Acylated GLP-1 derivative
Provided are a GLP-1 (7-37) polypeptide analogue, a fatty acid-modified derivative of the analogue, and a medicament comprising the derivative. Further, also provided are a preparation method of the derivative, and use of the same in the preparation of a medicament.
1 . A derivative of a GLP-1(7-37) analogue or a pharmaceutically acceptable salt thereof, wherein the GLP-1(7-37) analogue comprises the amino acid sequence of:
(i) HVEGTFTSDVSSYLEEKAAREFIAWLVRGRG (SEQ ID NO: 6); or
(ii) HVEGTFTSDVSSYLEEQAAREFIKWLVRGRG (SEQ ID NO: 10),
wherein the derivative comprises an extension portion linked to the K residue of the GLP-1(7-37) analogue, wherein the extension portion is
and
wherein x is an integer selected from 4 to 38.
2 . The derivative or pharmaceutically acceptable salt thereof according to claim 1 , wherein the extension portion is selected from the group consisting of:
HOOC(CH 2 ) 14 CO—, HOOC(CH 2 ) 15 CO—, HOOC(CH 2 ) 16 CO—, HOOC(CH 2 ) 17 CO—, HOOC(CH 2 ) 18 CO—, HOOC(CH 2 ) 19 CO—, HOOC(CH 2 ) 20 CO—, HOOC(CH 2 ) 21 CO—, and HOOC(CH 2 ) 22 CO—.
3 . The derivative or pharmaceutically acceptable salt thereof according to claim 1 , wherein the extension portion is linked to the K residue of the GLP-1(7-37) analogue through a linker.
4 . The derivative or pharmaceutically acceptable salt thereof according to claim 3 , wherein the linker is:
wherein m is 0, 1, 2, or 3; n is 1, 2, or 3; s is any integer selected from 0 to 6; and p is any integer selected from 1 to 8.
5 . The derivative or pharmaceutically acceptable salt thereof according to claim 4 , wherein the linker is:
and wherein m is 1, and n is 1 or 2.
6 . The derivative or pharmaceutically acceptable salt thereof according to claim 1 , wherein the derivative is:
N-ε 23 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 23 Arg 26,34 -GLP-1(7-37)) peptide (M2), or N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide (M4).
7 . A method for preparing a derivative of a GLP-1(7-37) analogue or a pharmaceutically acceptable salt thereof according to claim 1 , comprising:
(1) mixing a solution in which the GLP-1(7-37) analogue according to claim 1 is dissolved with a solution in which the extension portion according to claim 1 is dissolved;
(2) adjusting the pH to 4-5 to quench the reaction, standing until a precipitate is generated, and then collecting the precipitate; and
(3) adding trifluoro acetic acid (TFA) to the precipitate and adjusting the pH to 7.5-8.5 to quench the reaction.
8 . The method according to claim 7 , further comprising: adding triethylamine to the solution in which the GLP-1(7-37) analogue is dissolved, followed by mixing with the solution in which the extension portion is dissolved.
9 . The method according to claim 7 , wherein the extension portion is dissolved by acetonitrile.
10 . A pharmaceutical composition, comprising the derivative or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.
11 . A method for treating diabetes or diabetic complications in a subject in need thereof, comprising: administering a therapeutically effective amount of the derivative or pharmaceutically acceptable salt thereof according to claim 1 to the subject.
12 . The method according to claim 11 , wherein the diabetic complication is diabetic nephropathy.
13 . A method for reducing blood glucose, increasing glucose tolerance, reducing islet β-cell apoptosis, enhancing islet β-cell function, increasing islet β-cell number, and/or restoring islet β-cell glucose sensitivity in a subject in need thereof, comprising: administering a therapeutically effective amount of the derivative or pharmaceutically acceptable salt thereof according to claim 1 to the subject.
14 . The method according to claim 13 , wherein said reducing blood glucose comprises reducing fasting blood glucose and/or postprandial blood glucose.
15 . A GLP-1(7-37) analogue, comprising the amino acid sequence of:
(i) HVEGTFTSDVSSYLEEKAAREFIAWLVRGRG (SEQ ID NO: 6); or
(ii) HVEGTFTSDVSSYLEEQAAREFIKWLVRGRG (SEQ ID NO: 10).
16 . A pharmaceutical composition, comprising the GLP-1(7-37) analogue according to claim 15 .
17 . A product comprising: a container in which the pharmaceutical composition according to claim 10 is contained, and a package insert, wherein the package insert contains instructions for use of the pharmaceutical composition.
18 . The product according to claim 17 , further comprising a container containing one or more other medicaments.
19 . The product according to claim 18 , wherein the one or more other medicaments are other medicaments for treating diabetes or diabetic complications.
20 . A product comprising: a container in which the pharmaceutical composition according to claim 16 is contained, and a package insert, wherein the package insert contains instructions for use of the pharmaceutical composition.
21 . The derivative or pharmaceutically acceptable salt thereof according to claim 4 , wherein the linker is:
wherein m is 1 or 2; n is 1 or 2; and p is any integer selected from 1 to 5.