ACYLATED GLUCAGON ANALOGUES

• US 20180141990A1
• Filed: 12/22/2017
• Published: 05/24/2018
• 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
• Granted Patent: US 10,457,714 B2
• Time in Patent Office: Days
• 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 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—

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;

2. A compound according to claim 1 wherein P¹ has the sequence:

3. A compound according to claim 2 which is:

15. A compound according to any one of claims 1 to 14 wherein —

Z¹ is an acyl group of formula;

A-B-Alk-(CO)—

or a sulfonyl group of formula;

A-B-Alk-(SO₂)—

;

A is —

COOH or a carboxylic acid bioisostere;

B is a bond, C₆arylene, or C₆arylene-O—

;

Alk is a saturated or unsaturated fatty chain of 6 to 18 carbon atoms in length, optionally substituted with one or more substituents selected from fluoro, C_1-4alkyl, trifluoromethyl, hydroxymethyl, amino, hydroxyl, C_1-4alkoxy, oxo, and carboxyl;

—

Z²—

is —

S_A—

, —

S_A-S_B-, or —

S_B-S_A-;

—

S_A—

is a single amino acid residue selected from γ

-Glu, α

-Glu, α

-Asp, β

-Asp, Ala, β

-Ala β

-aminopropanoic acid), and Gaba (4-aminobutanoic acid);

—

S_B—

is a linker of general formula;

16. A compound according to any one of claims 1 to 14 wherein Z¹—

Z² is selected from;

(i) [17-Carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3;

(ii) [17-Carboxy-heptadecanoyl]-isoGlu

(iii) [13-Carboxy-tridecanoyl]-isoGlu-Peg3-Peg3;

(iv) [Carboxyphenoxynonanoyl]-isoGlu-Peg3-Peg3;

(v) [13-Carboxy-tridecanoyl]-isoGlu-Peg4-Peg4;

(vi) [17-Carboxy-heptadecanoyl]-Peg3-Peg3-isoGlu;

(vii) [17-Carboxy-heptadecanoyl]-isoGlu-GSGSGG; and

(viii) [17-Carboxy-heptadecanoyl]-AA-Peg3-Peg3.

17. A compound according to claim 1 wherein P1 has the sequence:

18. A compound according to claim 17 which is:

26. A composition comprising a compound according to any one of the preceding claims in admixture with a carrier.

27. A composition according to claim 26 wherein the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier.

28. A compound according to any one of claims 1 to 25 for use in a method of medical treatment.

29. A compound according to any one of claims 1 to 25 for use in a method of preventing weight gain or promoting weight loss in an individual in need thereof.

30. A compound according to any one of claims 1 to 25 for use in a method of lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof.

31. A compound according to any one of claims 1 to 25 for use in a method of treatment of a condition caused or characterised by excess body weight.

32. A compound according to any one of claims 1 to 25 for use in a method 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 dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease.

33. A compound for use according to any one of claims 29 to 32 wherein the compound is administered as part of a combination therapy together with an agent for treatment of diabetes, obesity, dyslipidemia or hypertension.

34. A compound for use according to claim 33 wherein the agent for treatment of diabetes is a biguanide (e.g. metformin), a sulfonylurea, a meglitinide or glinide (e.g. nateglinide), a DPP-IV inhibitor, an SGLT2 inhibitor, a glitazone, a different GLP-1 agonist, an insulin or an insulin analogue.

35. A compound for use according to claim 33, 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, melanin concentrating hormone receptor 1 antagonist, phentermine, a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist (e.g. a combination of phentermine and topiramate), a combination of bupropion and naltrexone, or a serotonergic agent.

36. A compound for use according to claim 33 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

37. A compound for use according to claim 33 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin and/or a cholesterol absorbtion inhibitor.

38. A therapeutic kit comprising a compound according to any of claims 1 to 25 or a composition according to claim 26 or 27.

39. A method of synthesis of a compound according to any one of claims 1 to 25.

40. A method of producing a compound according to any one of claims 1 to 25, 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 any one of claims 1 to 25.

41. A method according to claim 40 comprising modifying the precursor peptide to introduce the substituent at residue ψ

.

4. 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;

5. A compound according to claim 4 wherein:

X2 is selected from Aib and Ac4c;

X3 is Gin;

X15 is selected from Asp and Glu;

X16 is ψ

;

X17 is Arg;

X18 is Ala;

X20 is selected from Lys and His;

X24 is Glu;

X28 is Ser.

6. A compound according to claim 4 or claim 5 wherein:

X2 is Ac4c and X20 is Lys;

X2 is Aib and X20 is His.

7. A compound according to any one of claims 4 to 6 wherein

X2 is Aib if X15 is E;

or

X15 is D if X2 is Ac4c.

8. A compound according to any one of claims 4 to 7 wherein P¹ has a sequence selected from:

9. A compound according to claim 8 which is selected from:

10. A compound according to claim 4 wherein:

X2 is selected from Aib and Ac4c;

X3 is selected from Gin and His;

X15 is Asp;

X16 is Glu;

X17 is selected from Arg and ψ

;

X18 is selected from Ala and Arg;

X20 is Lys;

X24 is selected from Glu and ψ

;

X28 is selected from Ser and ψ

;

11. A compound according to claim 10 wherein, when X28 is ψ

, X2 is Ac4c.

12. A compound according to claim 10 wherein, when X3 is His, X2 is Ac4c and X17 is ψ

.

13. A compound according to claim 10 wherein P¹ has a sequence selected from:

14. A compound according to claim 13 which is selected from:

19. A compound according to any one of claims 4 to 7 wherein Z²—

Z¹ is [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3 or [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG.

20. A compound according to claim 10 or claim 12 wherein, when X17 is ψ

, Z²Z¹ is [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3 or [17-Carboxy-heptadecanoyl]-isoGlu.

21. A compound according to claim 10 or claim 11 wherein, when X24 or X28 is ψ

, Z²Z1 is [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG.

22. A compound according to claim 8 wherein P¹ has a sequence selected from:

23. A compound according to claim 22 which is selected from:

24. A compound according to claim 13 wherein P¹ has a sequence selected from:

25. A compound according to claim 24 which is selected from: