Hepcidin analogues and uses thereof

Patent metadata

Field	Value
Publication number	US-10030061-B2
Application number	US-201715828214-A
Country	US
Kind code	B2
Filing date	Nov 30, 2017
Priority date	Mar 15, 2013
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The present invention relates, inter alia, to certain hepcidin peptide analogs, including peptides and dimers thereof, and to the use of the peptides and peptide dimers in the treatment and/or prevention of a variety of diseases, conditions or disorders, including treatment and/or prevention of iron overload diseases, which include hereditary hemochromatosis and iron-loading anemias, and other conditions and disorders described herein.

First claim

What is claimed:

1. A peptide of formula I:
R 1 —X—Y—R 2   (I)(SEQ ID NO:12)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, isovaleric acid, isobutyric acid or acetyl;
R 2 is —NH 2 or —OH;
X is a peptide sequence having a formula Id:
X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10  (Id)(SEQ ID NO:24)

wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent;
wherein Y is a peptide sequence having a formula IIf:
Y1-Pro-Y3-Ser-Y5-Y6-Y7-Y8-Cys-Y10  (IIf)(SEQ ID NO:10)

wherein
Y1 is Gly, Glu, Val or Lys;
Y3 is Arg or Lys;
Y5 is Arg or Lys;
Y6 is Gly, Ser, Lys, Ile or Arg;
Y7 is Trp or absent;
Y8 is Val, Thr, Asp, Glu or absent; and
Y10 is Lys or absent;
wherein the peptide comprises a disulfide bond between the two Cys;
wherein said peptide of formula I is optionally PEGylated on R 1 , X, or Y;
wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or polymeric moiety; and
wherein Ida is iminodiacetic acid; pGlu is pyroglutamic acid; bhAsp is β-homoaspartic acid; and bhPro is β-homoproline.

2. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH 2 (SEQ ID NO:38).

3. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH 2 (SEQ ID NO:128).

4. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH 2 (SEQ ID NO:172).

5. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH 2 (SEQ ID NO:173).

6. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH 2 (SEQ ID NO:201).

7. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH 2 (SEQ ID NO:183).

8. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKF(K(Palm))PRSKGWVCK-NH 2 (SEQ ID NO:217).

9. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH 2 (SEQ ID NO:219).

10. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH 2 (SEQ ID NO:221).

11. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH 2 (SEQ ID NO:222).

12. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH 2 (SEQ ID NO:223).

13. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH 2 (SEQ ID NO:224).

14. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH 2 (SEQ ID NO:225).

15. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-NH 2 (SEQ ID NO:226).

16. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH 2 (SEQ ID NO:176).

17. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH 2 (SEQ ID NO:241).

18. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKF(K(isoGlu-Palm))PRSKGCK-NH 2 (SEQ ID NO:242).

19. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH 2 (SEQ ID NO:243).

20. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH 2 (SEQ ID NO:244).

21. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCI(K(Dapa-Palm))FEPRSKGCK-NH 2 (SEQ ID NO:248).

22. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is: Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH 2 (SEQ ID NO:250).

23. A pharmaceutical composition comprising the peptide or pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier or excipient.

24. The peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide is selected from the group consisting of:
(a)

Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH 2 (SEQ ID NO:223);

(b)

Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH 2 (SEQ ID NO:241);

(c)

Isovaleric acid-DTHFPCIKF(K(isoGlu-Palm))PRSKGCK-NH 2 (SEQ ID NO:242);

(d)

Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH 2 (SEQ ID NO:243); and

(e)

Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH 2 (SEQ ID NO:244), wherein the amino acids are L-amino acids.

Assignees

• Protagonist Therapeutics Inc

Inventors

• Smythe Mark Leslie
• Bourne Gregory
• Vink Simone
• Frederick Brian T
• Madala Praveen
• Tofteng Shelton Anne Pernille
• Fog Jacob Ulrik

Classifications

• A61P3/12

  for electrolyte homeostasis · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07K14/575 Primary

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695) · 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