(27)..(27)MeIleMOD_RES(38)..(38)4Hyp 202Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Glu Arg Leu Ala His Phe1 5 10 15Leu Gln Arg Ser Ser Asn Asn Phe Gly Ala Ile Leu Ser Ser Thr Glu 20 25 30Val Gly Ser Asn Thr Pro 3520338PRTArtificial sequenceSynthetic control sequence Compd. 100SITE(1)..(1)Xaa is isoGluSITE(1)..(1)Linked to [19-carboxynonadecanoyl]DISULFID(3)..(8)Intramolecular disulphide bridge between the side chains of cysteine residues at positions 3 and 8MOD_RES(15)..(15)AadMOD_RES(25)..(25)MeGlyMOD_RES(27)..(27)MeIleMOD_RES(- 38)..(38)4Hyp 203Xaa Arg Cys Gln Thr Ala Thr Cys Ala Thr Asp Arg Leu Ala Glu Phe1 5 10 15Leu Gln Arg Ser Ser Asn Asn Phe Gly Ala Ile Leu Ser Ser Thr Glu 20 25 30Val Gly Ser Asn Thr Pro 35

Claims

1. An amylin analogue which is a compound having the formula: R.sup.1--Z--R.sup.2 wherein R.sup.1 is hydrogen, C.sub.1-4 acyl, benzoyl or C.sub.1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R.sup.2 is OH or NHR.sup.3, wherein R.sup.3 is hydrogen or C.sub.1-3-alkyl; and Z is an amino acid sequence of formula I: TABLE-US-00021 (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: TABLE-US-00022 (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: TABLE-US-00023 (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: TABLE-US-00024 (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.sup.1--Z--R.sup.2 wherein R.sup.1 is hydrogen, C.sub.1-4 acyl, benzoyl or C.sub.1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R.sup.2 is OH or NHR.sup.3, wherein R.sup.3 is hydrogen or C.sub.1-3-alkyl; and Z is an amino acid sequence selected from the group consisting of: TABLE-US-00025 (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.sup.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.sup.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, .alpha.-Glu, .gamma.-Glu, .epsilon.-Lys, Asp, .beta.-Asp, Ser, Thr, Gaba, Aib, .beta.-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 .gamma.-Glu residue.

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

26. An amylin analogue according to claim 1 which is selected from the group consisting of: TABLE-US-00026 (SEQ ID NO: 103) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2, (SEQ ID NO: 104) [19CD]-isoGlu-RCNTATCATQRLANFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2, (SEQ ID NO: 107) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 108) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 109) [19CD]-isoGlu-RCGTATCATERLAHFLERSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 110) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 111) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2, (SEQ ID NO: 112) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2, (SEQ ID NO: 113) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2, (SEQ ID NO: 114) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2, (SEQ ID NO: 115) [19CD]-isoGlu-RCNTATCATQRLAHFLHRF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2, (SEQ ID NO: 116) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 117) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 118) [19CD]-isoGlu-RCGTATCATERLANFLVRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 119) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 120) [19CD]-isoGlu-RCGTATCATERLAHFLKRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 121) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSVF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2, (SEQ ID NO: 122) [19CD]-isoGlu-RCNTATCATQRLAHFLHRVSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2, (SEQ ID NO: 123) [19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2, (SEQ ID NO: 124) [19CD]-isoGlu-RCPTATCATDRLAHFLVRSSF-Gly(Me)-A- Ile(Me)-LSSTDVGSDTP-NH.sub.2, (SEQ ID NO: 125) [19CD]-isoGlu-RCNTATCATQRLAHFLVRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2, (SEQ ID NO: 126) [19CD]-isoGlu-RCPTATCATDRLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTDVGSNTP-NH.sub.2, (SEQ ID NO: 127) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2, (SEQ ID NO: 128) [19CD]-isoGlu-RCPTATCATDRLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTDVGSDTP-NH.sub.2, (SEQ ID NO: 129) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 130) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 131) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 132) [19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 133) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2, (SEQ ID NO: 134) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2, (SEQ ID NO: 135) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSSTP-NH.sub.2, (SEQ ID NO: 136) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSSTP-NH.sub.2, (SEQ ID NO: 137) [19CD]-isoGlu-RCGTATCATERLAHFLERSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSSTP-NH.sub.2, (SEQ ID NO: 138) [19CD]-isoGlu-RCGTATCATERLAHFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSSTP-NH.sub.2, (SEQ ID NO: 139) [19CD]-isoGlu-RCGTATCATERLAHFLVRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSSTP-NH.sub.2, (SEQ ID NO: 140) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSFTP-NH.sub.2, (SEQ ID NO: 141) [19CD]-isoGlu-RCGTATCATERLAHFLNRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSFTP-NH.sub.2, (SEQ ID NO: 142) [19CD]-isoGlu-RCGTATCATERLADFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 143) [19CD]-isoGlu-RCGTATCATERLADFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSFT-Hyp-NH.sub.2, (SEQ ID NO: 144) [19CD]-isoGlu-RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)- A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 145) [19CD]-isoGlu-RCGTATCATERLA-Aad-FLTRSSF-Gly(Me)- A-Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2, (SEQ ID NO: 146) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Apr-NH.sub.2, (SEQ ID NO: 147) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSSTP-NH.sub.2, (SEQ ID NO: 148) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Orn-TP-NH.sub.2, (SEQ ID NO: 149) [19CD]-isoGlu-RCGTATCATERLAHFLTRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2, (SEQ ID NO: 150) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 151) [19CD]-isoGlu-RCNTATCATQRLAHFL-Aad-RSSF-Gly(Me)- A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 152) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Orn-T-Hyp-NH.sub.2, (SEQ ID NO: 153) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2, (SEQ ID NO: 154) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2,

