Peptide analogues of glucagon and GLP1

Patent metadata

Field	Value
Publication number	US-9546205-B2
Application number	US-201314428599-A
Country	US
Kind code	B2
Filing date	Sep 17, 2013
Priority date	Sep 17, 2012
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

Peptide analogs of glucagon and peptide analogs of GLP1 are provided herein. Also provided herein are pharmaceutical compositions comprising the analogs, and methods of using the analogs for the treatment and/or prevention of conditions such as obesity and diabetes.

First claim

The invention claimed is:

1. An analogue of glucagon which is:
a compound comprising the amino acid sequence represented by formula (I)
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa 10 -Ser-Xaa 12 -Xaa 13 -Leu-Xaa 15 -Xaa 16 -Xaa 17 -Xaa 18 -Ala-Xaa 20 -Xaa 21 -Phe-Xaa 23 -Xaa 24 -Trp-Leu-Leu-Asn-Xaa 29 -V   (I)

wherein V is selected from the group consisting of His (SEQ ID NO: 716), His-NH 2 (SEQ ID NO: 717), His-His (SEQ ID NO: 718), His-His-NH 2 (SEQ ID NO: 719), Gly-His (SEQ ID NO: 720), Gly-His-NH 2 (SEQ ID NO: 721), Lys-His (SEQ ID NO: 722), Lys-His-NH 2 (SEQ ID NO: 723), Gly-His-His (SEQ ID NO: 724), Gly-His-His-NH 2 (SEQ ID NO: 725), His-His-His (SEQ ID NO: 726) and His-His-His-NH 2 (SEQ ID NO: 727);
Xaa 10 is selected from the group consisting of Tyr and Leu;
Xaa 12 is selected from the group consisting of Lys, His and Arg;
Xaa 13 is selected from the group consisting of Tyr, Gln and His;
Xaa 15 is selected from the group consisting of Asp and Glu;
Xaa 16 is selected from the group consisting of Glu, Gln and Ser;
Xaa 17 is selected from the group consisting of Arg, His and Lys;
Xaa 18 is selected from the group consisting of Arg and Lys;
Xaa 20 is selected from the group consisting of His and Gln;
Xaa 21 is selected from the group consisting of Glu, His and Asp;
Xaa 23 is selected from the group consisting of Be and Val;
Xaa 24 is selected from the group consisting of Gln and Glu; and
Xaa 29 is selected from the group consisting of Thr and Gly; and

wherein —NH 2 represents a C-terminal amide group;
or a derivative of the compound;
or a salt of the compound or the derivative.

2. The analogue as claimed in claim 1 , wherein Xaa 20 is His.

3. The analogue as claimed in claim 2 , wherein Xaa 10 is Tyr and Xaa 16 is Ser.

4. The analogue as claimed in claim 1 , wherein V is selected from the group consisting of His-His (SEQ ID NO: 718), His-His-NH 2 (SEQ ID NO: 719), Gly-His (SEQ ID NO: 720), and Gly-His-NH 2 (SEQ ID NO 721).

5. The analogue as claimed in claim 1 , wherein Xaa 13 is Tyr.

6. The analogue as claimed in claim 1 , wherein the compound consists of the amino acid sequence represented by formula (I).

