Derivatives of GLP-1 like peptides, and uses thereof

1. A derivative of a GLP-1 analogue, wherein the GLP-1 analogue comprises a sequence of Formula I:

Formula I:

Xaa 7 -Xaa 8 -Glu-Gly-Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-

Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Ala-Xaa 25 -Xaa 26 -

Xaa 27 -Phe-Ile-Xaa 30 -Xaa 31 -Leu-Xaa 33 -Xaa 34 -Xaa 35 -

Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -Xaa 41 -Xaa 42 ,

wherein

Xaa 7 is L-histidine, (S)-2-Hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D-histidine, desamino-histidine, homohistidine, N α -acetyl-histidine, N α -formyl-histidine, N α -methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine;

Xaa 8 is Aib;

Xaa 12 is Phe or Leu;

Xaa 16 is Val or Leu;

Xaa 18 is Ser, Arg, Val, or Leu;

Xaa 19 is Tyr or Gln;

Xaa 20 is Leu or Met;

Xaa 22 is Glu;

Xaa 23 is Gln, Glu, or Arg;

Xaa 25 is Ala or Val;

Xaa 26 is Arg;

Xaa 27 is Glu or Leu;

Xaa 30 is Ala, Glu, or Arg;

Xaa 31 is Trp or His;

Xaa 33 is Val or Arg;

Xaa 34 is Arg, His, Asn, or Gln;

Xaa 35 is Gly or Ala;

Xaa 36 is Lys;

Xaa 37 is Gly or Pro;

Xaa 38 is Ser, Gly, Ala, Glu, or Pro;

Xaa 39 is Ser, Gly, Ala, Glu, or Pro;

Xaa 40 is Ser, Gly, Ala, Glu, or Pro;

Xaa 41 is Ser, Gly, Ala, Glu, or Pro; and

Xaa 42 is Lys;

wherein Lys at Xaa 42 is a first K residue, and Lys at Xaa 36 is a second K residue;

wherein Lys at Xaa 42 and Lys at Xaa 36 are the only Lys residues;

which derivative comprises a first and a second protracting moiety connected to said first and second K residue, respectively, wherein the first and the second protracting moiety is selected from Chem. 1, Chem. 1a, and Chem. 1b:

HOOC—(CH 2 ) 18 —CO—*,  Chem. 1:

HOOC—(CH 2 ) 17 —CO—*, and  Chem. 1a:

HOOC—(CH 2 ) 20 —CO—*;  Chem. 1b:

or a pharmaceutically acceptable salt, amide, or ester thereof.

2. The derivative of claim 1 , wherein Xaa 34 is Arg.

3. The derivative of claim 2 , wherein the GLP-1 analogue has a maximum of 12 amino acid changes when compared with GLP-1(7-37) (SEQ ID NO: 1).

4. The derivative of claim 3 , wherein each of the first and the second protracting moiety is attached to the first and the second K residue, respectively, via a first and a second linker, respectively.

5. The derivative of claim 4 , wherein each of the first and the second linker comprises at least one linker element selected from the following:

wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5;

wherein q is an integer in the range of 0-5, and w is an integer in the range of 0-5, with the provisos that when w is 0 then q is an integer in the range of 1-5, and when q is 0 then w is an integer in the range of 1-5;

wherein y is 1 or 2, z is 1 or 2, p is 0 or 1, and X designates a carbon atom or an oxygen atom; and

6. The derivative of claim 1 , wherein in Formula I

Xaa 7 is L-histidine, (S)-2-Hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D-histidine, desamino-histidine, N α -acetyl-histidine, N α -formyl-histidine, or N α -methyl-histidine;

Xaa 8 is Aib;

Xaa 12 is Phe;

Xaa 16 is Val or Leu;

Xaa 18 is Ser or Arg;

Xaa 19 is Tyr or Gln;

Xaa 20 is Leu or Met;

Xaa 22 is Glu;

Xaa 23 is Gln, Glu, or Arg;

Xaa 25 is Ala or Val;

Xaa 26 is Arg;

Xaa 27 is Glu or Leu;

Xaa 30 is Ala or Glu;

Xaa 31 is Trp or His;

Xaa 33 is Val or Arg;

Xaa 34 is Arg or Asn;

Xaa 35 is Gly;

Xaa 36 is Lys;

Xaa 37 is Gly or Pro;

Xaa 38 is Gly, Ala, Glu, or Pro;

Xaa 39 is Ser, Gly, Ala, Glu, or Pro;

Xaa 40 is Ser, Gly, Ala, Glu, or Pro;

Xaa 41 is Ser, Gly, Ala, Glu, or Pro; and

Xaa 42 is Lys.

7. The derivative of claim 6 , wherein the analogue has a maximum of 12 amino acid changes when compared with GLP-1(7-37) (SEQ ID NO: 1).

8. The derivative of claim 7 , wherein each of the first and the second protracting moiety is attached to the first and the second K residue, respectively, via a first and a second linker, respectively.

9. The derivative of claim 8 , wherein each of the first and the second linker comprises at least one linker element selected from the following:

wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5;

wherein q is an integer in the range of 0-5, and w is an integer in the range of 0-5, with the provisos that when w is 0 then q is an integer in the range of 1-5, and when q is 0 then w is an integer in the range of 1-5;

wherein y is 1 or 2, z is 1 or 2, p is 0 or 1, and X designates a carbon atom or an oxygen atom; and

10. The derivative of claim 9 , wherein in Formula I

Xaa 7 is L-histidine;

Xaa 12 is Phe;

Xaa 16 is Val;

Xaa 18 is Ser;

Xaa 19 is Tyr;

Xaa 20 is Leu;

Xaa 23 is Gln;

Xaa 25 is Ala;

Xaa 27 is Glu;

Xaa 30 is Ala;

Xaa 31 is Trp;

Xaa 33 is Val;

Xaa 34 is Arg; and

Xaa 37 is Gly.

11. The derivative of claim 10 , wherein in Formula I

Xaa 38 is Gly, Ala, Glu, or Pro;

Xaa 39 is Gly, Ala or Glu;

Xaa 40 is Ser, Gly, or Pro; and

Xaa 41 is Ser, Ala, Glu, or Pro.

12. A GLP-1 derivative selected from the following:

where the amino acid sequence is that of SEQ ID NO:6,

where the amino acid sequence is that of SEQ ID NO:9,

where the amino acid sequence is that of SEQ ID NO: 11, and

where the amino acid sequence is that of SEQ ID NO: 10, or a pharmaceutically acceptable salt, amide, or ester thereof.

13. A pharmaceutical composition comprising a derivative according to claim 1 and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising a derivative according to claim 12 and a pharmaceutically acceptable excipient.

15. A method for treating a subject having hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetes of the young), and/or gestational diabetes, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 13 .

16. A method for treating obesity in a subject, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 13 .