(SEQ ID NO: 155) [19CD]-isoGlu-RCGTATCATERLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 156) [19CD]-isoGlu-RCGTATCATERLA-Aad-FLQRSSF-Gly(Me)- A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 157) [19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 158) [19CD]-isoGlu-RCQTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 159) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 160) [19CD]-isoGlu-RCPTATCATDRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTDVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 161) [19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSDT-Hyp-NH.sub.2, (SEQ ID NO: 162) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 163) [19CD]-isoGlu-RCNTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 164) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 165) [19CD]-isoGlu-RCPTATCATQRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 166) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 167) [19CD]-isoGlu-RCNTATCATERLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 168) [19CD]-isoGlu-RCPTATCATERLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 169) [19CD]-isoGlu-RCNTATCATERLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 170) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 171) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 172) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2, (SEQ ID NO: 173) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2, (SEQ ID NO: 174) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2, (SEQ ID NO: 175) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2, (SEQ ID NO: 176) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2, (SEQ ID NO: 177) [19CD]-isoGlu-RCPTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGS-Aad-T-Hyp-NH.sub.2, (SEQ ID NO: 178) [19CD]-isoGlu-RCGTATCATERLAHFLQRF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 179) [19CD]-isoGlu-RCGTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 180) [19CD]-isoGlu-RCNTATCATQRLAHFLQRF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2, (SEQ ID NO: 181) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGTP-NH.sub.2, (SEQ ID NO: 182) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2, (SEQ ID NO: 183) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSTTP-NH.sub.2, (SEQ ID NO: 184) [19CD]-isoGlu-RCNTATCATQRLADFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSTT-Hyp-NH.sub.2, (SEQ ID NO: 185) [19CD]-isoGlu-RCNTATCATQRLAHFLERSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSSTP-NH.sub.2, (SEQ ID NO: 186) [19CD]-isoGlu-RCNTATCATQRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSSTP-NH.sub.2, (SEQ ID NO: 187) [19CD]-isoGlu-RCNTATCATQRLA-Aad-FLQRSSF- Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 188) [19CD]-isoGlu-RCNTATCATQRLA-Aad-FLQRSSF-Gly(Me)- A-Ile(Me)-LSSTEVGSST-Hyp-NH.sub.2, (SEQ ID NO: 189) [19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 190) [19CD]-isoGlu-RCQTATCATDRLA-Aad-FLQRSSF-Gly(Me)- A-Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 191) [19CD]-isoGlu-RCQTATCATERLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2, (SEQ ID NO: 192) [19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSGT-Hyp-NH.sub.2, (SEQ ID NO: 193) [19CD]-isoGlu-RCQTATCATDRLAHFLQRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 194) [19CD]-isoGlu-RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)- A-Ile(Me)-LSSTEVGSNTP-NH.sub.2, (SEQ ID NO: 195) [19CD]-isoGlu-RCQTATCATERLA-Aad-FLQRSSF-Gly(Me)- A-Ile(Me)-LSSTEVGSGTP-NH.sub.2, (SEQ ID NO: 196) [19CD]-isoGlu-RCQTATCATDRLA-Aad-FLQRF-Gly(Me)-A- Ile(Me)-LSSTEVGSNT-Hyp-NH.sub.2, (SEQ ID NO: 197) [19CD]-isoGlu-RCQTATCATERLAHFLQRF-Gly(Me)-A- Ile(Me)-LSSTEVGSNTP-NH.sub.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: TABLE-US-00027 (SEQ ID NO 102) [19CD]-isoGlu-RCNTATCATQRLADFLHRSSF-Gly(Me)-A- Ile(Me)-LSSTEVGSETP-NH.sub.2; (SEQ ID NO 105) [19CD]-isoGlu-RCNTATCATQRLADFLHRSSNNF-Gly(Me)-A- Ile(Me)-LSSTNVGSNT-Apr-NH.sub.2; and (SEQ ID NO 106) [19CD]-isoGlu-RCNTATCATQRLAHFLHRSSNNF-Gly(Me)-A- Ile(Me)-LSSTNVGSNT-Apr-NH.sub.2;

wherein [19CD] represents [19-carboxynonadecanoyl]: or a pharmaceutically acceptable salt thereof.

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