# US 2014/0155328 A1 · Alpha-and gamma-msh analogues

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- Number: US 2014/0155328 A1
- Document ID: US20140155328A1
- Status: Published application
- Kind: A1
- Application number: 14/058,790
- Filed: 2013-10-21
- Published: 2014-06-05
- Earliest claimed: 2012-10-19
- Assignees: TXP Pharma GmbH
- Applicants: Txp Pharma GmbH
- Inventors: Thomas BOESEN
- Web page: https://patentgrep.com/patent/US20140155328A1

## CPC

- C07K 14/685: Alpha-melanotropin
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/06: Antiarrhythmics
- 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 13/12: of the kidneys
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07K 14/68: Melanocyte-stimulating hormone [MSH]
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- 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 present invention provides peptide analogues of α-MSH and γ-MSH, comprising the amino acid sequence of human α-MSH or γ-MSH, or variants thereof, and having a branched amino acid probe in the N-terminal part of the peptide.

## Claims

### Claim at position 1

-81. (canceled)

### Claim 82

A peptide consisting of from 14 to 16 amino acid residues comprising the amino acid sequence:
X-(aa1)n-Y-(aa2)m-Z
wherein X is a branched amino acid probe consisting of 3 lysine residues having the formula Ac-(Ac-Lys-Lys)Lys1-; and
wherein (aa1)n is an amino acid sequence consisting of 4 or 5 contiguous amino acid residues selected from the group consisting of Ser-Tyr-Ser-Met-Glu (SEQ ID NO:17), Ser-Tyr-Ser-Nle-Glu (SEQ ID NO:18), Ser-Ser-Ile-Ile-Ser (SEQ ID NO:19), Tyr-Val-Met-Gly (SEQ ID NO:20) and Tyr-Val-Nle-Gly (SEQ ID NO:21); and
wherein Y is an amino acid sequence consisting of 4 contiguous amino acid residues selected from the group consisting of His-Phe-Arg-Trp (SEQ ID NO:16); His-(D-Phe)-Arg-Trp; His-Phe-(D-Arg)-Trp; His-Phe-Arg-(D-Trp); His-(D-Phe)-Arg-(D-Trp); His-NaI-Arg-Trp and His-(D-Nal)-Arg-Trp; and
wherein (aa2)m is selected from the group consisting of Gly and Asp; and
wherein Z is an amino acid sequence consisting of 2 or 3 contiguous amino acid residues selected from the group consisting of Lys-Pro-Val; Lys-Pro-(D-Val); Arg-Phe-Gly; Arg-(D-Phe)-Gly; Arg-Phe and Arg-(D-Phe);
wherein said carboxy terminal Val, D-Val, Gly, Phe or D-Phe of Z may optionally be modified by amidation (—NH2).

### Claim 83 (depends on 81)

The peptide according to claim 81, wherein said peptide consists of 16 amino acid residues and (aa1)n is selected from the group consisting of Ser-Tyr-Ser-Met-Glu (SEQ ID NO:17), Ser-Tyr-Ser-Nle-Glu (SEQ ID NO:18), Ser-Ser-Ile-Ile-Ser (SEQ ID NO:19); and
Y is selected from the group consisting of His-Phe-Arg-Trp (SEQ ID NO:16); His-(D-Phe)-Arg-Trp; His-Phe-(D-Arg)-Trp; His-Phe-Arg-(D-Trp); His-(D-Phe)-Arg-(D-Trp); His-Nal-Arg-Trp and His-(D-Nal)-Arg-Trp; and
(aa2)m is Gly; and
Z is selected from the group consisting of Lys-Pro-Val and Lys-Pro-(D-Val);
wherein said carboxy terminal Val or D-Val of Z may optionally be modified by amidation (—NH2).

### Claim 83 (depends on 81)

The peptide according to claim 81, wherein said peptide consists of 14 or 15 amino acid residues and (aa1)n is selected from the group consisting of Tyr-Val-Met-Gly (SEQ ID NO:20) and Tyr-Val-Nle-Gly (SEQ ID NO:21); and
Y is selected from the group consisting of His-Phe-Arg-Trp (SEQ ID NO:16); His-(D-Phe)-Arg-Trp; His-Phe-(D-Arg)-Trp; His-Phe-Arg-(D-Trp); His-(D-Phe)-Arg-(D-Trp); His-Nal-Arg-Trp and His-(D-Nal)-Arg-Trp; and
(aa2)m is Asp; and
Z is selected from the group consisting of Arg-Phe-Gly; Arg-(D-Phe)-Gly; Arg-Phe and Arg-(D-Phe),
wherein said carboxy terminal Gly, Phe or D-Phe of Z may optionally be modified by amidation (—NH2).

### Claim 84 (depends on 82)

The peptide according to claim 82, wherein said peptide is selected from the group consisting of:
(Ac-(Ac-Lys-Lys)Lys-SEQ ID NO: 2)
Ac-(Ac-Lys-Lys)Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-
Arg-Trp-Gly-Lys-Pro-Val-NH2;
Ac-(Ac-Lys-Lys)Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-
Arg-Trp-Gly-Lys-Pro-(D-Val)-NH2;
and
Ac-(Ac-Lys-Lys)Lys-Ser-Tyr-Ser-Nle-Glu-His-
(D-Phe)-Arg-Trp-Gly-Lys-Pro-Val-NH2.

