Double-acylated GLP-1 derivatives
The invention relates to a derivative of a GLP-1 peptide, which peptide comprises a first K residue and a second K residue, at positions corresponding to position 26, and 34, respectively, of GLP-1(7-37) (SEQ ID NO:1), and a maximum of eight amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is Chem. 2: HOOC—C 6 H 4 —O—(CH 2 ) y —CO—*, in which y is an integer in the range of 6-13; and the linker comprises Chem. 3a: *—NH—(CH 2 ) q —CH[(CH 2 ) w —NR 1 R 2 ]—CO—*, wherein q is an integer in the range of 0-5, R 1 and R 2 independently represent *—H or *—CH 3 , and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptide and linker intermediates. The derivatives are potent, stable, protracted, and suitable for oral administration.
1. A compound selected from the following:
where the amino acid sequence is that of SEQ ID NO: 4, or a pharmaceutically acceptable salt, amide, or ester of any of the preceding compounds.
2. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 4, or a pharmaceutically acceptable salt, amide, or ester thereof.
3. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 4, or a pharmaceutically acceptable salt, amide, or ester thereof.
4. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 5, or a pharmaceutically acceptable salt, amide, or ester thereof.
5. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 1, or a pharmaceutically acceptable salt, amide, or ester thereof.
6. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 1, or a pharmaceutically acceptable salt, amide, or ester thereof.
7. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 4, or a pharmaceutically acceptable salt, amide, or ester thereof.
8. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 4, or a pharmaceutically acceptable salt, amide, or ester thereof.
9. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 4, or a pharmaceutically acceptable salt, amide, or ester thereof.
10. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 6, or a pharmaceutically acceptable salt, amide, or ester thereof.
11. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 7, or a pharmaceutically acceptable salt, amide, or ester thereof.
12. The compound of claim 1 , wherein the compound is
where the amino acid sequence is that of SEQ ID NO: 4, or a pharmaceutically acceptable salt, amide, or ester thereof.
13. A method for treating diabetes in a subject in need of such treatment, said method comprising administering to a subject a pharmaceutically active amount of the compound of claim 1 .
14. A composition comprising the compound of claim 1 and an antidiabetic agent.
15. The composition of claim 14 , wherein the antidiabetic agent is insulin.