Stable glucagon analogues and use for treatment of hypoglycaemia

Patent metadata

Field	Value
Publication number	US-9963496-B2
Application number	US-201515117993-A
Country	US
Kind code	B2
Filing date	Feb 18, 2015
Priority date	Feb 18, 2014
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

The invention relates to derivatives of glucagon analogs comprising the substitutions Imp1 and His3, a substituent having three to ten negatively charged moieties covalently attached to a side chain of a lysine as well as intermediates and compositions thereof and their use in medicine.

First claim

The invention claimed is:

1. A derivative of a glucagon analogue, comprising a peptide and a substituent;
wherein the peptide comprises the amino acid sequence Imp-X 2 -His-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -Tyr-Leu-X 15 -X 16 -Arg-Arg-Ala-X 20 -X 21 -Phe-Val-X 24 -Trp-Leu-X 27 -X 28 -X 29 -X 30 ;
wherein

X 2 is Ser or Aib;
X 10 is Tyr, Leu, Ile or Val;
X 12 is Lys or Arg;
X 15 is Asp or Glu;
X 16 is Ser, Ala, Leu, Thr, Aib, Ile, Val or Lys;
X 20 is Gln, Glu, Aib or Lys;
X 21 is Asp, Glu or Lys;
X 24 is Gln, Ala, Glu, Aib or Lys;
X 27 is Met, Leu or Val;
X 28 is Asn, Ser, Thr, Gln, Ala, Gly, Glu or Lys;
X 29 is Thr, Gly, Ser, Gln, Ala, Glu or Lys; and
X 30 is absent or is Lys;
wherein the substituent is covalently attached to the nitrogen atom of the side chain of a lysine in the peptide at a position selected from the group consisting of X 12 , X 16 , X 20 , X 21 , X 24 , X 28 , X 29 and X 30 ;
wherein the substituent comprises the formula Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -Y 9 -Y 10 -Y 11 -Y 12 -;
wherein Y 1 is selected from the group consisting of hydrogen, a C 2-6 acyl group, and a succinoyl moiety;
wherein Y 2 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 and Y 12 individually are absent or represents an amino acid residue selected from the group consisting of Ser, Ala, Gly,

wherein

individually has stereochemistry L or D;
or a pharmaceutically acceptable salt, amide, or ester thereof.

2. The derivative according to claim 1 , wherein Y 12 is present and attached to the nitrogen atom of the side chain of the lysine.

3. The derivative according to claim 1 , wherein the substituent is covalently attached to the epsilon-nitrogen atom of the side chain of the lysine.

4. The derivative according to claim 1 , wherein the substituent is attached to the lysine in position X 24 .

5. The derivative according to claim 1 , wherein the substituent has 3, 4, 5, 6, 7, 8, or 9 negatively charged moieties.

6. The derivative according to claim 1 , wherein the substituent comprises 3-10 amino acid residues of

7. The derivative according to claim 1 , wherein Y 1 is an acetyl group.

8. The derivative according to claim 1 , wherein the derivative is selected from the group consisting of

9. A glucagon analogue comprising modifications of SEQ ID NO: 1, wherein the glucagon analogue is selected from the group consisting of
[Imp1, Aib2, His3, Leu16, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Glu15, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Leu10, Glu15, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Glu15, Ala24, Leu27, Lys28]-Glucagon;
[Imp1, His3, Glu15, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Glu21, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Glu15, Glu21, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Leu16, Glu21, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Leu16, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Val16, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Lys16, Glu21, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Lys20, Glu21, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Lys21, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Glu21, Leu27, Lys28]-Glucagon;
[Imp1, His3, Glu15, Glu21, Leu27, Ser28, Lys29]-Glucagon;
[Imp1, His3, Glu15, Glu21, Leu27, Ser28, Lys30]-Glucagon;
[Imp1, His3, Ala16, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Aib16, Lys24, Leu27, Ser28]-Glucagon; and
[Imp1, His3, Glu15, Glu21, Lys24, Leu27, Glu28]-Glucagon;
or a pharmaceutically acceptable salt, amide, or ester thereof.

10. A pharmaceutical composition comprising the derivative according to claim 1 and one or more pharmaceutically acceptable excipients.

11. The derivative according to claim 8 , wherein the derivative is

12. The derivative according to claim 8 , wherein the derivative is

13. The derivative according to claim 8 , wherein the derivative is

14. The derivative according to claim 8 , wherein the derivative is

15. The pharmaceutical composition according to claim 10 , wherein the peptide is selected from the group consisting of:
[Imp1, Aib2, His3, Leu16, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Glu15, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Leu10, Glu15, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Glu15, Ala24, Leu27, Lys28]-Glucagon;
[Imp1, His3, Glu15, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Glu21, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Glu15, Glu21, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Leu16, Glu21, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Leu16, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, Aib2, His3, Val16, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Lys16, Glu21, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Lys20, Glu21, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Lys21, Leu27, Ser28]-Glucagon;
[Imp1, His3, Glu15, Glu21, Leu27, Lys28]-Glucagon;
[Imp1, His3, Glu15, Glu21, Leu27, Ser28, Lys29]-Glucagon;
[Imp1, His3, Glu15, Glu21, Leu27, Ser28, Lys30]-Glucagon;
[Imp1, His3, Ala16, Lys24, Leu27, Ser28]-Glucagon;
[Imp1, His3, Aib16, Lys24, Leu27, Ser28]-Glucagon; and
[Imp1, His3, Glu15, Glu21, Lys24, Leu27, Glu28]-Glucagon;
or a pharmaceutically acceptable salt, amide, or ester thereof.

16. The pharmaceutical composition according to claim 10 , wherein the derivative is

17. The pharmaceutical composition according to claim 10 , wherein the derivative is

18. The pharmaceutical composition according to claim 10 , wherein the derivative is

19. The pharmaceutical composition according to claim 10 , wherein the derivative is

Assignees

• Novo Nordisk As

Inventors

• Lau Jesper F
• Kruse Thomas
• Nielsen Peter Kresten

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• C07K14/605 Primary

  Glucagons · CPC title

• A61K38/26

  Glucagons · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title