### Claim 85 (depends on 84)

The peptide according to claim 84, wherein said peptide is Ac-(Ac-Lys-Lys)Lys-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2(Ac-(Ac-Lys-Lys)Lys-SEQ ID NO:2)

### Claim 86 (depends on 83)

The peptide according to claim 83, wherein said peptide is selected from the group consisting of:
Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Met-Gly-His-Phe-Arg-
(D-Trp)-Asp-Arg-Phe-Gly-NH2;
(Ac-(Ac-Lys-Lys)Lys-SEQ ID NO: 8)
Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Met-Gly-His-Phe-Arg-
Trp-Asp-Arg-Phe-Gly-NH2;
Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Met-Gly-His-(D-Phe)-
Arg-(D-Trp)-Asp-Arg-Phe-Gly-NH2;
Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Met-Gly-His-Phe-Arg-
(D-Trp)-Asp-Arg-(D-Phe)-Gly-NH2;
Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Nle-Gly-His-Phe-Arg-
(D-Trp)-Asp-Arg-Phe-Gly-NH2;
(Ac-(Ac-Lys-Lys)Lys-SEQ ID NO: 9)
Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Nle-Gly-His-Phe-Arg-
Trp-Asp-Arg-Phe-Gly-NH2;
Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Nle-Gly-His-(D-Phe)-
Arg-Trp-Asp-Arg-Phe-Gly-NH2;
and
Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Nle-Gly-His-(D-Phe)-
Arg-(D-Trp)-Asp-Arg-Phe-Gly-NH2.

### Claim 87 (depends on 86)

The peptide according to claim 86, wherein said peptide is Ac-(Ac-Lys-Lys)Lys-Tyr-Val-Met-Gly-His-Phe-Arg-(D-Trp)-Asp-Arg-Phe-Gly-NH2.

### Claim 88 (depends on 81)

A pharmaceutical composition comprising the peptide according to claim 81.

### Claim 89 (depends on 81)

A method for treatment of an ischemic and/or inflammatory condition in the tissue of one or more organs, said method comprising the step of administering a therapeutically effective amount of a peptide according to claim 81 to an individual in need thereof.

### Claim 90 (depends on 89)

The method according to claim 89, wherein said organ is selected from the group consisting of kidney, liver, brain, heart, muscles, bone marrow, skin, skeleton, lungs, the respiratory tract, spleen, exocrine glands, bladder, endocrine glands, reproduction organs including the phallopian tubes, eye, ear, vascular system, the gastrointestinal tract including small intestines, colon, rectum, canalis analis and prostate gland.

### Claim 91 (depends on 89)

The method according to claim 89, wherein said ischemic condition is secondary ischemia.

### Claim 92 (depends on 91)

The method according to claim 91, wherein said ischemic condition is due to stroke, injury, septic shock, systemic hypotension, cardiac arrest due to heart attack, cardiac arrhythmia, atheromatous disease with thrombosis, embolism from the heart or from blood vessel from any organ, vasospasm, aortic aneurysm or aneurisms in other organs, coronary stenosis, myocardial infarction, angina pectoris, pericarditis, myocarditis, myxodemia, or endocarditis.

### Claim 93 (depends on 89)

The method according to claim 89, wherein said ischemic and/or inflammatory condition is associated with surgery, such as major surgery.

### Claim 94 (depends on 93)

The method according to claim 93, wherein said surgery is selected from the group consisting of cardiothoracic surgery, abdominal surgery, surgery on the aorta and/or other major blood vessels, repair of one or more cardiac valves, cardiac artery bypass grafting (CABG), surgery on the aortic root or the aortic branch including the common carotic arteries, combined cardiac surgery such as valve(s) replacement and CABG, and aortic root surgery.

### Claim 95 (depends on 89)

The method according to claim 89, wherein said ischemic and/or inflammatory condition is post-surgical systemic inflammatory response syndrome (SIRS) or post-surgical organ dysfunction.

### Claim 96 (depends on 95)

The method according to claim 95, wherein said post-surgical organ dysfunction is selected from the group consisting of post-surgical renal failure, acute kidney injury (AKI), neprotoxicity and chronic renal failure (CRF).

### Claim 97 (depends on 89)

The method according to claim 89, wherein said ischemic and/or inflammatory condition is associated with organ transplantation, such as solid organ transplantation.

### Claim 98 (depends on 97)

The method according to claim 97, wherein said organ transplantation is selected from the group consisting of heart transplantation, lung transplantation, combined heart and lung transplantation, liver transplantation and kidney transplantation.

### Claim 99 (depends on 89)

The method according to claim 89, wherein said ischemic and/or inflammatory condition is reperfusion injury.

### Claim 100 (depends on 89)

The method according to claim 89, wherein said inflammatory disease is selected from the group consisting of arthropathy (joint disease), rheumatoid arthritis (RA), gout, inflammatory diseases of the gastrointestinal system, and multiple sclerosis.