# US 2013/0157935 A1 · Glucagon analogues

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- Number: US 2013/0157935 A1
- Document ID: US20130157935A1
- Status: Published application
- Kind: A1
- Application number: 13/702,841
- Filed: 2011-06-23
- Published: 2013-06-20
- Earliest claimed: 2010-06-23
- Assignees: Zealand Pharma A/S
- Inventors: Eddi Meier; Ditte Riber; Jens Rosengren Daugaard; Marie Skovgaard
- Web page: https://patentgrep.com/patent/US20130157935A1

## CPC

- C07K 14/605: Glucagons
- A61K 38/26: Glucagons
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 5/48: of the pancreatic hormones
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides materials and methods for promoting weight loss or preventing weight gain without affecting glycemic control. In particular, the invention provides novel 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

### Claim 1

A compound having the formula
R1—X—Z—R2.
wherein
R1 is H, C1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;
R2 is OH or NH2;
X is a peptide which has the formula I:
(SEQ ID NO: 11)
His-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-
Tyr-Leu-Asp-X16-X17-Arg-Ala-X20-Asp-Phe-Ile-Glu-
Trp-Leu-X27-X28-X29 (I)
wherein
X2 is selected from Ser and Aib;
X16 is selected from Glu and Y;
X17 is selected from Arg and Y;
X20 is selected from Lys and Y;
X27 is selected from Leu and Y;
X28 is selected from Ser and Y or absent;
X29 is Ala or absent;
wherein at least one of X16, X17, X20, X27 and X28 is Y;
wherein each residue Y is independently selected from Lys, Cys and Orn;
wherein the side chain of at least one amino acid residue Y of X is conjugated to a lipophilic substituent having the formula:
(i) Z1, wherein Z1 is a lipophilic moiety conjugated directly to the side chain of Y; or
(ii) Z1Z2, wherein Z1 is a lipophilic moiety, Z2 is a spacer, and Z1 is conjugated to the side chain of Y via Z2;
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.

### Claim 2 (depends on 1)

A compound according to claim 1 having the sequence
(SEQ ID NO: 12)
HSQGTFTSDYSKYLDERRAKDFIEWLKSA
(SEQ ID NO: 13)
HSQGTFTSDYSKYLDERRAKDFIEWLLSA
(SEQ ID NO: 14)
HSQGTFTSDYSKYLDERRAKDFIEWLLKA
(SEQ ID NO: 15)
HSQGTFTSDYSKYLDKRRAKDFIEWLLSA
(SEQ ID NO: 16)
HSQGTFTSDYSKYLDEKRAKDFIEWLLSA
or
(SEQ ID NO: 17)
H-Aib-QGTFTSDYSKYLDEKRAKDFIEWLLSA.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein said lipophilic substituent is attached to the amino acid residue at position 16, 17, 20, 27 or 28.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R1 is H.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R2 is NH2.

### Claim 6 (depends on 1)

A compound according to claim 1, having the sequence
(SEQ ID NO: 5)
H-HSQGTFTSDYSKYLDERRAKDFIEWL-K(Hexadecanoyl-isoGlu)-SA-NH2
(SEQ ID NO: 6)
H-HSQGTFTSDYSKYLDERRA-K(Hexadecanoyl-isoGlu)-DFIEWLLSA-NH2
(SEQ ID NO: 7)
H-HSQGTFTSDYSKYLDERRAKDFIEWLL-K(Hexadecanoyl-isoGlu)-A-NH2
(SEQ ID NO: 8)
H-HSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)-RRAKDFIEWLLSA-NH2
(SEQ ID NO: 9)
H-HSQGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-RAKDFIEWLLSA-NH2
or
(SEQ ID NO: 10)
H-H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-RAKDFIEWLLSA-NH2.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein one or more of the amino acid side chains in the compound is conjugated to a polymeric moiety.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein one or more of the amino acid side chains in peptide X is conjugated to a polymeric moiety.

### Claim 9 (depends on 1)

A composition comprising a compound according to claim 1, or a salt or derivative thereof, in admixture with a carrier.

### Claim 10 (depends on 9)

A composition according to claim 9 wherein the composition is a pharmaceutically acceptable composition, and the carrier is a pharmaceutically acceptable carrier.

### Claim 11

(canceled)

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

A method of treating a condition caused or characterised by excess body weight in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a compound according to claim 1.

### Claim 15 (depends on 1)

A method of treatment and/or prevention of obesity, morbid obesity, morbid obesity prior to surgery, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a compound according to claim 1.

### Claim 16 (depends on 13)

The method according to claim 13 wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity, dyslipidemia or hypertension.

### Claim 17 (depends on 16)

The method according to claim 16, 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.

### Claim 18 (depends on 16)

The method according to claim 16 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

### Claim 19 (depends on 16)

The method according to claim 16 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or and/or a cholesterol absorption inhibitor.

### Claim 20 (depends on 14)

The method according to claim 14 wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity, dyslipidemia or hypertension.

### Claim 21 (depends on 20)

The method according to claim 20, 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.

### Claim 22 (depends on 20)

The method according to claim 20 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

### Claim 23 (depends on 20)

The method according to claim 20 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or a cholesterol absorption inhibitor.

### Claim 24 (depends on 15)

The method according to claim 15 wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity, dyslipidemia or hypertension.

### Claim 25 (depends on 24)

The method according to claim 24, 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.

### Claim 26 (depends on 24)

The method according to claim 24 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

### Claim 27 (depends on 24)

The method according to claim 24 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or a cholesterol absorption inhibitor.