# US 9,434,764 B2 · Skin care compositions and methods comprising selective agonists of melanocortin 1 receptor

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,434,764 B2
- Document ID: US9434764B2
- Status: Granted
- Kind: B2
- Application number: 14/646,407
- Filed: 2013-11-20
- Published: 2015-10-22
- Granted: 2016-09-06
- Earliest claimed: 2012-11-21
- Assignees: University of Cincinnati
- Applicants: University of Cincinnati
- Inventors: Zalfa A. Abdel-Malek; Leonid Koikov; James J. Knittel
- Web page: https://patentgrep.com/patent/US9434764B2

## CPC

- C07K 5/1024: {with the first amino acid being heterocyclic}
- A61K 8/06: Emulsions
- A61K 8/64: Proteins; Peptides; Derivatives or degradation products thereof
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 38/06: Tripeptides
- A61K 38/07: Tetrapeptides
- A61P 17/00: Drugs for dermatological disorders
- A61P 35/00: Antineoplastic agents
- A61Q 17/04: Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
- A61Q 19/004: {Aftersun preparations}
- A61Q 19/04: for chemically tanning the skin (topical sun or radiation screening or tanning preparations A61Q17/04)
- A61Q 19/08: Anti-ageing preparations
- C07K 5/0821: {with the first amino acid being heterocyclic, e.g. His, Pro, Trp}
- 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
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

Short tri- and tetrapeptides according to the following Formula I Ar(CH2)mX1—X2—CO—X3—X4—X5-(Trp)n-NX6R are potent, selective agonists of melanocortin 1 receptor (MC1R). Provided herein are skin care compositions including Formula I peptide agonists of MC1R and methods of regulating a skin condition of a mammal that include applying to a treatment surface of the body a safe and effective amount of a skin care composition including a Formula I peptide. The peptides, skin care compositions, and skin care methods described herein are useful in regulating a skin condition of a mammal associated with exposure ultraviolet (UV) radiation, including sunburn, UV sensitivity, photoaging, and skin pigmentation, particularly in the absence of sun exposure.

## Claims

### Claim 1

A peptide agonist of melanocortin 1 receptor (MC1R) selective for MC1R versus melanocortin 3 receptor (MC3R), melanocortin 4 receptor (MC4R), and melanocortin 5 receptor (MC5R) according to the following formula:
Ar(CH2)mX1—X2—CO—X3—X4—X5-(Trp)n-NX6R Formula I
or a dermatologically-acceptable salt, solvate, or enantiomer thereof, wherein:
Ar is selected from the group consisting of unsubstituted or substituted phenyl and 5- or 6-membered heteroaryl;
m is 0, 1, 2, or 3;
X1 is absent or X1 is selected from the group consisting of O, NR′, S, Se, and CR′R″ wherein R′ is selected from the group consisting of H, linear or branched C1-C4 alkyl, OH, and linear or branched C1-C4 O-alkyl and R″ is selected from the group consisting of H and linear or branched C1-C4 alkyl; or wherein CR′R″ is a C3-C6 cycloalkyl;
X2 is absent or X2 is selected from the group consisting of 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, and CQ′Q″ wherein Q′ and Q″ are each independently selected from the group consisting of H and linear or branched C1-C4 alkyl;
X3 is selected from the group consisting of unsubstituted or substituted L-histidine (His), 3-(2-pyridyl)-L-alanine (2-PAL), 3-(3-pyridyl)-L-alanine (3-PAL), 3-(4-pyridyl)-L-alanine (4-PAL), 3-(2-thienyl)-L-alanine (2-Thi), 3-(3-thienyl)-L-alanine (3-Thi), 3-(2-furyl)-L-alanine (2-FurAla), 3-(3-furyl)-L-alanine (3 FurAla), L-homoserine (HoSer), O-methyl-L-homoserine (HoSer(Me)), and L-allylglycine;
X4 is selected from the group consisting of unsubstituted or substituted L-alpha-MePhe, 3-(2-thienyl)-D-alanine (D-2-Thi), 3-(3-thienyl)-D-alanine (D-3-Thi), 3-(2-furyl)-D-alanine (D-2-FurAla), 3-(3-furyl)-D-alanine (D-3-FurAla), and substituted D-phenylalanine (D-Phe);
X5 is selected from the group consisting of unsubstituted or substituted L-arginine (Arg) and L-citrulline;
n is 0 or 1;
X6 is selected from the group consisting of H, linear or branched C1-C4 alkyl, and C3-C4 cycloalkyl; and
R is selected from the group consisting of H, linear or branched C1-C12 alkyl, linear or branched C1-C12 arylalkyl, and C3-C5 cycloalkyl;
or wherein X6 and R together form a C3-C5 heterocycloalkyl.

