GLUCAGON ANALOGUES

• US 20140127175A1
• Filed: 01/07/2014
• Published: 05/08/2014
• Est. Priority Date: 12/15/2008
• Status: Abandoned Application

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: MEIER, Eddi, Riber, Ditte, Skovgaard, Marie, Larsen, Bjarne Due, Daugaard, Jens Rosengren
• Application Number:
  US14/149,669
• Publication Number:
  US 20140127175A1
• Time in Patent Office: Days
• US Class Current: 424/93.21
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

The invention provides materials and methods for promoting weight loss or preventing weight gain, and in the treatment of diabetes, metabolic syndrome and associated disorders. In particular, the invention provides novel glucagon analogue peptides effective in such methods. The peptides may mediate their effect by having increased selectivity for the GLP-1 receptor as compared to human glucagon.

Claims

1. A nucleic acid encoding a peptide having the formula X-Z

wherein

X is a peptide which has the formula I

2. The nucleic acid according to claim 1, wherein X differs from formula I at up to 4 of the following positions whereby, if different from formula I:

the residue at position 2 is selected from;

Aib, D-Ser;

the residue at position 18 is selected from;

Lys, H is, Ala, Ser, Tyr;

the residue at position 20 is selected from;

Gln, H is, Lys, Arg, Glu;

the residue at position 24 is selected from;

Gln, Leu, Glu, Lys, Arg;

the residue at position 27 is selected from;

Met, Cys, Arg, Glu, Leu;

the residue at position 28 is selected from;

Asn, Ser, Arg, Lys, Ala, Leu; and

the residue at position 29 is selected from;

Thr, Glu, Lys.

3. The nucleic acid according to claim 2, comprising the residues 27-Lys and 28-Ser.

4. The nucleic acid according to claim 3, wherein X additionally differs from formula I at one or two of the following positions whereby, if different from formula I:

the residue at position 2 is selected from;

Aib, D-Ser;

the residue at position 18 is selected from;

Lys, H is, Ala, Ser, Tyr;

the residue at position 20 is selected from;

Gln, H is, Lys, Arg, Glu;

the residue at position 24 is selected from;

Gln, Leu, Glu, Lys, Arg; and

the residue at position 29 is selected from;

Thr, Glu, Lys.

5. The nucleic acid according to claim 1, wherein the residues at positions 16 and 20 are capable of forming a salt bridge.

6. The nucleic acid according to claim 5, comprising the residues 16-Arg, 20-Asp.

7. The nucleic acid according to claim 1, wherein X comprises one or more of the following sets of residues:

16-Arg;

16-Arg, 20-Asp;

16-Arg, 20-Asp, 24-Ala;

16-Arg, 20-Asp, 27-Lys, 28-Ser;

16-Arg, 20-Asp, 29-Ala;

16-Arg, 27-Lys, 28-Ser;

16-Arg, 27-Lys, 28-Ser, 29-Ala;

24-Ala, 27-Lys, 28-Ser;

24-Ala, 27-Lys, 28-Ser, 29-Ala;

24-Ala;

27-Lys;

28-Ser;

20-Glu, 28-Ser, 29-Thr;

24-Glu, 28-Ser, 29-Thr;

27-Glu, 28-Arg;

2-D-Ser, 28-Ser, 29-Thr;

or

20-His, 28-Ser, 29-Thr.

8. The nucleic acid according to claim 1, wherein X has the sequence:

9. The nucleic acid according to claim 1, wherein Z has no more than 25% sequence identity with the corresponding portion of the IP-1 sequence of human oxyntomodulin having the sequence Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala (SEQ ID NO:

2).

10. The nucleic acid according to claim 1, wherein Z has a Cys as the C-terminal residue.

11. The nucleic acid according to claim 1, wherein Z is absent.

12. An expression vector comprising the nucleic acid according to claim 1.

13. A host cell comprising the nucleic acid according to claim 1.

14. A host cell comprising the expression vector according to claim 12.

15. A pharmaceutical composition comprising the nucleic acid according to claim 1, in admixture with a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising the expression vector according to claim 12, in admixture with a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising the host cell according to claim 13, in admixture with a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising the host cell according to claim 14, in admixture with a pharmaceutically acceptable carrier.

19. A method of reducing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke in a subject in need thereof, said method comprising administering the nucleic acid according to claim 1 to said subject.

20. A method of reducing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke in a subject in need thereof, said method comprising administering the expression vector according to claim 12 to said subject.

21. A method of reducing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke in a subject in need thereof, said method comprising administering the host cell according to claim 13 to said subject.

22. A method of reducing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke in a subject in need thereof, said method comprising administering the host cell according to claim 14 to said subject.