GLP-1 derivatives and uses thereof

1. A derivative of a GLP-1 peptide, wherein the GLP-1 peptide is of 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 -Xaa 43 , 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, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine;

Xaa 8 is Ala, Gly, Ser, Aib, (1-aminocyclopropyl) carboxylic acid, or(1-aminocyclobutyl) carboxylic acid;

Xaa 12 is Phe or Leu;

Xaa 16 is Val or Leu;

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

Xaa 19 is Tyr or Gln;

Xaa 20 is Leu or Met;

Xaa 22 is Gly or Glu;

Xaa 23 is Gln, Glu, or Arg;

Xaa 25 is Ala or Val;

Xaa 26 is Arg or Lys;

Xaa 27 is Glu, Lys, or Leu;

Xaa 30 is Ala, Glu, or Arg;

Xaa 31 is Trp or His;

Xaa 33 is Val, Lys, or Arg;

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

Xaa 35 is Gly or Ala;

Xaa 36 is Arg or Gly;

Xaa 37 is Gly, Pro, or Lys;

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

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

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

Xaa 41 is Ser, Gly, Ala, Glu, Pro, Lys, or absent;

Xaa 42 is Ser, Gly, Ala, Glu, Pro, Lys, or absent; and

Xaa 43 is Ser, Gly, Ala, Glu, Pro, Lys, or absent;

wherein

i) if Xaa 42 is absent, then Xaa 43 is also absent;

ii) if Xaa 41 is absent, then Xaa 42 and Xaa 43 is also absent;

iii) if Xaa 40 is absent, then Xaa 41 , Xaa 42 , and Xaa 43 are also absent;

iv) if Xaa 39 is absent, then Xaa 40 , Xaa 41 , Xaa 42 , and Xaa 43 are also absent; and/or

v) if Xaa 38 is absent, then Xaa 39 , Xaa 40 , Xaa 41 , Xaa 42 , and Xaa 43 are also absent;

wherein the GLP-1 peptide comprises a Lys residue at a position corresponding to position 27, 37, 38, 39, 40, 41, 42, or 43 of GLP-1(7-37) (SEQ ID NO: 1);

wherein the derivative comprises

a first and a second protracting moiety selected from Chem. 1 and Chem. 1a:

HOOC—(CH 2 ) 18 —CO—*, and  Chem. 1:

HOOC—(CH 2 ) 20 —CO—*;  Chem. 1a:

a branched linker of formula Chem. 2:

wherein

R 1 is —(CH 2 ) q —NH—*, wherein q is an integer in the range of 0-5,

R 2 is —(CH 2 ) w —NH—*, wherein w is an integer in the range of 0-5,

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

a first and a second further linker, each comprising an element_1 of formula Chem. 3:

wherein k is an integer in the range of 1-15, and n is an integer in the range of 1-5;

wherein

the first protracting moiety is attached at its *—CO end to a first *—NH end of the branched linker, via the first further linker,

the second protracting moiety is attached at its *—CO end to a second *—NH end of the branched linker, via the second further linker; and

the branched linker is attached at its *—CO end to the epsilon amino group of the Lys residue at a position corresponding to position 27,37,38,40,41,42, or 43 of GLP-1(7-37) (SEQ ID NO: 1) of the GLP-1 peptide;

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

2. The derivative of claim 1 , wherein q=4 and w=0.

3. The derivative of claim 1 , wherein the first further linker and the second further linker each comprises an element _2 of formula Chem. 4:

4. The derivative of claim 1 , wherein Xaa 8 is Aib.

5. The derivative of claim 1 , wherein 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 α-methyl-histidine; Xaa 8 is Ala, Gly, Ser, Aib, (1-aminocyclopropyl) carboxylic acid, or(1-aminocyclobutyl) carboxylic acid; Xaa 12 is Phe; Xaa 16 is Val or Leu; Xaa 18 is Ser, Lys, or Arg; Xaa 19 is Tyr or Gln; Xaa 20 is Leu or Met; Xaa 22 is Gly or Glu; Xaa 23 is Gln, Glu, or Arg; Xaa 25 is Ala or Val; Xaa 26 is Arg or Lys; Xaa 27 is Glu, Lys, or Leu; Xaa 30 is Ala or Glu; Xaa 31 is Trp or His; Xaa 33 is Val, Lys, or Arg; Xaa 34 is Arg, Lys, or Asn; Xaa 35 is Gly; Xaa 36 is Arg or Gly; Xaa 37 is Gly, Pro, or Lys; Xaa 38 is Ser, Gly, Ala, Glu, Pro, Lys, or absent; Xaa 39 is Ser, Gly, Ala, Glu, Pro, Lys, or absent; Xaa 40 is Ser, Gly, Ala, Glu, Pro, Lys, or absent; Xaa 41 is Ser, Gly, Ala, Glu, Pro, Lys, or absent; Xaa 42 is Gly, Ala, Glu, Pro, Lys, or absent; and Xaa 43 is Lys or absent.

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

7. The derivative of claim 1 , wherein the first further linker and the second further linker each comprises an element _3 of formula Chem. 5:

8. The derivative of claim 1 , wherein the first further linker and the second further linker each comprises an element _4 of formula Chem. 6:

9. A GLP-1 derivative selected from the following: Chem. 21

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

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

11. A method for

treating 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 in a subject in need of such treatment;

wherein said method comprises administering to said subject a pharmaceutically active amount of a derivative according to claim 1 .

12. A method for

treating 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 in a subject in need of such treatment;

wherein said method comprises administering to said subject a pharmaceutically active amount of a derivative according to claim 9 .