Glucagon analogues

• US 9,180,169 B2
• Filed: 09/17/2013
• Issued: 11/10/2015
• Est. Priority Date: 09/17/2012
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Tolborg, Jakob Lind, Fosgerau, Keld, Nrregaard, Pia, Just, Rasmus, Riber, Ditte, Hamprecht, Dieter Wolfgang, Augustin, Robert, Thomas, Leo, Rist, Wolfgang
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US14/029,529
• Publication Number:
  US 20140080757A1
• Time in Patent Office: 784 Days
• US Class Current: 1/1
• 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 analog 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;

HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAEDFVEWLLRA (SEQ ID NO;

7),

and Z is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn,

or a pharmaceutically acceptable salt thereof.

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

HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAEDFVEWLLRA (SEQ ID NO;

7),

or a pharmaceutically acceptable salt thereof.

3. A composition comprising a compound according to claim 1 or 2 in admixture with a carrier.

4. A composition according to claim 3, wherein the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier.

5. A method of inhibiting weight gain or promoting weight loss in an individual in need thereof comprising administering a compound according to claim 1 or 2.

6. 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 or 2.

7. 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, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease comprising administering a compound according to claim 1 or 2 to a patient in need thereof.

8. The method of claims 5 to 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 biguanide, 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, peptide YY receptor agonist or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, or melanin concentrating hormone receptor 1 antagonist.

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

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

13. A therapeutic kit comprising a compound according to claim 1 or 2 or a composition according to claim 3 or 4.

15. The method of claim 9, wherein the biguanide is metformin.

14. The compound H-HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAEDFVEWLLRA-NH₂ (Compound 7) (SEQ ID NO:

7), or a pharmaceutically acceptable salt thereof.