Chimeric melanocortin ligands and methods of use thereof

1. A cyclic compound of formula I:

wherein:

Pro is L-proline, wherein the pyrrolidinyl ring is optionally substituted with one or more halo groups, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or —O(C 1 -C 4 )haloalkyl;

DPhe is D-phenylalanine, wherein the phenyl ring is optionally substituted with one or more halo groups, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or —O(C 1 -C 4 )haloalkyl;

Arg is L-arginine;

Trp is L-tryptophan, wherein the indolyl ring is optionally substituted with one or more halo groups, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or —O(C 1 -C 4 )haloalkyl;

DPro is D-proline, wherein the pyrrolidinyl ring is optionally substituted with one or more halo groups, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or —O(C 1 -C 4 )haloalkyl;

X 1 is a direct bond or an amino acid;

X 2 is a direct bond or an amino acid;

X 3 is a direct bond or an amino acid;

X 4 is an amino acid, dipeptide or tripeptide;

wherein when X 1 , X 2 , X 3 or X 4 is a lysine or comprises a lysine, the side-chain amine of the lysine is optionally linked through an amide bond to the carboxy terminus of an amino acid or the carboxy terminus of a peptide that is 2, 3, or 4 amino acids in length, and wherein the amino acid or peptide linked to the lysine is optionally acylated;

or a salt thereof.

2. The compound of claim 1 , wherein:

Pro is L-proline, wherein the pyrrolidinyl ring is optionally substituted with one or more halo groups, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or —O(C 1 -C 4 )haloalkyl;

DPhe is D-phenylalanine, wherein the phenyl ring is optionally substituted with one or more halo groups, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or —O(C 1 -C 4 )haloalkyl;

Arg is L-arginine;

Trp is L-tryptophan, wherein the indolyl ring is optionally substituted with one or more halo groups, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or —O(C 1 -C 4 )haloalkyl;

DPro is D-proline, wherein the pyrrolidinyl ring is optionally substituted with one or more halo groups, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or —O(C 1 -C 4 )haloalkyl;

X 1 is a direct bond, or an amino acid;

X 2 is a direct bond or an amino acid;

X 3 is an amino acid;

X 4 is an amino acid, dipeptide or tripeptide;

or a salt thereof.

3. The compound of claim 1 , wherein Pro is L-proline; DPro is D-proline; DPhe is D-phenylalanine; Trp is L-tryptophan; and Arg is L-arginine.

4. The compound of claim 1 , wherein X 1 , X 2 , X 3 and/or X 4 are an amino acid independently selected from the group consisting of L-Ala, L-Asp, L-Glu, L-Phe, L-Gly, L-His, L-Ile, L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Gln, L-Arg, L-Ser, L-Thr, L-Val, L-Trp, L-Tyr, L-Dap, D-Ala, D-Asp, D-Glu, D-Phe, D-His, D-Ile, D-Lys, D-Leu, D-Met, D-Asn, D-Pro, D-Gln, D-Arg, D-Ser, D-Thr, D-Val, D-Trp, D-Tyr, D-Dap, L-Nle, D-Nle, L-Cha, D-Cha, L-PyrAla, D-PyrAla, L-ThiAla, D-ThiAla, L-Tic, D-Tic, (pCl)L-Phe, (pCl)D-Phe, (pI)L-Phe, (pI)D-Phe, (pNO2)L-Phe, (pNO2)D-Phe, 2-L-Nal, 2-D-Nal, β-Ala, ε-Aminocaproic acid, Met[O2], dehydPro, and (3I)Tyr.

5. The compound of claim 1 , wherein X 1 is a direct bond.

6. The compound of claim 1 , wherein X 1 is L-histidine.

7. The compound of claim 1 , wherein X 2 is a direct bond.

8. The compound of claim 1 , wherein X 2 is L-asparagine or L-diaminopropionic acid.

9. The compound of claim 1 , wherein X 3 is a direct bond.

10. The compound of claim 1 , wherein X 3 is L-alanine or L-lysine.

11. The compound of claim 1 , wherein X 3 is L-lysine, and wherein the side-chain of the L-lysine is linked through an amide bond to the carboxy terminus of an amino acid or the carboxy terminus of a peptide that is 2, 3, or 4 amino acids in length.

12. The compound of claim 11 , wherein the amine terminus of the amino acid or peptide linked to the L-lysine is acylated.

13. The compound of claim 11 , wherein the amino acid linked to the lysine is L-arginine or wherein peptide linked the lysine comprises an L-arginine.

14. The compound of claim 1 , wherein X 4 is L-phenylalanine.

15. The compound of claim 1 which is selected from the group consisting of:

c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] (SEQ ID NO:1);

c[Pro-His-DPhe-Arg-Trp-Dap-Ala-Phe-DPro] (SEQ ID NO:2);

c[Pro-His-DPhe-Arg-Trp-Asn-Ala-DPro] (SEQ ID NO:3);

c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro] (SEQ ID NO:4);

c[Pro-His-DPhe-Arg-Trp-Asn-DPro] (SEQ ID NO:5);

c[Pro-His-DPhe-Arg-Trp-Dap-DPro] (SEQ ID NO:6);

c[Pro-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] (SEQ ID NO:8);

c[Pro-DPhe-Arg-Trp-Dap-Ala-Phe-DPro] (SEQ ID NO:9);

c[Pro-DPhe-Arg-Trp-Asn-Ala-DPro] (SEQ ID NO:10);

c[Pro-DPhe-Arg-Trp-Dap-Ala-DPro] (SEQ ID NO:11);

c[Pro-DPhe-Arg-Trp-Asn-DPro] (SEQ ID NO:12);

c[Pro-DPhe-Arg-Trp-Dap-DPro] (SEQ ID NO:13);

c[Pro-His-DPhe-Arg-Trp-Asn-Lys-Phe-DPro] (SEQ ID NO:34);

c[Pro-His-DPhe-Arg-Trp-Asn-Lys(Ac-Arg)-Phe-DPro] (SEQ ID NO:35);

c[Pro-His-DPhe-Arg-Trp-Asn-Lys(Ac-Arg-Arg)-Phe-DPro] (SEQ ID NO:36);

c[Pro-His-DPhe-Arg-Trp-Asn-Lys(Ac-Arg-Arg-Arg)-Phe-DPro] (SEQ ID NO:37);

c[Pro-His-DPhe-Arg-Trp-Dap-Lys-DPro] (SEQ ID NO:38);

c[Pro-His-DPhe-Arg-Trp-Dap-Lys(Ac-Arg)-DPro] (SEQ ID NO:39);

c[Pro-His-DPhe-Arg-Trp-Dap-Lys(Ac-Arg-Arg)-DPro] (SEQ ID NO:40); and

c[Pro-His-DPhe-Arg-Trp-Dap-Lys(Ac-Arg-Arg-Arg)-DPro] (SEQ ID NO:41);

and salts thereof.

16. The compound of claim 1 which is selected from the group consisting of (SEQ ID NOS 34-41, respectively, in order of appearance):

and salts thereof.

17. A composition comprising a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A compound selected from the group consisting of:

and salts thereof.

19. The compound of claim 18 , which is

or a salt thereof.

20. The compound of claim 18 , which is

or a salt thereof.

21. A method of modulating the activity of a melanocortin receptor in vitro or in vivo comprising contacting the receptor with an effective amount of a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof.

22. A method of modulating metabolic: activity, modulating appetite and/or ameliorating obesity in an animal in need thereof, comprising administering an effective amount of a compound of formula I as described in claim 18 , or a pharmaceutically acceptable salt thereof, to the animal.