Chimeric melanocortin ligands and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11124541-B2
Application number	US-201715786005-A
Country	US
Kind code	B2
Filing date	Oct 17, 2017
Priority date	Oct 18, 2016
Publication date	Sep 21, 2021
Grant date	Sep 21, 2021

Abstract

The invention provides compounds having the general formula I:

and salts thereof, wherein the variables Pro, DPro, DPhe, Arg, Trp, X 1 , X 2 , X 3 and X 4 have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

First claim

What is claimed is:

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.

Assignees

• Univ Minnesota

Inventors

• Haskell-Luevano Carrie
• Ericson Mark David

Classifications

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title