Amylin analogues and pharmaceutical compositions thereof

1. A polypeptide comprising SEQ ID NO:3:

Formula (I)

(SEQ ID No: 3)

Xaa 1 -Cys-Xaa 3 -Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-

Ala-Xaa 14 -Phe-Leu-Xaa 17 -Xaa 18 -Ser-Ser-Xaa 21 -Xaa 22 -

Phe-Gly-Pro-Xaa 26 -Leu-Pro-Pro-Thr-Xaa 31 -Val-Gly-

Ser-Xaa 35 -Thr-Pro;

wherein

Xaa 1 is deleted or independently selected from Ala, Cys, Glu, Gly, His, Arg, Ser and Lys;

Xaa 3 is independently selected from Gly, His, Arg, Ser and Asn;

Xaa 14 is independently selected from Glu and Asn;

Xaa 17 is independently selected from His, Arg, Lys and Val;

Xaa 18 is independently selected from Arg, Lys and His;

Xaa 21 is independently selected from Ala, Lys, Gln, Ser and Asn;

Xaa 22 is independently selected from Glu, Gln, Ser, Thr and Asn;

Xaa 26 is independently selected from Pro, Arg and Ile;

Xaa 31 is independently selected from Ser, Glu, Asp and Asn; and

Xaa 35 is independently selected from His, Arg, Lys, Asp, Gln and Glu:

and wherein the C-terminal may optionally be derivatized.

2. The polypeptide according to claim 1 wherein Xaa 14 is glutamic acid.

3. The polypeptide according to claim 1 wherein Xaa 17 is arginine.

4. The polypeptide according to claim 1 , wherein Xaa 14 is glutamic acid, and Xaa 17 is arginine.

5. The polypeptide according to claim 1 wherein at least one substituent is attached to at least one amino acid residue of said polypeptide.

6. The polypeptide according to claim 5 wherein the substituent group is selected from the group consisting of C20diacid, C20diacid-γGlu, C20diacid-γGlu-γGlu, C20diacid-γGlu-γGlu-γGlu, C20diacid-OEG, C20diacid-γGlu-OEG, C20diacid-γGlu-OEG-OEG, C18diacid-γGlu, C16diacid-γGlu, and C14diacid-γGlu.

7. The polypeptide according to claim 5 wherein a substituent is attached to the α-amino group of the N-terminal amino acid residue or to a Lys residue.

8. A polypeptide selected from the group consisting of

N-alpha-[(S)-4-Carboxy-4-(19-carboxynonadecanoylamino)butyryl]-Gly-[His1,Glu14,Arg17,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[His1,Glu14,Arg17,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Gly1,Glu14,Arg17,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Arg1,Glu14,His17,Pro37]-pramlintide

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-Gly-[Arg1,Glu14,His17,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Glu14,Arg17,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Glu14,His17,GIn21,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Glu14,His17,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Lys11,Glu14,His17,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-Glu-Arg-[Glu1,Glu14,Arg17,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Glu14,Arg18,Ser21,Ser22,Ser28,Ser29,Asp31,Asp35,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Glu14,His17,GIn21,GIn35,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]- [Glu14,His17,Thr21,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-[Glu14,His17,GIn35,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryl]-Glu-Arg-[Glu1,Glu14,Arg17,GIn21,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryI]-Glu-Arg-[Glu1,Glu14,Arg17,GIn21,GIn35,Pro37]-pramlintide,

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryI]-Glu-Arg-[Glu1,Glu14,Arg17,GIn21,GIn31,GIn35,Pro37]-pramlintide, and

N-alpha-[(S)-4-Carboxy-4-(19carboxynonadecanoylamino)butyryI]-Glu-Arg-[Glu1,Glu14,Arg17,GIn21,GIn22,GIn31,GIn35,Pro37]-pramlintide.

9. A method of treating, type 2 diabetes, or obesity comprising administering the polypeptide of claim 1 to a subject in need thereof.

10. A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable excipient.

11. A process for preparing a pharmaceutical composition comprising mixing the polypeptide of claim 1 with at least one pharmaceutically acceptable excipient.