Acylated glucagon analogue

• US 10,336,802 B2
• Filed: 04/15/2016
• Issued: 07/02/2019
• Est. Priority Date: 04/16/2015
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Riber, Ditte, Tolborg, Jakob Lind, Hamprecht, Dieter Wolfgang, Thomas, Leo
• Primary Examiner(s): Heard, Thomas S
• Application Number:
  US15/566,338
• Publication Number:
  US 20180094038A1
• Time in Patent Office: 1,173 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 38/2271 Neuropeptide Y
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 acylated 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-H-Aib-QGTFTSDYSKYLDERAAKDFIEWLE-K([17-Carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-R² 

 

(SEQ ID NO;

     1)

wherein

R¹ is H (hydrogen), C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl; and

R² is OH or NH₂;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 which is:

H-H-Aib-QGTFTSDYSKYLDERAAKDFIEWLE-K([17-Carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH₂ 

 

(SEQ ID NO;

     1)

or a pharmaceutically acceptable salt thereof.

3. A composition comprising a compound according to claim 1 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 preventing weight gain or promoting weight loss in an individual in need thereof comprising administering an effective amount of a compound according to claim 1.

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

7. A method of improving glycemic control or 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 dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease comprising administering an effective amount of a compound according to claim 1.

8. The method according to claim 5, 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 according to claim 8 wherein the agent for treatment of diabetes is a biguanide, a sulfonylurea, a meglitinide or glinide, a DPP-IV inhibitor, an SGLT2 inhibitor, a glitazone, a GLP-1 receptor agonist, an SGLT2 inhibitor, a GPR40 agonist, or an insulin or an insulin analogue.

10. The method according to claim 8, wherein the agent for treatment of obesity is a GLP-1 receptor agonist, peptide YY or analogue thereof, neuropeptide Y (NPY) or an analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, Human prolslet Peptide (HIP), melanocortin receptor 4 agonist, melanin concentrating hormone receptor 1 antagonist, phentermine (alone or in combination with topiramate), a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist, Orlistat™

, Sibutramine™

, CCK, amylin, pramlintide and leptin and analogues thereof, or a serotonergic agent.

11. The method according to 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 according to claim 8 wherein the agent for treatment of dyslipidemia is a statin, a fibrate, a niacin, a PSCK9 (Proprotein convertase subtilisin/kexin type 9) inhibitor and/or a cholesterol absorption inhibitor.

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

14. A method of synthesis of a compound according to claim 1, wherein the synthesis comprises the step of solid-phase or liquid-phase peptide coupling in a method for synthesizing said compound.

15. A method of producing a compound according to claim 1, the method comprising expressing a precursor peptide sequence from a nucleic acid construct that encodes the precursor peptide, recovering the expression product, and modifying the precursor peptide to yield a compound according to claim 1.