Double-acylated GLP-1 compounds
The invention relates to a derivative of a GLP-1 peptide, which peptide comprises a first Lys residue at a position corresponding to position 36 of GLP-1(7-37) (SEQ ID NO: 1), a second Lys residue at a position corresponding to position 37 of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of seven amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 1); which derivative comprises two protractors attached to said first and second Lys residue, respectively, each via a linker; wherein the protractor is selected from: HOOC—C 6 H 4 —O—(CH 2 ) y —CO—*, and Chem. 1: HOOC—(CH 2 ) x —CO—*, Chem. 2: wherein y is an integer in the range of 8-11, and x is 12; and the linker comprises at least one of: *—NH—CH(COOH)—(CH 2 ) 2 —CO—*, Chem. 3: *—NH—CH((CH 2 ) 2 —COOH)—CO—*, and/or Chem. 4: *—NH—(CH 2 ) 2 —[O—(CH 2 ) 2 ] k —O—[CH 2 ] n —CO—*, Chem. 5: wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical uses thereof, such as for the treatment of diabetes and obesity, as well as to the GLP-1 peptides forming part of these derivatives which have Lys residues at positions 36 and 37 and no other Lys residues, and the GLP-1(9-37) fragments thereof. The invention furthermore relates to an intermediate product comprising 3-carboxyphenoxy-nonanoic acid with a protection group at the carboxy group of the nonanoic acid, optionally via a linker. The derivatives have a very good potency and a long half-life which makes them potentially useful for, e.g., oral administration.
1. A derivative of a GLP-1 (7-37) analogue,
wherein said analogue comprises a first Lys residue at a position corresponding to position 36 of GLP-1(7-37) (SEQ ID NO: 1), a second Lys residue at a position corresponding to position 37 of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of seven amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 1);
which derivative comprises two protractors attached to said first and second Lys residue, respectively, each via a linker; wherein
the protractor is selected from:
HOOC—C 6 H 4 —O—(CH 2 ) y —CO—*, and Chem. 1:
HOOC—(CH 2 ) x —CO—*, Chem. 2:
wherein y is an integer in the range of 8-11, and x is 12; and
the linker comprises at least one of:
*—NH—CH(COOH)—(CH 2 ) 2 —CO—*, Chem. 3:
*—NH—CH((CH 2 ) 2 —COOH)—CO—*, and/or Chem. 4:
*—NH—(CH 2 ) 2 —[O—(CH 2 ) 2 ] k —O—[CH 2 ] n —CO—*, Chem. 5:
wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5, and wherein the amino acid in position 31 of GLP-1(7-37) (SEQ ID NO: 1) is Trp;
or a pharmaceutically acceptable salt, amide, or ester thereof.
2. The derivative of claim 1 , wherein the linker comprises Chem. 5.
3. The derivative of claim 2 , wherein k=n=1.
4. The derivative of claim 3 , wherein Chem. 5 is included one, two, three, or four times.
5. The derivative of claim 1 , wherein the linker comprises Chem. 3 or Chem. 4.
6. The derivative of claim 1 , wherein the GLP-1 (7-37) analogue comprises the sequence of Formula I:
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-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 -Lys-Lys (SEQ ID NO: 7),
wherein
Xaa 7 is L-histidine, (S)-2-Hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D-histidine, desamino-histidine (desH), N a -acetyl-histidine, N a -formyl-histidine;
Xaa 8 is Ala, Gly, Ser, Aib, (1-aminocyclopropyl) carboxylic acid, or (1-aminocyclobutyl) carboxylic acid;
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 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 or Leu;
Xaa 30 is Ala, or Glu;
Xaa 31 is Trp or His;
Xaa 33 is Val or Arg;
Xaa 34 is Arg, Lys, His, Asn, or Gln; and
Xaa 35 is Gly or Aib.
7. A GLP-1 derivative selected from the following:
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 22
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 23
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 24
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 25
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 26
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 27
where the amino acid sequence is that of SEQ ID NO:4,
Chem. 28
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 29
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 30
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 31
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 32
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 33
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 34
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 35
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 36
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 37
where the amino acid sequence is that of SEQ ID NO:5,
Chem. 38
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 39
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 40
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 41
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 42
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 43
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 44
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 45
where the amino acid sequence is that of SEQ ID NO:3,
Chem. 46
where the amino acid sequence is that of SEQ ID NO:2,
Chem. 47
where the amino acid sequence is that of SEQ ID NO:6, or
Chem. 48
where the amino acid sequence is that of SEQ ID NO:6; or a pharmaceutically acceptable salt, amide, or ester thereof.
8. A peptide consisting of SEQ ID NO: 7 wherein amino acid position Xaa 25 is Trp.
9. A peptide consisting of SEQ ID NO: 7 wherein amino acid positions Xaa 1 and Xaa 2 are absent and amino acid position Xaa 25 is Trp.
10. A method for treating diabetes, eating disorders, cardiovascular diseases, gastrointestinal diseases, diabetic complications, critical illness, and/or polycystic ovary syndrome; and/or for improving lipid parameters, improving β-cell function, and/or for delaying diabetic disease progression—by administering a pharmaceutically active amount of a derivative according to claim 1 .
11. A method for treating diabetes, eating disorders, cardiovascular diseases, gastrointestinal diseases, diabetic complications, critical illness, and/or polycystic ovary syndrome; and/or for improving lipid parameters, improving β-cell function, and/or for delaying diabetic disease progression—by administering a pharmaceutically active amount of a derivative according to claim 7 .