Mu opioid receptor agonist analogs of the endomorphins

Patent metadata

Field	Value
Publication number	US-10919939-B2
Application number	US-201715477907-A
Country	US
Kind code	B2
Filing date	Apr 3, 2017
Priority date	Jul 9, 2010
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

The invention relates to cyclic peptide agonists that bind to the mu (morphine) opioid receptor and their use in the treatment of acute and/or chronic pain. Embodiments of the invention are directed to cyclic analogs of endomorphin. These peptide analogs exhibit decreased tolerance relative to morphine, increased solubility compared to similar tetrapeptide analogs, while maintaining favorable or improved therapeutic ratios of analgesia to side effects.

First claim

What is claimed is:

1. A cyclic peptide of Formula I:
H-Tyr-cyclo[X 1 -X 2 -X 3 -X 4 ]-X 5   (I), and salts thereof,

wherein
X 1 is a basic D-amino acid;
X 2 is Trp;
X 3 is an aromatic amino acid;
X 4 is an acidic amino acid;
X 5 is selected from the group consisting of Ala-NHR, Arg-NHR, Asn-NHR, Asp-NHR, Cys-NHR, Glu-NHR, Gln-NHR, Gly-NHR, His-NHR, Ile-NHR, Leu-NHR, Met-NHR, Orn-NHR, Phe-NHR, Pro-NHR, Ser-NHR, Thr-NHR, Trp-NHR, Tyr-NHR, and Val-NHR, wherein R is H or an alkyl group; and
there is an amide bond between an amino group and a carboxylic acid group on side chains of amino acids X 1 and X 4 .

2. The cyclic peptide of claim 1 , wherein X 1 is selected from the group consisting of D-Lys and D-Orn.

3. The cyclic peptide of claim 1 , wherein X 4 is selected from the group consisting of D-Asp, D-Glu, Asp, and Glu.

4. The cyclic peptide of claim 1 , wherein X 1 is selected from the group consisting of D-Lys and D-Orn; and X 4 is selected from the group consisting of D-Asp, D-Glu, Asp, and Glu.

5. The cyclic peptide of claim 1 , wherein X 3 is selected from the group consisting of Phe, D-Phe, and p-Y-Phe, wherein Y is NO 2 , F, Cl, or Br.

6. The cyclic peptide of claim 1 , wherein X 3 is Phe.

7. The cyclic peptide of claim 1 , wherein X 3 is p-Cl-Phe.

8. The cyclic peptide of claim 1 , wherein R is H.

9. The cyclic peptide of claim 1 , wherein R is H and X 5 is Gly-NH 2 .

10. The cyclic peptide of claim 1 , wherein the alkyl group is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, or isoheptyl group.

11. The cyclic peptide of claim 1 , wherein the peptide is Tyr-cyclo[D-Lys-Trp-Phe-Glu]-Gly-NH 2 (SEQ ID NO: 3).

12. The cyclic peptide of claim 1 , wherein X 5 is Arg-NH 2 .

13. The cyclic peptide of claim 1 , wherein X i is D-Lys.

14. The cyclic peptide of claim 1 , wherein X i is D-Orn.

15. The cyclic peptide of claim 1 , wherein X 4 is Glu.

16. The cyclic peptide of claim 1 , wherein X 4 is Asp.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the cyclic peptide of claim 1 .

18. The pharmaceutical composition of claim 17 , wherein the cyclic peptide is in the form of an acetate salt.

19. The pharmaceutical composition of claim 18 , wherein the cyclic peptide is Tyr-cyclo[D-Lys-Trp-Phe-Glu]-Gly-NH 2 (SEQ ID NO: 3).

20. A method of treating pain comprising administering to a subject in need thereof an analgesic amount of the cyclic peptide of claim 1 .

21. The method of claim 20 , wherein the cyclic peptide is Tyr-cyclo[D-Lys-Trp-Phe-Glu]-Gly-NH 2 (SEQ ID NO: 3).

22. A method of treating pain comprising intravenously administering to a subject in need thereof an analgesic amount of the pharmaceutical composition of claims 18 .

Assignees

• The Administrators Of The Tulane Educational Fund
• United States Dept Of Veterans Affairs

Inventors

• Zadina James E
• Hackler Laszlo

Classifications

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• A61K38/00

  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) · CPC title

• C07K7/56

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title

• G01N33/9486

  Analgesics, e.g. opiates, aspirine · CPC title

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · CPC title