Melanocortin receptor ligands

1. A compound according to formula (I):

(R 2 R 3 )-A 1 - c (A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1

wherein:

A 1 is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val or deleted;

A 2 is Cys, Pen or Asp;

A 3 is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, or D-Val;

A 4 is His or 3-Pal;

A 5 is D-Phe, D-2-Nal or D-(Et)Tyr;

A 6 is Arg or hArg;

A 7 is Trp, 2-Nal, Bal, Bip or D-Trp;

A 8 is Gly, Ala, β-Ala, Gaba, Apn, Ahx or deleted;

A 9 is Cys, D-Cys, Pen or Lys;

A 10 is Thr or deleted; and

R 2 and R 3 is, independently for each occurrence, H or acyl;

R 1 is —OH or —NH 2 ;

provided that

(I). when A 2 is Cys or Pen, then A 9 is Cys, D-Cys, or Pen;

(II). when A 2 is Asp, then A 9 is Lys;

(III). when A 1 is deleted, then R 2 and R 3 cannot both be H;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein said compound is:

SEQ ID NO: 50

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 51

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

SEQ ID NO: 51

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

SEQ ID NO: 7

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 21

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 22

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

SEQ ID NO: 28

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH 2 ;

SEQ ID NO: 28

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH 2 ;

SEQ ID NO: 29

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;

SEQ ID NO: 30

Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 30

Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 30

Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 30

Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 30

Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 30

Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 36

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;

SEQ ID NO: 16

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 16

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH 2 ;

SEQ ID NO: 20

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH 2 ;

SEQ ID NO: 49

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 17

n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-

Cys)-NH 2 ;

SEQ ID NO: 17

n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-

Cys)-NH 2 ;

SEQ ID NO: 18

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH 2 ;

SEQ ID NO: 18

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH 2 ;

SEQ ID NO: 20

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH 2 ;

SEQ ID NO: 21

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 22

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

SEQ ID NO: 22

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

or

SEQ ID NO: 29

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;

SEQ ID NO: 46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH;

SEQ ID NO: 46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH;

SEQ ID NO: 46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH;

SEQ ID NO: 47

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;

SEQ ID NO: 29

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;

or

SEQ ID NO: 49

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein:

A 1 is Arg or D-Arg;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3 , wherein

A 3 is D-Ala;

A 4 is His;

A 7 is Trp, Bip, D-Trp or 2-Nal;

A 8 is Ala, β-Ala, Gaba, Apn or Ahx;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 , wherein:

R 2 and R 3 is, independently for each occurrence, H, acyl, n-propanoyl or n-butanoyl;

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 , wherein

A 2 is Cys or Asp;

A 3 is D-Ala;

A 4 is His;

A 5 is D-Phe or D-2-Nal;

A 6 is Arg;

A 7 is Trp;

A 8 is Ala, Gaba or deleted;

A 9 is Cys, Pen or Lys;

A 10 is deleted;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 6 , wherein said compound is:

SEQ ID NO: 50

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 51

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

SEQ ID NO: 51

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

or

SEQ ID NO: 49

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;

or pharmaceutically acceptable salts thereof.

8. A compound according to claim 7 , wherein said compound is:

SEQ ID NO: 50

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

SEQ ID NO: 51

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

or

SEQ ID NO: 49

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8 , wherein said compound is:

SEQ ID NO: 50

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 8 , wherein said compound is:

SEQ ID NO: 51

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 8 , wherein said compound is:

SEQ ID NO: 49

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

13. A pharmaceutical composition according to claim 12 , wherein said compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition according to claim 13 , wherein said compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin-1 receptor, the human melanocortin-3 receptor and the human melanocortin-5 receptor.

15. A pharmaceutical composition according to claim 14 , wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-3 receptor.

16. A pharmaceutical composition according to claim 14 , wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-3 receptor.

17. A pharmaceutical composition according to claim 14 , wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-5 receptor.

18. A pharmaceutical composition according to claim 14 , wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-5 receptor.

19. A compound according to formula II:

(R 2 R 3 )-A 1 - c (A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-NH 2

wherein:

A 1 is Nle or deleted;

A 2 is Cys or Asp;

A 3 is D-Ala;

A 4 is His;

A 5 is D-Phe;

A 6 is Arg;

A 7 is Trp, 2-Nal or Bal;

A 8 is Gly, Ala, D-Ala, β-Ala, Gaba or Apn;

A 9 is Cys or Lys;

each of R 2 and R 3 is independently selected from the group consisting of H or (C 1 -C 6 )acyl;

provided that

(I). when R 2 is (C 1 -C 6 )acyl, then R 3 is H;

(II). when A 2 is Cys, then A 9 is Cys; and

(III). when A 2 is Asp, then A 9 is Lys,

or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 19 , wherein said compound is:

SEQ ID NO: 54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH 2 ;

SEQ ID NO: 54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-

NH 2 ;

SEQ ID NO: 54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-

NH 2 ;

SEQ ID NO: 54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-

NH 2 ;

SEQ ID NO: 54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ;

SEQ ID NO: 56

Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH 2 ;

SEQ ID NO: 56

Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH 2 ;

SEQ ID NO: 57

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH 2 ;

SEQ ID NO: 57

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-

NH 2 ;

SEQ ID NO: 57

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-

NH 2 ;

or

SEQ ID NO: 58

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH 2 ;

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 19 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

22. A pharmaceutical composition according to claim 21 , wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition according to claim 22 , wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.

24. A pharmaceutical composition according to claim 23 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

25. A pharmaceutical composition according to claim 23 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

26. A pharmaceutical composition according to claim 23 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

27. A pharmaceutical composition according to claim 23 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.