Acylated glucagon analogues

• US 9,156,901 B2
• Filed: 06/24/2010
• Issued: 10/13/2015
• Est. Priority Date: 07/13/2009
• Status: Expired due to Fees

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Camilla Aerteberg Baek
• Inventors: Riber, Ditte, Meier, Eddi, Daugaard, Jens Rosengren, Skovgaard, Marie, Tolborg, Jakob Lind, Kampen, Gita, Bk, Camilla rteberg
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US13/383,783
• Publication Number:
  US 20120178670A1
• Time in Patent Office: 1,937 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• 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 and associated metabolic disorders. In particular, the invention provides novel acylated 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—

Z—

R²

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

R² is OH or NH₂;

and Z is a peptide having the formula

H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl- γ

-Glu)-AAHDFVEWLLSA (SEQ ID NO;

     89),

or a salt thereof.

2. A pharmaceutically acceptable composition comprising a compound of claim 1, or a salt or derivative thereof, in a mixture with a pharmaceutically acceptable carrier.

3. A compound according to claim 1 having the formula:

H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl- γ

-Glu)-AAHDFVEWLLSA-NH₂ (SEQ ID NO;

89),

or a pharmaceutically acceptable salt thereof.

4. A method of inhibiting weight gain or promoting weight loss in an individual in need thereof comprising administering a compound according to claim 1.

5. A method of lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof comprising administering a compound according to claim 1.

6. A method of treating or reducing 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, atheroscierois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke, or microvascular disease comprising administering a compound according to claim 1.

7. A method of inhibiting weight gain or promoting weight loss;

lowering circulating LDL levels, and/or increasing HDL/LDL ratio;

or treating or reducing 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 in an individual in need thereof comprising administering a compound according to claim 1.

8. The method of claim 7, wherein the compound is administered as part of a combination therapy together with an agent for treatment of diabetes, obesity dyslipidemia, or hypertension.

9. The method of claim 8, wherein the agent for treatment of diabetes is a biquanide, a sulfonylurea, a meglitinide, a glinide, a DPP-IV inhibitor, a glitazone, a GLP-1 agonist, an insulin, or an insulin analogue.

10. The method of claim 8, wherein the agent for treatment of obesity is a glucagon-like peptide receptor 1 agonist, a peptide YY receptor agonist or analogue thereof, a cannabinoid receptor 1 antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, or a melanin concentrating hormone receptor 1 antagonist.

11. The method of claim 8, wherein the agent for treatment of hypertension is an angiotensin-converting an enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker, or a calcium channel blocker.

12. The method of claim 8, wherein the agent for treatment of dyslipidemia is a statin, a fibrate, a niacin or a cholesterol absorption inhibitor.

13. A therapeutic kit comprising a compound according to claim 1.

14. A therapeutic kit comprising a composition according to claim 2.