Granted Patent B2

US 11,382,956 · App. 16/664,168 · Granted Jul 12, 2022

Inventors: Jesper Mosolff Mathiesen (Farum, DK); Jesper Skodborg Villadsen (Skovlunde, DK); Lise Giehm (Frederiksberg, DK); Henrik Kofoed Munch (Frederiksberg, DK); Dieter Wolfgang Hamprecht (Pozzolengo, IT); Alexander Heim-Riether (Ingelheim am Rhein, DE); Giacomo Fossati (Ingelheim am Rhein, DE)

Assignee: Zealand Pharma A/S

A61K38/22C07K14/575

Abstract

Claims (326)

1. A method of synthesizing an amylin analogue, said method comprising solid-phase or liquid-phase peptide synthesis of the amylin analogue, wherein the amylin analogue is a compound having the formula:

R 1 —Z—R 2

wherein

R 1 is hydrogen, C 1-4 acyl, benzoyl or C 1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

R 2 is OH or NHR 3 , wherein R 3 is hydrogen or C 1-3 -alkyl; and

Z is an amino acid sequence of formula I:

(I)

(SEQ ID NO: 3) 

X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-

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

X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37

wherein

X1 is selected from the group consisting of Arg, Lys and Glu;

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

X4 is selected from the group consisting of Thr and Glu;

X5 is selected from the group consisting of Ala and Leu;

X6 is selected from the group consisting of Thr and Ser;

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

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

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

X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

X27 is selected from the group consisting of Leu and Pro;

X32 is selected from the group consisting of Val and Thr;

X35 is selected from the group consisting of Asn and Ser;

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

X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein X1 is selected from Arg and Lys.

3. The method of claim 1 , wherein:

(i) X3 is Gly, X4 is Thr, X5 is Ala and/or X6 is Thr;

(ii) X3 is Gly, X4 is Thr, X5 is Ala and X6 is Thr;

(iii) X14 is selected from His, Asp and Aad;

(iv) X17 is Gln;

(v) X19-X20 is selected from Ser-Ser and Thr-Thr, or is absent; or

(vi) X32 is Val, X35 is Asn and/or X37 is Hyp.

4. The method of claim 1 , wherein Z is an amino acid sequence of formula II:

(II)

(SEQ ID NO: 4)

X1-X2-Gly-Thr-Ala-Thr-X7-Ala-Thr-X10-Arg-Leu-Ala-

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

(Me)-X27-Ser-Ser-Thr-Glu-Val-Gly-Ser-Asn-Thr-Hyp

wherein

X1 is selected from Arg and Lys;

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

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

X19-X20 is selected from Ser-Ser and Thr-Thr or is absent;

X27 is selected from the group consisting of Leu and Pro; and

X2 and X7 are amino acid residues whose side chains together form a lactam bridge.

5. The method of claim 1 , wherein one of the residues at position X2 and X7 is selected from Asp, Glu and Aad, and the other is selected from Dap, Dab, Orn, Lys and hLys.

6. The method of claim 5 , wherein:

X2 is Asp and X7 is Lys;

X2 is Asp and X7 is Orn;

X2 is Asp and X7 is Dab;

X2 is Asp and X7 is hLys;

X2 is Dap and X7 is Aad;

X2 is Glu and X7 is Dab; or

X2 is Dab and X7 is Glu.

7. The method according to claim 6 , wherein:

X2 is Asp and X7 is Lys; or

X2 is Asp and X7 is Orn.

8. The method according to claim 1 , wherein X14 is selected from Asp and Aad.

9. The method according to claim 1 , wherein Z is an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 5)

RD()GTAT-Dap()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 6)

RD()GTAT-Dab()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 7)

RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 8)

RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp

(SEQ ID NO: 9)

RD()GTAT-Orn()-ATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 10)

RD()GTAT-Orn()-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNTP

(SEQ ID NO: 11)

RD()GTAT-Orn()-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 12)

RD()GTAT-Orn()-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp

(SEQ ID NO: 13)

RD()GTAT-Orn()-ATERLARFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 14)

ED()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 15)

RD()GEATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 16)

RD()GTLTK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 17)

RD()GTASK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 18)

RD()GTATK()ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp

(SEQ ID NO: 19)

RD()GTATK()ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 20)

RD()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp

(SEQ ID NO: 21)

RD()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 22)

RD()GTAT-hLys()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 23)

