# US 8,541,545 B2 · Stabilized melanocortin ligands

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- Number: US 8,541,545 B2
- Document ID: US8541545B2
- Status: Granted
- Kind: B2
- Application number: 13/389,820
- Filed: 2010-08-30
- Published: 2012-08-30
- Granted: 2013-09-24
- Earliest claimed: 2009-08-31
- Assignees: Tensive Controls, Inc.
- Applicants: Kenneth A. Gruber
- Inventors: Kenneth A. Gruber
- Web page: https://patentgrep.com/patent/US8541545B2

## CPC

- C07K 5/1024: {with the first amino acid being heterocyclic}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- C07K 14/665: derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

Compositions and methods are disclosed for a non-naturally occurring melanocortin ligand comprised of a melanocortin analog coupled to a degradation-resistant C-terminal extension and, optionally, an N-terminal extension, to produce a stable melanocortin ligand having diminished or abolished cardiovascular activity while retaining desired melanocortin regulatory activity.

## Claims

### Claim 1

A non-naturally occurring melanocortin ligand comprising a melanocortin analog coupled to a degradation-resistant C-terminal extension and an N-terminal extension, the non-naturally occurring melanocortin ligand comprising Formula I:
Y1-Y2-Y3-R1-R2-R3-R4-R5-R6-R7-X1-X2-X3 (Formula I)
wherein the melanocortin analog comprises R1 to R7, wherein:
R1 is absent or is selected from the group consisting of cysteine, norleucine, acetylated norleucine, acetylated cysteine, acetylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, aspartic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, and an n-hexanoyl group;
R2 is absent or is selected from the group consisting of proline, aspartic acid, glutamic acid, glycine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, and an n-hexanoyl group;
R3 is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, D-Nal(2′), L-Nal(2′), succinic acid, tButGly, Hyp(Bzl), Mamb, Oic, norleucine, Aba, β-alanine, and Tic;
R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2′), pCl-D-Phe, and (o-Phe)Phe;
R5 is selected from the group consisting of arginine, homoarginine, ornithine, alanine, proline, Pip, Nip, Tic, Phg, Sar, and Azt;
R6 is selected from D-tryptophan, L-tryptophan, D-Nal(2′), L-Nal(2′), Tic, and Bip;
R7 is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, and 2,3-diamino-propionic acid;
wherein if R3 is Aba, then R4 is selected from the group consisting of D-Phe, D-Nal(2′), and pCl-D-Phe; and
wherein if R2 is an n-pentanoyl group or an n-hexanoyl group, then R1, Y1, Y2, and Y3 are absent;
wherein the degradation-resistant C-terminal extension comprises X1 to X3:
X1 is selected from the group consisting of cysteine, D-threonine, D-proline, and L-proline and a piperazin-2-one ring;
X2 is absent or is selected from the group consisting D-threonine, D-proline, L-proline, and a piperazin-2-one ring;
X3 is absent or is selected from the group consisting of D-threonine, and a piperazin-2-one ring; and
wherein when X1 is cysteine, X2 is not absent;
wherein the N-terminal extension comprises Y1 to Y3:
Y1 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, and L-proline;
Y2 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring;
Y3 is absent or is selected from the group consisting of cysteine, D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring; and
wherein the melanocortin ligand is cyclized through a moiety selected from the group consisting of:
a disulfide bond between R1 or R2 and R7 or X1 when R1 or R2 is cysteine and R7 or X1 is cysteine;
a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid;
a side-chain lactam bridge between R2 and R7 when R2 is glutamic acid or aspartic acid and R7 is lysine;
a lactam closure between R1 and R7 when R1 is succinic acid or o-phthalic acid and R7 is lysine; and
a lactam closure between R2 or R3 and R7 when R2 or R3 is succinic acid and R7 is 2,3-diamino-propionic acid.

### Claim 2

A non-naturally occurring melanocortin ligand comprising a melanocortin analog coupled to a degradation-resistant C-terminal extension and an N-terminal extension, the non-naturally occurring melanocortin ligand comprising Formula II:
Y1-Y2-Y3-R1-R2-R3-R4-R5-R6-R7-R8-R9-X1 -X2-X3 (Formula II)
wherein the melanocortin analog comprises R1 to R9, wherein:
R1 is tyrosine;
R2 is valine;
R3 is selected from the group consisting of methionine, norleucine, cysteine, and L-penicillamine;
R4 is selected from the group consisting of glycine, D-cysteine, L-cysteine, aspartic acid, and norleucine;
R5 is selected from the group consisting of histidine, norleucine, proline, and Aib;
R6 is selected from the group consisting of phenylalanine, D-Nal(2′), and L-Nal(2′);
R7 is arginine;
R8 is selected from the group consisting of tryptophan and D-Nal(2′); and
R9 is absent or is selected from the group consisting of aspartic acid, cysteine, penicillamine, and lysine;
wherein the N-terminal extension comprises Y1 to Y3:
Y1 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, and L-proline;
Y2 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring;
Y3 is absent or is selected from the group consisting of cysteine, D-threonine, L-threonine, D-proline, L-proline and a piperazin-2-one ring;
wherein the degradation-resistant C-terminal extension comprises X1 to X3:
X1 is selected from the group consisting of cysteine, D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring;
X2 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring; and
X3 is absent or is selected from the group consisting of D-threonine, L-threonine, and a piperazin-2-one ring; and
wherein the melanocortin ligand is cyclized through a lactam side chain between R4 and R9 when R4 is aspartic acid and R9 is lysine.

### Claim 3 (depends on 1)

The non-naturally occurring melanocortin ligand of claim 1, wherein the melanocortin analog is an MC4 receptor agonist, an MC4 receptor antagonist, an MC3 receptor agonist, an MC3 receptor antagonist, and/or an MC5agonist.

### Claim 4 (depends on 2)

The non-naturally occurring melanocortin ligand of claim 2, wherein the melanocortin analog is an MC3 antagonist.

### Claim 5 (depends on 1)

The non-naturally occurring melanocortin ligand of claim 1, wherein D-phenylalanine is halogenated at the para position when R4 is D-phenylalanine.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising the non-naturally occurring melanocortin ligand of claim 1 and a pharmaceutical salt.

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6, wherein any cardiovascular effects are diminished.

### Claim 8 (depends on 6)

The pharmaceutical composition of claim 6, wherein the non-naturally occurring melanocortin ligand is AcNle-c[Asp-Pro-D-Nal(2′)-Arg-Trp-Lys]-D-Thr-D-Pro-D-Thr.

### Claim 9 (depends on 2)

A pharmaceutical composition comprising the non-naturally occurring melanocortin ligand of claim 2 and a pharmaceutical salt.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, wherein any cardiovascular effects are diminished.

### Claim 11 (depends on 9)

The pharmaceutical composition of claim 9, wherein the non-naturally occurring melanocortin ligand is Tyr-Val-Nle-c[Asp-Pro-D-Nal(2′)-Arg-Trp-Lys]-D-Thr-D-Pro-D-Thr.