Hepcidin analogues and uses thereof

• US 10,030,061 B2
• Filed: 11/30/2017
• Issued: 07/24/2018
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Smythe, Mark Leslie, Bourne, Gregory, Vink, Simone, Frederick, Brian T., Madala, Praveen, Tofteng Shelton, Anne Pernille, Fog, Jacob Ulrik
• Primary Examiner(s): Ha, Julie
• Assistant Examiner(s): Hellman, Kristina M
• Application Number:
  US15/828,214
• Publication Number:
  US 20180086811A1
• Time in Patent Office: 236 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 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 Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695

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.

Claims

1. A peptide of formula I:

R¹—

X—

Y—

R² 

 

(I)(SEQ ID NO;

12)

or a pharmaceutically acceptable salt thereof, wherein;

R¹ is hydrogen, isovaleric acid, isobutyric acid or acetyl;

R² is —

NH₂ 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 R¹, 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-NH₂ (SEQ ID NO;

38).

3. The peptide or pharmaceutically acceptable salt thereof of claim 1, wherein the peptide is:

Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH₂ (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-NH₂ (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-NH₂ (SEQ ID NO;

173).

6. The peptide or pharmaceutically acceptable salt thereof of claim 1, wherein the peptide is:

Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH₂ (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-NH₂ (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-NH₂ (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-NH₂ (SEQ ID NO;

219).

10. The peptide or pharmaceutically acceptable salt thereof of claim 1, wherein the peptide is:

Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH₂ (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-NH₂ (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-NH₂ (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-NH₂ (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-NH₂ (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))-NH₂ (SEQ ID NO;

226).

16. The peptide or pharmaceutically acceptable salt thereof of claim 1, wherein the peptide is:

Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH₂ (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-NH₂ (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-NH₂ (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-NH₂ (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-NH₂ (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-NH₂ (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-NH₂ (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)