Skin care compositions and methods comprising selective agonists of melanocortin 1 receptor

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(CH 2 ) m X 1 —X 2 —CO—X 3 —X 4 —X 5 -(Trp) n -NX 6 R  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;

X 1 is absent or X 1 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;

X 2 is absent or X 2 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;

X 3 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;

X 4 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);

X 5 is selected from the group consisting of unsubstituted or substituted L-arginine (Arg) and L-citrulline;

n is 0 or 1;

X 6 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 X 6 and R together form a C3-C5 heterocycloalkyl.

2. 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-NO 2 Phe, or 3-NO 2 Phe.

3. 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;

X 1 is absent;

X 2 is absent;

X 3 is His;

X 4 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;

X 5 is selected from the group consisting of unsubstituted or substituted Arg and L-citrulline;

n is 0 or 1;

X 6 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.

4. The peptide agonist of MC1R of claim 2 , wherein:

Ar is unsubstituted or substituted phenyl;

m is 3;

X 1 is absent;

X 2 is absent;

X 3 is His;

X 4 is selected from the group consisting of D-4-tBuPhe, D-4-Bip, D-1-Nal, and D-2-Nal;

X 5 is unsubstituted or substituted Arg;

n is 0 or 1;

X 6 is H, methyl, or ethyl; and

R is H, methyl, or ethyl.

5. The peptide agonist of MC1R of claim 1 , wherein Ar is unsubstituted or substituted phenyl, m is 3, and X 1 and X 2 are absent.

6. The peptide agonist of MC1R of claim 1 , wherein X 3 is His and X 5 is Arg.

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

8. The peptide agonist of MC1R of claim 1 , wherein X 6 is H and R is H, methyl, or ethyl.

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(CH 2 ) 3 CO-His-(D-Phe)-Arg-Trp-NHEt;

Ph(CH 2 ) 3 CO-His-(D-1-Nal)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-Bip)-Arg-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-Bip)-Arg-NHMe; and

Ph(CH 2 ) 3 CO-His-(D-4-tBuPhe)-Arg-NH 2 .

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

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

12. 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.

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

14. 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.

15. 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 .

16. 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.

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

18. 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.

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

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(CH 2 ) 3 CO-His-(D-Phe)-Arg-Trp-NHEt;

Ph(CH 2 ) 3 CO-His-(D-1-Nal)-Arg-Trp-NHEt;

Ph(CH 2 ) 3 CO-His-(D-2-Nal)-Arg-Trp-NHEt;

Ph(CH 2 ) 3 CO-His-(D-4-Bip)-Arg-Trp-NHEt;

Ph(CH 2 ) 3 CO-His-(D-4-tBuPhe)-Arg-Trp-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-Phe)-Arg-Trp-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-1-Nal)-Arg-Trp-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-2-Nal)-Arg-Trp-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-4-Bip)-Arg-Trp-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-4-tBuPhe)-Arg-Trp-NHEt;

Ph(CH 2 ) 3 CO-His-(D-Phe)-Arg-Trp-NHMe;

4-FC 6 H 4 CH 2 CO-His-(D-Phe)-Arg-Trp-NHMe;

Ph(CH 2 ) 3 CO-His-(D-1-Nal)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-2-Nal)-Arg-Trp-NH 2 ;

4-BrC 6 H 4 CH 2 CO-His-(D-Phe)-Arg-Trp-NH 2 ;

4-FC 6 H 4 CH 2 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

4-BrC 6 H 4 CH 2 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

4-CF3C 6 H 4 CH 2 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

3,4-O(CH 2 ) 2 C 6 H 4 CH 2 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

(D)-C 6 H 4 CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

(L)-C 6 H 4 CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

(D,L)-C 6 H 4 CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

(D,L)-C 6 H 4 CH(OMe)CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

(D)-4-ClC 6 H 4 CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

(L)-4-ClC 6 H 4 CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

(D,L)-4-ClC 6 H 4 CH(OH)CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

C 6 F 5 CH 2 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

4-C 6 H 5 C 6 H 4 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

4-C 6 H 5 OC 6 H 4 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

3-C 6 H 5 OC 6 H 4 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-FPhe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-ClPhe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-BrPhe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-IPhe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-2-Thi)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-NO 2 Phe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-3-NO 2 Phe)-Arg-Trp-NH 2 ;

4-IC 6 H 4 CH 2 CO-His-(D-Phe)-Arg-Trp-NH 2 ;

4-IC 6 H 4 CH 2 CO-His-(D-4-IPhe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-(4-PAL)-(D-Phe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-(2-Thi)-(D-Phe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-(3-Thi)-(D-Phe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-(2-FurAla)-(D-Phe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO—(HoSer)-(D-Phe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO—(HoSer(Me))-(D-Phe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-(AllGly)-(D-Phe)-Arg-Trp-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-1-Nal)-Arg-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-2-Nal)-Arg-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-Bip)-Arg-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-4-tBuPhe)-Arg-NH 2 ;

4-BrC 6 H 4 CH 2 CO-His-(D-4-FPhe)-Arg-NH 2 ;

4-HOC 6 H 4 CH 2 CO-His-(D-4-FPhe)-Arg-NH 2 ;

3,4-O(CH 2 ) 2 C 6 H 4 CH 2 CO-His-(D-4-FPhe)-Arg-NH 2 ;

Ph(CH 2 ) 3 CO-His-(D-1-Nal)-Arg-NHMe;

Ph(CH 2 ) 3 CO-His-(D-2-Nal)-Arg-NHMe;

Ph(CH 2 ) 3 CO-His-(D-4-Bip)-Arg-NHMe;

Ph(CH 2 ) 3 CO-His-(D-4-tBuPhe)-Arg-NHMe;

Ph(CH 2 ) 3 CO-His-(D-1-Nal)-Arg-NHEt;

Ph(CH 2 ) 3 CO-His-(D-2-Nal)-Arg-NHEt;

Ph(CH 2 ) 3 CO-His-(D-4-Bip)-Arg-NHEt;

Ph(CH 2 ) 3 CO-His-(D-4-tBuPhe)-Arg-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-Phe)-Arg-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-4-FPhe)-Arg-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-1-Nal)-Arg-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-2-Nal)-Arg-NHEt;

4-FC 6 H 4 CH 2 CO-His-(D-4-Bip)-Arg-NHEt; and

4-FC 6 H 4 CH 2 CO-His-(D-4-tBuPhe)-Arg-NHEt.