Cardiovascular Therapeutics

Abstract

Compounds and compositions comprising a B-type natriuretic signal peptide fragment agent, and methods of use thereof, are provided for the treatment or prevention of cardiovascular diseases, disorders, and conditions.

1 . A pharmaceutical composition for use in preventing and/or treating a cardiovascular disorder, comprising a therapeutically effective amount of a Type-B natriuretic signal peptide fragment agent and a pharmaceutically acceptable carrier. 
     
     
         2 .- 10 . (canceled) 
     
     
         11 . A substantially pure peptide having the amino acid sequence selected from the group consisting of
   LH X 1  X 2  X 3  X 4  X 5  X 6  X 7  X g   a.
   wherein X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2  is Val, Leu or Ile or Gly; X 3  is Leu, Val, Ile, Ala, Tyr or Gly; X 4  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 5  is Pro, Ala, Arg or Ser; X 6  is Pro, Ala, Arg or Ser; X 7  is Gln, Asn or Gly; and X 8  is Ser, Thr or Gly;
   LH X 1  X 2  X 3  X 4  X 5  X 6  X 7   b.
 
   wherein X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2  is Val, Leu, Ile or Gly; X 3  is Leu, Val, Ile, Ala, Tyr or Gly; X 4  is; Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 5  is Pro, Ala, Arg or Ser; X 6  is Pro, Ala, Arg or Ser; and X 7  is Arg, Gln, Asn or Gly; provided that   where X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 2  is Val, Leu or Ile or Gly, X 1  can also be Leu, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 3  is Leu, Val, Ile, Ala, Tyr or Gly, X 1  can also be Leu, X 2  can also be Ala, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 4  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 5  is Pro, Ala, Arg or Ser, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 6  can also be Gly, and X 7  can also be Arg;   where X 6  is Pro, Ala, Arg or Ser, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, and X 7  can also be Arg;   where X 7  is Lys, Gln, Asn or Gly, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, and X 6  can also be Gly;
   LH X 1  X 2  X 3  X 4  X 5  X 6   c.
 
   wherein X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2  is Val, Leu, Ile or Gly; X 3  is Leu, Val, Ile, Ala, Tyr or Gly; X 4  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 5  is Pro, Ala, Arg or Ser; and X 6  is Pro, Ala, Arg or Ser; provided that   where X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 2  is Val, Leu or Ile or Gly, X 1  can also be Leu, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 3  is Leu, Val, Ile, Ala, Tyr or Gly, X 1  can also be Leu, X 2  can also be Ala, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 4  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 5  is Pro, Ala, Arg or Ser, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 6  can also be Gly, and X 7  can also be Arg;   where X 6  is Pro, Ala, Arg or Ser, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, and X 7  can also be Arg;
   L H X 1  X 2  X 3  X 4  1 S X 5   d.
 
   wherein X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2  is Val, Leu, Ile or Gly; X 3  is Leu, Val, Ile, Ala, Tyr or Gly; X 4  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; and X 5  is Pro, Ala, Arg or Ser; provided that   where X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 2  is Val, Leu or Ile or Gly, X 1  can also be Leu, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 3  is Leu, Val, Ile, Ala, Tyr or Gly, X 1  can also be Leu, X 2  can also be Ala, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 4  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 5  is Pro, Ala, Arg or Ser, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 6  can also be Gly, and X 7  can also be Arg;
   L H X 1  X 2  X 3  X 4   e.
 
   wherein X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2  is Val, Leu, Ile or Gly; X 3  is Leu, Val, Ile, Ala, Tyr or Gly; and X 4  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; provided that   where X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2  can also be Ala, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 2  is Val, Leu or Ile or Gly, X 1  can also be Leu, X 3  can also be Phe, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 3  is Leu, Val, Ile, Ala, Tyr or Gly, X 1  can also be Leu, X 2  can also be Ala, X 4  can also be Leu, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;   where X 4  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 1  can also be Leu, X 2  can also be Ala, X 3  can also be Phe, X 5  can also be Gly, X 6  can also be Gly, and X 7  can also be Arg;
   L H X 1  X 2  X 3   f.
 
   wherein X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2  is Val, Leu, Ile or Gly; and X 3  is Leu, Val, Ile, Ala, Tyr or Gly; provided that   where X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2  can also be Ala, and X 3  can also be Phe;   where X 2  is Val, Leu or Ile or Gly, X 1  can also be Leu, and X 3  can also be Phe; and   where X 3  is Leu, Val, Ile, Ala, Tyr or Gly, X 1  can also be Leu, and X 2  can also be Ala;
   L H X 1  X 2   g.
 
   wherein X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly; and X 2  is Val, Leu, Ile or Gly; provided that   where X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2  can also be Ala; and   where X 2  is Val, Leu or Ile or Gly, X 1  can also be Leu; and
   L H X 1   h.
 
   wherein X 1  is Norleucine, Ile, Val, Met, Ala, Phe or Gly.   
     
     
         12 . A method selected from the group consisting of:
 a. treating a subject having or at risk for developing a cardiovascular disorder, comprising increasing Type-B natriuretic signal peptide fragment activity in said subject;   b. treating a subject having or at risk for developing an acute coronary syndrome, comprising administering to the subject a composition comprising a Type-B natriuretic signal peptide fragment or Type-B natriuretic signal peptide fragment analog; and   c. preparing a medicament for preventing or treating a cardiovascular disorder or an acute coronary syndrome, comprising bringing together a therapeutically effective amount of a Type-B natriuretic signal peptide fragment or a Type-B natriuretic signal peptide fragment analog and a pharmaceutically acceptable carrier;
 wherein the Type-B natriuretic signal peptide fragment optionally comprises a substantially pure peptide according to  claim 11 , or an analog, derivative, or prodrug or such a peptide. 
   
     
     
         13 .- 19 . (canceled)