GLUCAGON ANALOGUES

• US 20140080757A1
• Filed: 09/17/2013
• Published: 03/20/2014
• Est. Priority Date: 09/17/2012
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG), Zealand Pharma A/S
• Inventors: Fosgerau, Keld, Hamprecht, Dieter Wolfgang, Thomas, Leo, TOLBORG, Jakob Lind, Nrregaard, Pia, Just, Rasmus, Riber, Ditte, Augustin, Robert
• Granted Patent: US 9,180,169 B2
• Time in Patent Office: Days
• US Class Current: 514/11.7
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• 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 the treatment of obesity and excess weight, diabetes, and other associated metabolic 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 compound having the formula:

R¹—

X—

Z—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide which has the formula;

9. A compound according to any one of claims 1 to 8 having the formula:

10. A compound according to any one of claims 1 to 8 wherein one or more of the amino acid side chains in the peptide X or Z is conjugated to a lipophilic substituent.

11. A compound according to any one of claims 1 to 8 or claim 10 wherein one or more of the amino acid side chains in the peptide X or Z is conjugated to a polymeric substituent.

12. A compound according to claim 10 or claim 11 wherein peptide X has the formula:

13. A compound according to claim 12 having the formula:

14. A compound according to claim 12 wherein peptide X has the formula:

15. A compound according to claim 14 having the formula:

16. A composition comprising a compound according to any one of claims 1 to 15 in admixture with a carrier.

17. A composition according to claim 16 wherein the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier.

18. A compound according to any one of claims 1 to 15 for use in a method of medical treatment.

19. A compound according to any one of claims 1 to 15 for use in a method of preventing weight gain or promoting weight loss in an individual in need thereof.

20. A compound according to any one of claims 1 to 15 for use in a method of lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof.

21. A compound according to any one of claims 1 to 15 for use in a method of treatment of a condition caused or characterised by excess body weight.

22. A compound according to any one of claims 1 to 15 for use in a method of prevention or treatment of obesity, morbid obesity, morbid obesity prior to surgery, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, diabetes, metabolic syndrome, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease.

23. A compound for use according to any one of claims 18 to 22 wherein the compound is administered as part of a combination therapy together with an agent for treatment of diabetes, obesity, dyslipidemia or hypertension.

24. A compound for use according to claim 23 wherein the agent for treatment of diabetes is a biguanide (e.g. metformin), a sulfonylurea, a meglitinide or glinide (e.g. nateglinide), a DPP-IV inhibitor, a glitazone, a different GLP-1 agonist, an insulin or an insulin analogue.

25. A compound for use according to claim 23, wherein the agent for treatment of obesity is a glucagon-like peptide receptor 1 agonist, peptide YY receptor agonist or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 1 agonist, or melanin concentrating hormone receptor 1 antagonist.

26. A compound for according to claim 23 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

27. A compound for use according to claim 23 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin and/or a cholesterol absorption inhibitor.

28. A nucleic acid encoding the amino acid sequence X or X—

Z of a compound according to any of claims 1 to 15.

29. An expression vector comprising the nucleic acid sequence of claim 28.

30. A host cell comprising the nucleic acid of claim 28 or the expression vector of claim 29 and capable of expressing and optionally secreting a compound having the amino acid sequence X or X—

Z.

31. A therapeutic kit comprising a compound according to any of claims 1 to 15 or a composition according to claim 14 or 15.

32. A method of synthesis of a compound according to any one of claims 1 to 15.

33. A method of producing a compound according to any one of claims 1 to 15, the method comprising culturing a host cell according to claim 30 under conditions suitable for expressing the peptide sequence X or X—

Z and purifying the compound thus produced.

34. A method of producing a compound according to any one of claims 1 to 15, the method comprising expressing a peptide sequence containing one or more differences from the sequence X or X—

Z in a host cell, optionally purifying the compound thus produced, and adding or modifying one or more amino acids to produce the compound.

35. A method according to claim 33 or claim 34 comprising modifying the sequence X or X—

Z to introduce one or more lipophilic and/or polymeric moieties.

2. A compound having the formula:

R¹—

X—

OH

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

and X is a peptide which has the formula;

3. A compound having the formula:

R¹—

X—

Z—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide of SEQ ID NO;

15;

4. A compound according to claim 3 wherein the residue at position 20 is His.

5. A compound according to claim 3 having the formula:

R¹—

X—

Z—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide of SEQ ID NO;

15;

8. A compound according to any of claims 3 to 7 wherein X is a peptide having the sequence:

6. A compound having the formula:

R¹—

X—

Z—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide of SEQ ID NO;

16;

7. A compound according to claim 6 having the formula:

R¹—

X—

Z—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide of SEQ ID NO;

16;