RD()GTAT-Orn()-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 24)

RD()GTAT-Orn()-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp

(SEQ ID NO: 25)

RD()GTAT-Orn()-ATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSST-Hyp

(SEQ ID NO: 26)

RD()GTAT-Orn()-ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 27)

RD()GTAT-Orn()-ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp

(SEQ ID NO: 28)

RD()GTAT-Orn()-ATERLA-Aad-FLQRATF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 29)

RD()GTAT-Orn()-ATERLA-Aad-FLQRAAF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 30)

RD()GTAT-Orn()-ATERLA-Aad-FLQRGTF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 31)

RD()QTAT-Orn()-ATERLA-Aad-FLQRGTF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 32)

RD()PTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 33)

ED()GTATK()ATE RLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp

(SEQ ID NO: 34)

RD()GTATK()ATERLA-Aad-FLQRAAF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 35)

RD()GTATK()ATERLA-Aad-FLQRGGF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 36)

RD()GTATK()ATERLA-Aad-FLQRANF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 37)

RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-PSSTEVGSNT-Hyp

(SEQ ID NO: 38)

RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 39)

RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTETGSNT-Hyp

(SEQ ID NO: 40)

ED()GTATK()ATERLA-Aad-FLQRSSFGly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 41)

RD()GTATK()ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 42)

KD()GTATK()ATQRLA-Aad-FLQRSSF-Gly(Me)-AIle(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 43)

RD()GTATK()ATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 44)

RD()GTATK()ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 45)

RD()GTATK()ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTETGSNT-Hyp

(SEQ ID NO: 46)

KD()GTATK()ATQRLANFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 47)

KD()GTATK()ATQRLANFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTETGSNT-Hyp

(SEQ ID NO: 48)

R-Dap()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 49)

R-Dab()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 50)

R-Orn()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 51)

R-Dap()-GTAT-Aad()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 52)

R-Dab()-GTATE()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 53)

R-Aad()-GTAT-Dap()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

(SEQ ID NO: 54)

RE()GTAT-Dab()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein R 1 is M or M-L-.

11. The method of claim 10 , wherein M is a lipophilic substituent comprising a hydrocarbon chain having from 10 to 24 C atoms.

12. The method of claim 11 , wherein the lipophilic substituent comprises a carboxylic acid group at the end of the hydrocarbon chain.

13. The method of claim 12 , wherein the lipophilic substituent is a 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl or 19-carboxy-nonadecanoyl moiety.

14. The method of claim 10 , wherein the linker L comprises a residue of Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, ε-Lys, Asp, β-Asp, Ser, Thr, Gaba, Aib, β-Ala (i.e. 3-aminopropanoyl), 4-aminobutanoyl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl or 8Ado (i.e. 8-amino-3,6-dioxaoctanoyl).

15. The method of claim 14 , wherein L is a residue of Glu, γ-Glu, ε-Lys, β-Ala, 4-aminobutanoyl, β-aminooctanoyl or 8Ado.

16. The method of claim 15 , wherein R1 is [19CD]-isoGlu.

17. The method of claim 1 , wherein R 2 is NH 2 .

18. The method of claim 1 , wherein the amylin analog is:

[19CD]-isoGlu-RD()GTAT-Dap()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 1)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 55)

[19CD]-isoGlu-RD()GTAT-Dab()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 2)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 56)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 3)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 57)

[19CD]-isoGlu-isoGlu-RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-

(Compound 4)

Ile(Me)-LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 58)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 5)

PSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 59)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLAHFLQRF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 6)

VGSNT-Hyp-NH 2  (SEQ ID NO: 60)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLAHFLHRSSF-Gly(Me)-A-Ile(Me)-

(Compound 7)

LSSTEVGSNTP-NH 2  (SEQ ID NO: 61)

[19CD]-isoGlu-RD()GTAT-Orn()-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 8)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 62)

[19CD]-isoGlu-RD()GTAT-Orn()-ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 9)

PSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 63)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLARFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 10)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 64)

[19CD]-isoGlu-ED()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 11)

VGSNT-Hyp-NH 2  (SEQ ID NO: 65)

[19CD]-isoGlu-RD()GEATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 12)

VGSNT-Hyp-NH 2  (SEQ ID NO: 66)

[19CD]-isoGlu-RD()GTLTK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 13)

VGSNT-Hyp-NH 2  (SEQ ID NO: 67)

