Thrombopoietic compounds

• US 20070142295A1
• Filed: 12/22/2006
• Published: 06/21/2007
• Est. Priority Date: 10/23/1998
• Status: Abandoned Application

• Current Assignee: Kirin-Amgen Inc. (Amgen Inc.)
• Original Assignee: Amgen Inc.
• Inventors: Liu, Chuan-Fa, Feige, Ulrich, Cheetham, Janet
• Application Number:
  US11/644,757
• Publication Number:
  US 20070142295A1
• Time in Patent Office: Days
• US Class Current: 514/7.800
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 14/524 Thrombopoietin, i.e. C-MPL ligand
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/75 containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The invention relates to the field of compounds, especially peptides or polypeptides, that have thrombopoietic activity. The peptides and polypeptides of the invention may be used to increase platelets or platelet precursors (e.g., megakaryocytes) in a mammal.

Claims

1. A TMP compound that binds to an mp1 receptor comprising the core structure:

X₂—

X₃—

X₄—

X₅—

X₆—

X₇—

X₈—

X₉—

X₁₀,

wherein,

X₂ is selected from the group consisting of Glu, Asp, Lys, and Val;

X₃ is selected from the group consisting of Gly and Ala;

X₄ is Pro;

X₅ is selected from the group consisting of Thr and Ser;

X₆ is selected from the group consisting of Leu, Ile, Val, Ala, and Phe;

X₇ is selected from the group consisting of Arg and Lys;

X₈ is selected from the group consisting of Gln, Asn, and Glu;

X₉ is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe;

X₁₀ is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; and

wherein any of X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, and X₁₀ is a non-naturally occurring amino acid; and

physiologically acceptable salts thereof.

2. The TMP of claim 1 further comprising the structure:

X₁—

X₂—

X₃—

X₄—

X₅—

X₆—

X₇—

X₈—

X₉—

X₁₀—

X₁₁—

X₁₂—

X₁₃—

X₁₄;

wherein,

X₁ is selected from the group consisting of Ile, Ala, Val, Leu, Ser, and Arg;

X₁₁ is selected from the group consisting of Ala, Ile, Val, Leu, Phe, Ser, Thr, Lys, His, and Glu;

X₁₂ is selected from the group consisting of Ala, Ile, Val, Leu, Phe, Gly, Ser, and Gin;

X₁₃ is selected from the group consisting of Arg, Lys, Thr, Val, Asn, Gln, and Gly;

X₁₄ is selected from the group consisting of Ala, Ile, Val, Leu, Phe, Thr, Arg, Glu, and Gly, and

wherein any of X₁₁, X₁₂, X₁₃, or X₁₄ is a non-naturally-occurring amino acid.

3. The TMP of claim 1,

wherein,

X₂ is selected from the group consisting of Glu, Asp, Lys, Val, and a non-naturally occurring amino acid.

4. The TMP of claim 1,

wherein,

X₃ is selected from the group consisting of Gly, Ala, and a non-naturally occurring amino acid.

5. The TMP of claim 1,

wherein,

X₄ is Pro or a non-naturally-occurring amino acid;

6. The TMP of claim 1,

wherein,

X₅ is selected from the group consisting of Thr, Ser, and a non-naturally occurring amino acid.

7. The TMP of claim 1,

wherein,

X₆ is selected from the group consisting of Leu, Ile, Val, Ala, Phe, and a non-naturally occurring amino acid.

8. The TMP of claim 1,

wherein,

X₇ is selected from the group consisting of Arg, Lys, and a non-naturally occurring amino acid.

9. The TMP of claim 1,

wherein,

X₈ is selected from the group consisting of Gln, Asn, Glu, and a non-naturally occurring amino acid.

10. The TMP of claim 1,

wherein,

X₉ is selected from the group consisting of Trp, Tyr, Cys, Ala, Phe, and a non-naturally occurring amino acid.

11. The TMP of claim 1,

wherein,

X₁₀ is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, Lys, and a non-naturally occurring amino acid.

12. The TMP of claim 2,

wherein,

X₁ is selected from the group consisting of Ile, Ala, Val, Leu, Ser, Arg, and a non-naturally occurring amino acid.

13. The TMP of claim 2,

wherein,

X₁₁ is selected from the group consisting of Ala, Ile, Val, Leu, Phe, Ser, Thr, Lys, His, Glu, and a non-naturally occurring amino acid.

14. The TMP of claim 2,

wherein,

X₁₃ is selected from the group consisting of Ala, Ile, Val, Leu, Phe, Gly, Ser, Gln, and a non-naturally occurring amino acid.

15. The TMP of claim 2,

wherein,

X₁₃ is selected from the group consisting of Arg, Lys, Thr, Val, Asn, Gin, Gly, and a non-naturally occurring amino acid.

16. The TMP of claim 2,

wherein,

X₁₄ is selected from the group consisting of Ala, Ile, Val, Leu, Phe, Thr, Arg, Glu, Gly, and a non-naturally occurring amino acid.

17. The TMP of claim 1 wherein the core structure

X₂—

X₃—

X₄—

X₅—

X₆—

X₇—

X₈—

X₉—

X₁₀ is;


E-G-P-T-L-R-Q-W-L

and

wherein, optionally, any of X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, and X₁₀ is substituted with a non-naturally-occurring amino acid.

18. The TMP of claim 17 wherein the core structure:

X₁—

X₂—

X₃—

X₄—

X₅—

X₆—

X₇—

X₈—

X₉—

X₁₀—

X₁₁—

X₁₂—

X₁₃—

X₁₄ is;

I-E-G-P-T-L-R-Q-W-L-A-A-R-A

and

wherein, optionally any of X₁, X₁₁, X₁₂, X₁₃ and X₁₄ is substituted with a non-naturally-occurring amino acid.

19. The TMP of claim 17,

wherein,

X₂ is substituted with a non-naturally-occurring amino acid.

20. The TMP of claim 17,

wherein,

X₃ is substituted with a non-naturally-occurring amino acid.

21. The TMP of claim 17,

wherein,

X₄ is substituted with a non-naturally-occurring amino acid.

22. The TMP of claim 17,

wherein,

X₅ is substituted with a non-naturally-occurring amino acid.

23. The TMP of claim 17,

wherein,

X₆ is substituted with a non-naturally-occurring amino acid.

24. The TM P of claim 17,

wherein,

X₇ is substituted with a non-naturally-occurring amino acid.

25. The TMP of claim 17,

wherein,

X₈ is substituted with a non-naturally-occurring amino acid.

26. The TMP of claim 17,

wherein,

X₉ is substituted with a non-naturally-occurring amino acid.

27. The TMP of claim 17,

wherein,

X₁₀ is substituted with a non-naturally-occurring amino acid.

28. The TMP of claim 18,

wherein,

X₁ is substituted with a non-naturally-occurring amino acid.

29. The TMP of claim 18,

wherein,

X₁₁ is substituted with a non-naturally-occurring amino acid.

30. The TMP of claim 18,

wherein,

X₁₂ is substituted with a non-naturally-occurring amino acid.

31. The TMP of claim 18,

wherein,

X₁₃ is substituted with a non-naturally-occurring amino acid.

32. The TMP of claim 18,

wherein,

X₁₄ is substituted with a non-naturally-occurring amino acid.