### Claim 2 (depends on 1)

The selective peptide agonist of MC1R of claim 1, wherein the substituted D-Phe comprises D-4-t-Bu-phenylalanine (D-4-tBuPhe), D-alpha-methylphenylalanine (D-alpha-MePhe), D-4-biphenylalanine (D-4-Bip), D-1-naphthylalanine (D-1-Nal), D-2-naphthylalanine (D-2-Nal), 4-FPhe, 4-ClPhe, 4-BrPhe, 4-IPhe, 4-NO2Phe, or 3-NO2Phe.

### Claim 3 (depends on 2)

The peptide agonist of MC1R of claim 2, wherein:
Ar is selected from the group consisting of unsubstituted or substituted phenyl and 5- or 6-membered heteroaryl;
m is 1, 2, or 3;
X1 is absent;
X2 is absent;
X3 is His;
X4 is selected from the group consisting of D-2-Thi, D-3-Thi, D-4-tBuPhe, D-alpha-MePhe, L-alpha-MePhe, D-4-Bip, D-1-Nal, and D-2-Nal;
X5 is selected from the group consisting of unsubstituted or substituted Arg and L-citrulline;
n is 0 or 1;
X6 is selected from the group consisting of H, linear or branched C1-C4 alkyl, and C3-C4 cycloalkyl; and
R is selected from the group consisting of H, linear or branched C1-C12 alkyl, linear or branched C1-C12 arylalkyl, and C3-C5 cycloalkyl.

### Claim 4 (depends on 2)

The peptide agonist of MC1R of claim 2, wherein:
Ar is unsubstituted or substituted phenyl;
m is 3;
X1 is absent;
X2 is absent;
X3 is His;
X4 is selected from the group consisting of D-4-tBuPhe, D-4-Bip, D-1-Nal, and D-2-Nal;
X5 is unsubstituted or substituted Arg;
n is 0 or 1;
X6 is H, methyl, or ethyl; and
R is H, methyl, or ethyl.

### Claim 5 (depends on 1)

The peptide agonist of MC1R of claim 1, wherein Ar is unsubstituted or substituted phenyl, m is 3, and X1 and X2 are absent.

### Claim 6 (depends on 1)

The peptide agonist of MC1R of claim 1, wherein X3 is His and X5 is Arg.

### Claim 7 (depends on 1)

The peptide agonist of MC1R of claim 1, wherein X4 is selected from the group consisting of D-4-tBuPhe, D-4-Bip, D-1-Nal, and D-2-Nal.

### Claim 8 (depends on 1)

The peptide agonist of MC1R of claim 1, wherein X6 is H and R is H, methyl, or ethyl.

### Claim 9

A peptide agonist of melanocortin 1 receptor (MC1R) selective for MC1R versus melanocortin 3 receptor (MC3R), melanocortin 4 receptor (MC4R), and melanocortin 5 receptor (MC5R) selected from the group consisting of:
Ph(CH2)3CO-His-(D-Phe)-Arg-Trp-NHEt;
Ph(CH2)3CO-His-(D-1-Nal)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-4-Bip)-Arg-NH2;
Ph(CH2)3CO-His-(D-4-Bip)-Arg-NHMe; and
Ph(CH2)3CO-His-(D-4-tBuPhe)-Arg-NH2.