[19CD]-isoGlu-RD()GTASK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 14)

VGSNT-Hyp-NH 2  (SEQ ID NO: 68)

[19CD]-isoGlu-RD()GTATK()ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTE-

(Compound 15)

VGSNT-Hyp-NH 2  (SEQ ID NO: 69)

[19CD]-isoGlu-RD()GTATK()ATQRLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 16)

VGSNT-Hyp-NH 2  (SEQ ID NO: 70)

[19CD]-isoGlu-RD()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-PSSTE-

(Compound 17)

VGSNT-Hyp-NH 2  (SEQ ID NO: 71)

[19CD]-isoGlu-RD()GTATK()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 18)

VGSNT-Hyp-NH 2  (SEQ ID NO: 72)

[19CD]-isoGlu-RD()GTAT-hLys()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 19)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 73)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 20)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 74)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 21)

PSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 75)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLTRSSF-Gly(Me)-A-Ile(Me)-

(Compound 22)

LSSTEVGSST-Hyp-NH 2  (SEQ ID NO: 76)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-

(Compound 23)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 77)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-

(Compound 24)

PSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 78)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRATF-Gly(Me)-A-Ile(Me)-

(Compound 25)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 79)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRAAF-Gly(Me)-A-Ile(Me)-

(Compound 26)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 80)

[19CD]-isoGlu-RD()GTAT-Orn()-ATERLA-Aad-FLQRGTF-Gly(Me)-A-Ile(Me)-

(Compound 27)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 81)

[19CD]-isoGlu-RD()QTAT-Orn()-ATERLA-Aad-FLQRGTF-Gly(Me)-A-Ile(Me)-

(Compound 28)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 82)

[19CD]-isoGlu-RD()PTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 29)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 83)

[19CD]-isoGlu-ED()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 30)

PSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 84)

[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRAAF-Gly(Me)-A-Ile(Me)-

(Compound 31)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 85)

[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRGGF-Gly(Me)-A-Ile(Me)-

(Compound 32)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 86)

[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRANF-Gly(Me)-A-Ile(Me)-

(Compound 33)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 87)

[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 34)

PSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 88)

[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 35)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 89)

[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 36)

LSSTETGSNT-Hyp-NH 2  (SEQ ID NO: 90)

[19CD]-isoGlu-ED()GTATK()ATERLA-Aad-FLQRSSFGly(Me)-A-Ile(Me)-

(Compound 37)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 91)

[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRTTF-Gly(Me)-A-Ile(Me)-

(Compound 38)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 92)

[19CD]-isoGlu-KD()GTATK()ATQRLA-Aad-FLQRSSF-Gly(Me)-Alle(Me)-

(Compound 39)

LSSTEVGSNTHyp-NH 2  (SEQ ID NO: 93)

[19CD]-isoGlu-RD()GTATK()ATQRLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 40)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 94)

[19CD]-isoGlu-RD()GTATK()ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 41)

VGSNT-Hyp-NH 2  (SEQ ID NO: 95)

[19CD]-isoGlu-RD()GTATK()ATQRLADFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 42)

LSSTETGSNT-Hyp-NH 2  (SEQ ID NO: 96)

[19CD]-isoGlu-KD()GTATK()ATQRLANFLQRSSF-Gly(Me)-A-Ile(Me)-LSSTE-

(Compound 43)

VGSNT-Hyp-NH 2  (SEQ ID NO: 97)

[19CD]-isoGlu-KD()GTATK()ATQRLANFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 44)

LSSTETGSNT-Hyp-NH 2  (SEQ ID NO: 98)

[19CD]-isoGlu-R-Dap()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 45)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 99)

[19CD]-isoGlu-R-Dab()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 46)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 100)

[19CD]-isoGlu-R-Orn()-GTATD()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 47)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 101)

[19CD]-isoGlu-R-Dap()-GTAT-Aad()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 48)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 102)

[19CD]-isoGlu-R-Dab()-GTATE()ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 49)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 103)

[19CD]-isoGlu-R-Aad()-GTAT-Dap()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 50)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 104)

[19CD]-isoGlu-RE()GTAT-Dab()-ATERLAHFLQRSSF-Gly(Me)-A-Ile(Me)-

(Compound 51)

LSSTEVGSNT-Hyp-NH 2  (SEQ ID NO: 105)

or a pharmaceutically acceptable salt thereof.

Assignments (7)