Bna Conjugates and Methods of Use

• US 20080207505A1
• Filed: 01/12/2006
• Published: 08/28/2008
• Est. Priority Date: 01/12/2005
• Status: Abandoned Application

• Current Assignee: Kenneth D. James
• Original Assignee: Kenneth D. James
• Inventors: James, Kenneth D.
• Application Number:
  US11/813,830
• Publication Number:
  US 20080207505A1
• Time in Patent Office: Days
• US Class Current: 514/12
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/58 Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin

Abstract

Modified natriuretic compounds and conjugates thereof are disclosed in the present invention. In particular, conjugated forms of hBNP are provided that include at least one modifying moiety attached thereto. The modified natriuretic compound conjugates retain activity for stimulating cGMP production, binding to NPR-A receptor, decreasing arterial blood pressure and in some embodiments an improved half-life in circulation as compared to unmodified counterpart natriuretic compounds. Oral, parenteral, enteral, subcutaneous, pulmonary, and intravenous forms of the compounds and conjugates may be prepared as treatments and/or therapies for heart conditions particularly congestive heart failure. Modifying moieties comprising oligomeric structures having a variety of lengths and configurations are also disclosed. Analogs of the hBNP compound are also disclosed, having an amino acid sequence that is other than the native sequence.

Claims

1. A BNP compound conjugate comprising:

a BNP molecule;

and at least one modifying moiety conjugated to the BNP molecule,

wherein the BNP compound conjugate exhibits increased cGMP activity levels relative to a corresponding unconjugated BNP molecule.

2. The BNP compound conjugate according to claim 1, wherein the BNP molecule is hBNP or a homologous protein having at least 95% identity to SEQ ID NO. 99.

3. The BNP compound conjugate according to claim 2, wherein the hBNP has the amino acid sequence SEQ ID NO. 99.

5. The BNP compound conjugate according to claim 1, wherein the one modifying moiety is conjugated to a modifying moiety site on the BNP molecule selected from Lys3, Lys14 or Lys27.

6. The BNP compound conjugate according to claim 2, having the following formula:

7. The BNP compound conjugate according to claim 2, having the following formula:

8. The BNP compound conjugate according to claim 2, having the following formula:

9. The BNP compound conjugate according to claim 2, having the formula:

10. The BNP compound conjugate according to claim 2 having the formula:

11. The BNP compound conjugate according to claim 2 having the formula:

12. The BNP compound conjugate according to claim 2 having the formula:

13. The BNP compound conjugate according to claim 2, wherein the modifying moiety is

14. The BNP compound conjugate according to claim 2, wherein the modifying moiety is

15. The BNP compound conjugate according to claim 6, wherein the modifying moiety is conjugated to Lys3 of the BNP molecule.

21. The BNP compound conjugate according to claim 12, wherein the modifying moiety is conjugated to Lys3 of the BNP molecule.

22. Use of the BNP compound conjugates according to claim 1 for use in a medicament for treatment of hypertension and/or cardiac dysfunction.

23. The use according to claim 22, wherein the BNP compound conjugate is selected from the following conjugates:

24. The use according to claim 23, wherein the modifying moiety is conjugated to Lys3 of the BNP molecule.

4. (canceled)

16-20. -20. (canceled)

25. A in vivo method for increasing cGMP activity and/or reducing arterial pressure, the method comprising administering to a subject a BNP compound conjugate comprising:

a BNP molecule; and

at least one modifying moiety conjugated to the BNP molecule, in an amount sufficient to increase cGMP activity and/or reduce arterial pressure.

26. The method according to claim 25, wherein the BNP molecule is hBNP or a homologous protein having at least 95% identity to SEQ ID NO. 99.

27. The method according to claim 26, wherein the hBNP has the amino acid sequence SEQ ID NO. 99.

28. The method according to claim 25, wherein the at least one modifying moiety is conjugated to a modifying moiety site on the BNP molecule selected from Lys3, Lys14 or Lys27.

29. The method according to claim 26, wherein the BNP compound conjugate has the following formula:

30. The method according to claim 26, wherein the BNP compound conjugate has the following formula:

31. The method according to claim 26, wherein the BNP compound conjugate has the following formula:

32. The method according to claim 26, wherein the BNP compound conjugate has the following formula:

33. The method according to claim 26, wherein the BNP compound conjugate has the following formula:

34. The method according to claim 26, wherein the BNP compound conjugate has the following formula:

35. The method according to claim 26, wherein the BNP compound conjugate has the following formula:

36. The method according to claim 26, wherein the modifying moiety is

43. The method according to claim 35, wherein the modifying moiety is conjugated to Lys3 of the BNP molecule.

37-42. -42. (canceled)