### Claim 10 (depends on 1)

The peptide agonist of MC1R of claim 1, wherein the agonist is substantially free from conformational restraints imposed by secondary structure.

### Claim 11 (depends on 10)

The peptide agonist of MC1R of claim 10, wherein the secondary structure is not constrained by a beta-turn conformation.

### Claim 12 (depends on 1)

A skin care composition for regulating a skin condition of a mammal comprising:
(a) a safe and effective amount of a peptide agonist of MC1R according to claim 1; and
(b) one or more dermatologically acceptable carriers.

### Claim 13 (depends on 12)

The skin care composition of claim 12, wherein the skin care composition is an emulsion.

### Claim 14 (depends on 12)

The skin care composition of claim 12, further comprising an additional skin care active selected from the group consisting of desquamatory actives, anti-acne actives, wrinkle repair actives, antioxidants, radical scavengers, chelators, anti-inflammatory agents, topical anesthetics, anti-cellulite agents, flavonoids, antimicrobial actives, antifungal actives, sunscreen actives, conditioning agents, and combinations thereof.

### Claim 15 (depends on 12)

A method of regulating a skin condition of a mammal in need thereof, the method comprising the step of topically applying to a skin treatment surface of the mammal the skin care composition according to claim 12.

### Claim 16 (depends on 15)

The method of claim 15, wherein the condition to be regulated is selected from the group consisting of sunburn, ultraviolet (UV) sensitivity, photoaging, and skin pigmentation.

### Claim 17 (depends on 16)

The method of claim 16, wherein regulating a skin condition comprises stimulating skin pigmentation in the absence of ultraviolet (UV) exposure.

### Claim 18 (depends on 15)

The method of claim 15, wherein the selective peptide agonist of MC1R stimulates production of melanin by melanocytes, thereby providing increased skin protection from ultraviolet radiation.

### Claim 19 (depends on 15)

The method of claim 15, wherein the selective peptide agonist of MC1R activates DNA repair pathways.