7. The analogue as claimed in claim 1 , wherein the analogue is selected from the group consisting of:
i) Xaa 10 is Tyr, Xaa 12 is Lys, Xaa 13 is Tyr, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Arg, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Val, Xaa 24 is Gln, Xaa 29 is Thr and V is His-His (SEQ ID NO: 30);
ii) Xaa 10 is Tyr, Xaa 12 is Arg, Xaa 13 is Tyr, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Arg, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Val, Xaa 24 is Gln, Xaa 29 is Thr and V is His-His-NH 2 (SEQ ID NO: 32);
iii) Xaa 10 is Tyr, Xaa 12 is Arg, Xaa 13 is His, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Lys, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Val, Xaa 24 is Gln, Xaa 29 is Thr and V is His-His-NH 2 (SEQ ID NO: 143);
iv) Xaa 10 is Tyr, Xaa 12 is Arg, Xaa 13 is Tyr, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Lys, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Val, Xaa 24 is Gln, Xaa 29 is Thr and V is Gly-His (SEQ ID NO: 157);
v) Xaa 10 is Tyr, Xaa 12 is Lys, Xaa 13 is Tyr, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Arg, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Val, Xaa 24 is Gln, Xaa 29 is Gly and V is Gly-His (SEQ ID NO: 38);
vi) Xaa 10 is Tyr, Xaa 12 is Lys, Xaa 13 is Tyr, Xaa 15 is Glu, Xaa 16 is Ser, Xaa 17 is Arg, Xaa 18 is Lys, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Ile, Xaa 24 is Glu, Xaa 29 is Thr and V is Gly-His (SEQ ID NO: 101);
vii) Xaa 10 is Tyr, Xaa 12 is Lys, Xaa 13 is Tyr, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Arg, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Val, Xaa 24 is Glu, Xaa 29 is Thr and V is Gly-His (SEQ ID NO: 79);
viii) Xaa 10 is Tyr, Xaa 12 is Lys, Xaa 13 is Tyr, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Arg, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Val, Xaa 24 is Glu, Xaa 29 is Gly and V is Gly-His-NH 2 (SEQ ID NO: 117);
ix) Xaa 10 is Tyr, Xaa 12 is Lys, Xaa 13 is Tyr, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Arg, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Asp, Xaa 23 is Val, Xaa 24 is Glu, Xaa 29 is Thr and V is His-His-NH 2 (SEQ ID NO: 120); and
x) Xaa 10 is Tyr, Xaa 12 is His, Xaa 13 is Tyr, Xaa 15 is Asp, Xaa 16 is Ser, Xaa 17 is Arg, Xaa 18 is Arg, Xaa 20 is His, Xaa 21 is Glu, Xaa 23 is Val, Xaa 24 is Gln, Xaa 29 is Gly and V is Gly-His-NH 2 (SEQ ID NO: 130).

8. The analogue as claimed in claim 1 , which is a derivative selected from the group consisting of amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidization, pegylation and fusion to another peptide or protein to form a fusion protein.

9. The analogue as claimed in claim 1 , which is not a derivative.

10. The analogue as claimed in claim 1 , wherein said compound comprises any one of the amino acid sequences selected from the group consisting of SEQ ID NOS: 1-426.

11. A pharmaceutical composition comprising an analogue as claimed in claim 1 , together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.

12. The pharmaceutical composition as claimed in claim 11 , together with said therapeutic ingredients, for simultaneous, sequential or separate administration.

13. The pharmaceutical composition as claimed in claim 11 , present in a syringe or other administration device for subcutaneous administration to humans.

14. The pharmaceutical composition as claimed in claim 11 , wherein the composition has a pH of less than 5 prior to administration and wherein the composition comprises zinc ions.

15. The analogue as claimed in claim 1 , wherein Xaa 15 is Asp.

16. The analogue as claimed in claim 1 , wherein Xaa 17 is Arg.

17. The analogue as claimed in claim 1 , wherein Xaa 18 is Arg.

18. The analogue as claimed in claim 1 , wherein Xaa 21 is Glu.

19. The analogue as claimed in claim 1 , wherein Xaa 23 is Val.

20. A method of treating obesity or diabetes in a subject in need thereof comprising administration of a therapeutically effective amount of an analogue as claimed in claim 1 .

21. The method as claimed in claim 20 , wherein the subject is at least one of the following: overweight, obese, or diabetic.

22. A method of treating obesity or diabetes in a subject in need thereof comprising administration of a therapeutically effective amount of a pharmaceutical composition as claimed in claim 11 .

23. The method as claimed in claim 22 , wherein the subject is at least one of the following: overweight, obese, or diabetic.

Assignees

• Imp Innovations Ltd

Inventors

• Bloom Stephen Robert

Classifications

• C07K14/605 Primary

  Glucagons · CPC title

• A61K38/26

  Glucagons · CPC title