Glucagon analogues

• US 9,169,310 B2
• Filed: 06/24/2011
• Issued: 10/27/2015
• Est. Priority Date: 06/24/2010
• Status: Expired due to Fees

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Riber, Ditte, Meier, Eddi
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US13/704,299
• Publication Number:
  US 20130157929A1
• Time in Patent Office: 1,586 Days
• Field of Search: None
• US Class Current: 1/1
• 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: 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 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• 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 for treating diabetes and associated metabolic disorders. In particular, the invention provides novel glucagon analogue peptide compounds effective in such methods. The compounds may mediate their effect by having, for example, increased selectivity for the GLP-1 receptor compared to human glucagon.

Claims

1. A compound having the formula:

R¹—

Z—

R²,

or a pharmaceutically acceptable salt thereof,

wherein

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

R² is OH or NH₂; and

Z is a peptide having the formula I;

H-Aib-HGTFTSDYSKYLES-K(hexadecanoyl-isoGlu)-AAEEFVEWLLEA (SEQ ID NO;

75).

2. The compound according to claim 1, wherein the compound is:

H-H-Aib-HGTFTSDYSKYLESK(hexadecanoyl-isoGlu)-AAEEFVEWLLEA-NH₂ (SEQ ID NO;

75).

3. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

4. A method of promoting weight loss in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1.

5. A method of improving circulating glucose levels, glucose tolerance and/or circulating cholesterol levels, lowering circulating LDL levels, and/or increasing HDL/LDL ratio in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1.

6. A method of treating a condition caused by excess body weight in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1.

7. The method according to claim 5, wherein said compound is administered as part of a combination therapy together with an agent for treatment of diabetes, obesity, dyslipidaemia, or hypertension.

8. The method according to claim 7, wherein said agent for treatment of diabetes is metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, insulin, or an insulin analogue.

9. The method according to claim 7, wherein said agent for treatment of obesity is a glucagon-like peptide receptor 1 agonist, peptide YY or an analogue thereof, a cannabinoid receptor 1 antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, or a melanin concentrating hormone receptor 1 antagonist.

10. The method according to claim 7, wherein said agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker, or a calcium channel blocker.

11. The method according to claim 7, wherein said agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin, or a cholesterol absorption inhibitor.

12. The method according to claim 6, wherein said compound is administered as part of a combination therapy together with an agent for treatment of diabetes, obesity, dyslipidaemia, or hypertension.

13. The method according to claim 12, wherein said agent for treatment of diabetes is metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, insulin, or an insulin analogue.

14. The method according to claim 12, wherein said agent for treatment of obesity is a glucagon-like peptide receptor 1 agonist, peptide YY or an analogue thereof, a cannabinoid receptor 1 antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, or a melanin concentrating hormone receptor 1 antagonist.

15. The method according to claim 12, wherein said agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker, or a calcium channel blocker.

16. The method according to claim 12, wherein said agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin, or a cholesterol absorption inhibitor.

17. The method according to claim 6, wherein said condition caused by excess body weight is selected from the group consisting of:

obesity, morbid obesity, obesity-linked inflammation, obesity-linked gallbladder disease, obesity-induced sleep apnea, pre-diabetes, insulin resistance, glucose intolerance, type 2 diabetes, type I diabetes, hypertension, atherogenic dyslipidaemia, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke, or microvascular disease.