### Claim 20

A peptide agonist of melanocortin 1 receptor (MC1R) selective for MC1R versus melanocortin 3 receptor (MC3R), melanocortin 4 receptor (MC4R), and melanocortin 5 receptor (MC5R) selected from the group consisting of:
Ph(CH2)3CO-His-(D-Phe)-Arg-Trp-NHEt;
Ph(CH2)3CO-His-(D-1-Nal)-Arg-Trp-NHEt;
Ph(CH2)3CO-His-(D-2-Nal)-Arg-Trp-NHEt;
Ph(CH2)3CO-His-(D-4-Bip)-Arg-Trp-NHEt;
Ph(CH2)3CO-His-(D-4-tBuPhe)-Arg-Trp-NHEt;
4-FC6H4CH2CO-His-(D-Phe)-Arg-Trp-NHEt;
4-FC6H4CH2CO-His-(D-1-Nal)-Arg-Trp-NHEt;
4-FC6H4CH2CO-His-(D-2-Nal)-Arg-Trp-NHEt;
4-FC6H4CH2CO-His-(D-4-Bip)-Arg-Trp-NHEt;
4-FC6H4CH2CO-His-(D-4-tBuPhe)-Arg-Trp-NHEt;
Ph(CH2)3CO-His-(D-Phe)-Arg-Trp-NHMe;
4-FC6H4CH2CO-His-(D-Phe)-Arg-Trp-NHMe;
Ph(CH2)3CO-His-(D-1-Nal)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-2-Nal)-Arg-Trp-NH2;
4-BrC6H4CH2CO-His-(D-Phe)-Arg-Trp-NH2;
4-FC6H4CH2CO-His-(D-4-FPhe)-Arg-Trp-NH2;
4-BrC6H4CH2CO-His-(D-4-FPhe)-Arg-Trp-NH2;
4-CF3C6H4CH2CO-His-(D-4-FPhe)-Arg-Trp-NH2;
3,4-O(CH2)2C6H4CH2CO-His-(D-4-FPhe)-Arg-Trp-NH2;
(D)-C6H4CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH2;
(L)-C6H4CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH2;
(D,L)-C6H4CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH2;
(D,L)-C6H4CH(OMe)CO-His-(D-4-FPhe)-Arg-Trp-NH2;
(D)-4-ClC6H4CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH2;
(L)-4-ClC6H4CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH2;
(D,L)-4-ClC6H4CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH2;
C6F5CH2CO-His-(D-4-FPhe)-Arg-Trp-NH2;
4-C6H5C6H4CO-His-(D-4-FPhe)-Arg-Trp-NH2;
4-C6H5OC6H4CO-His-(D-4-FPhe)-Arg-Trp-NH2;
3-C6H5OC6H4CO-His-(D-4-FPhe)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-4-FPhe)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-4-ClPhe)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-4-BrPhe)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-4-IPhe)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-2-Thi)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-4-NO2Phe)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-3-NO2Phe)-Arg-Trp-NH2;
4-IC6H4CH2CO-His-(D-Phe)-Arg-Trp-NH2;
4-IC6H4CH2CO-His-(D-4-IPhe)-Arg-Trp-NH2;
Ph(CH2)3CO-(4-PAL)-(D-Phe)-Arg-Trp-NH2;
Ph(CH2)3CO-(2-Thi)-(D-Phe)-Arg-Trp-NH2;
Ph(CH2)3CO-(3-Thi)-(D-Phe)-Arg-Trp-NH2;
Ph(CH2)3CO-(2-FurAla)-(D-Phe)-Arg-Trp-NH2;
Ph(CH2)3CO—(HoSer)-(D-Phe)-Arg-Trp-NH2;
Ph(CH2)3CO—(HoSer(Me))-(D-Phe)-Arg-Trp-NH2;
Ph(CH2)3CO-(AllGly)-(D-Phe)-Arg-Trp-NH2;
Ph(CH2)3CO-His-(D-1-Nal)-Arg-NH2;
Ph(CH2)3CO-His-(D-2-Nal)-Arg-NH2;
Ph(CH2)3CO-His-(D-4-Bip)-Arg-NH2;
Ph(CH2)3CO-His-(D-4-tBuPhe)-Arg-NH2;
4-BrC6H4CH2CO-His-(D-4-FPhe)-Arg-NH2;
4-HOC6H4CH2CO-His-(D-4-FPhe)-Arg-NH2;
3,4-O(CH2)2C6H4CH2CO-His-(D-4-FPhe)-Arg-NH2;
Ph(CH2)3CO-His-(D-1-Nal)-Arg-NHMe;
Ph(CH2)3CO-His-(D-2-Nal)-Arg-NHMe;
Ph(CH2)3CO-His-(D-4-Bip)-Arg-NHMe;
Ph(CH2)3CO-His-(D-4-tBuPhe)-Arg-NHMe;
Ph(CH2)3CO-His-(D-1-Nal)-Arg-NHEt;
Ph(CH2)3CO-His-(D-2-Nal)-Arg-NHEt;
Ph(CH2)3CO-His-(D-4-Bip)-Arg-NHEt;
Ph(CH2)3CO-His-(D-4-tBuPhe)-Arg-NHEt;
4-FC6H4CH2CO-His-(D-Phe)-Arg-NHEt;
4-FC6H4CH2CO-His-(D-4-FPhe)-Arg-NHEt;
4-FC6H4CH2CO-His-(D-1-Nal)-Arg-NHEt;
4-FC6H4CH2CO-His-(D-2-Nal)-Arg-NHEt;
4-FC6H4CH2CO-His-(D-4-Bip)-Arg-NHEt; and
4-FC6H4CH2CO-His-(D-4-tBuPhe)-Arg-NHEt.