Acylated glucagon analogues

• US 9,896,495 B2
• Filed: 10/17/2014
• Issued: 02/20/2018
• Est. Priority Date: 10/17/2013
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Riber, Ditte, Tolborg, Jakob Lind, Hamprecht, Dieter Wolfgang, Rist, Wolfgang
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US14/517,497
• Publication Number:
  US 20150111826A1
• Time in Patent Office: 1,222 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 31/137 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 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• 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 38/26 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 11/00 Drugs for disorders of the respiratory system
• 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
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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—

P¹—

P²—

R²

wherein

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

R² is OH or NH₂;

P¹ is a peptide having the sequence;

H-Aib-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu)-AAKDFIEWLESA (SEQ ID NO;

     45);

H-Ac4c-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-RAKDFIEWLESA (SEQ ID NO;

     46);

H-Ac4c-HGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-RAKDFIEWLESA (SEQ ID NO;

     47);

H-Ac4c-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu)-AAKDFIEWLESA (SEQ ID NO;

     48);

H-Ac4c-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu)-RAKDFIEWLESA (SEQ ID NO;

     49);

H-Aib-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA (SEQ ID NO;

     50);

H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA (SEQ ID NO;

     51);

H-Ac4c-QGTFTSDYSKYLDERRAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA (SEQ ID NO;

     52);

H-Ac4c-QGTFTSDYSKYLDERAAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A (SEQ ID NO;

     53);

or

H-Ac4c-QGTFTSDYSKYLDERRAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A (SEQ ID NO;

     54);

and P² is absent;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 which is selected from:

H—

H-Aib-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu)-AAKDFIEWLESA-NH₂ (SEQ ID NO;

     55);

H—

H-Ac4c-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-RAKDFIEWLESA-NH₂ (SEQ ID NO;

     56);

H—

H-Ac4c-HGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-RAKDFIEWLESA-NH₂ (SEQ ID NO;

     57);

H—

H-Ac4c-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu)-AAKDFIEWLESA-NH₂ (SEQ ID NO;

     58);

H—

H-Ac4c-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu)-RAKDFIEWLESA-NH₂ (SEQ ID NO;

     59);

H—

H-Aib-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH₂ (SEQ ID NO;

     60);

H—

H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH₂ (SEQ ID NO;

     61);

H—

H-Ac4c-QGTFTSDYSKYLDERRAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH₂ (SEQ ID NO;

     62);

H—

H-Ac4c-QGTFTSDYSKYLDERAAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH₂ (SEQ ID NO;

     63); and

H—

H-Ac4c-QGTFTSDYSKYLDERRAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH₂ (SEQ ID NO;

     64).

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, said method comprising administering 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, said method comprising administering a compound according to claim 1.

7. A method of treating a condition caused or characterised by excess body weight, said method comprising administering a compound according to claim 1.

8. A method of preventing or treating 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, said method comprising administering a compound according to claim 1.

9. A method of preventing weight gain or promoting weight loss in an individual in need thereof;

lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof;

treating a condition caused or characterised by excess body weight;

or preventing or treating 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, said method comprising administering a compound according to claim 1 as part of a combination therapy together with an agent for treatment of diabetes, obesity, dyslipidemia or hypertension.

10. The method of claim 9, wherein the agent for treatment of diabetes is selected from the group consisting of a biguanide, a sulfonylurea, a meglitinide or glinide, a DPP-IV inhibitor, an SGLT2 inhibitor, a glitazone, a different GLP-1 agonist, an insulin, and an insulin analogue.

11. The method of claim 9, wherein the agent for treatment of obesity is selected from the group consisting of 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, a melanin concentrating hormone receptor 1 antagonist, phentermine, a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist, a combination of bupropion and naltrexone, and a serotonergic agent.

12. The method of claim 9, wherein the agent for treatment of hypertension is selected from the group consisting of an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker, and a calcium channel blocker.

13. The method of claim 9, wherein the agent for treatment of dyslipidaemia is selected from the group consisting of a statin, a fibrate, a niacin, and a cholesterol absorption inhibitor.

14. A therapeutic kit comprising a compound according to claim 1 optionally in admixture with a carrier.

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.

16. A compound selected from:

H-H-Ac4c-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-RAKDFIEWLESA-NH₂ (SEQ ID NO;

     56);

H-H-Aib-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH₂ (SEQ ID NO;

     60);

H-H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH₂ (SEQ ID NO;

61);

H-H-Ac4c-QGTFTSDYSKYLDERAAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH₂ (SEQ ID NO;

     63); and

H-H-Ac4c-QGTFTSDYSKYLDERRAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH₂ (SEQ ID NO;

     64);

or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 16, wherein the compound is:

H-H-Ac4c-QGTFTSDYSKYLDE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)-RAKDFIEWLESA-NH₂ (SEQ ID NO;

     56)

or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 16, wherein the compound is:

H-H-Aib-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH₂ (SEQ ID NO;

     60)

or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 16, wherein the compound is:

H-H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH₂ (SEQ ID NO;

     61)

or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 16, wherein the compound is:

H-H-Ac4c-QGTFTSDYSKYLDERAAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH₂ (SEQ ID NO;

     63)

or a pharmaceutically acceptable salt thereof.

21. A compound according to claim 16, wherein the compound is:

H-H-Ac4c-QGTFTSDYSKYLDERRAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH₂ (SEQ ID NO;

     64)

or a pharmaceutically acceptable salt thereof.