Method and compound for the treatment of valvular disease

Abstract

The present invention provides methods for preventing or treating a valvular stenosis or a valvular calcification in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide/phospholipid complex, wherein the peptide of the complex is an Apolipoprotein A-1 mimetic peptide. In one embodiment the Apolipoprotein A-1 mimetic peptide has the sequence set forth in SEQ ID NO: 1. In another embodiment the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.

1 - 23 . (canceled) 
     
     
         24 . A method for preventing or treating a valvular stenosis in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide/phospholipid complex, wherein the peptide of the complex is an Apolipoprotein A-1 mimetic peptide. 
     
     
         25 . The method of  claim 24 , wherein said valvular stenosis is an aortic valve stenosis. 
     
     
         26 . The method of  claim 24 , wherein said valvular stenosis is a calcific valve stenosis. 
     
     
         27 . The method of  claim 24 , wherein administering said peptide/phospholipid complex includes injecting said peptide/phospholipid complex in said subject. 
     
     
         28 . The method of  claim 27 , wherein said peptide/phospholipid complex is injected at a dosage of from about 1 μg to about 10 g of peptide per kg body weight of said subject. 
     
     
         29 . The method of  claim 28 , wherein said peptide/phospholipid complex is injected at a dosage of from about 1 mg to about 0.5 g of peptide per kg body weight of said subject. 
     
     
         30 . The method of  claim 29 , wherein said peptide/phospholipid complex is injected at a dosage of about 25 mg of peptide per kg body weight of said subject. 
     
     
         31 . The method of  claim 24 , wherein said subject is a mammal. 
     
     
         32 . The method of  claim 31 , wherein said subject is a human. 
     
     
         33 . The method of  claim 24 , wherein the valvular stenosis is prevented. 
     
     
         34 . The method of  claim 24 , wherein the valvular stenosis is treated. 
     
     
         35 . The method of  claim 24 , wherein treating said valvular stenosis includes reducing a rate of progression of said valvular stenosis. 
     
     
         36 . The method of  claim 24 , wherein the Apolipoprotein A-1 mimetic peptide has the sequence set forth in SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 24 , wherein the Apolipoprotein A-1 mimetic peptide has a sequence set forth in one of SEQ ID NOS: 3 to 51 or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The method of  claim 24 , wherein the Apolipoprotein A-1 mimetic peptide is a peptide of the following Formula (I)
   X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22      
       or a pharmaceutically acceptable salt thereof, wherein:
 X i  is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p); 
 X 2  is an aliphatic amino acid; 
 X 3  is Leu (L) or Phe (F); 
 X 4  is an acidic amino acid; 
 X 5  is Leu (L) or Phe (F); 
 X 6  is Leu (L) or Phe (F); 
 X 7  is a hydrophilic amino acid; 
 X 8  is an acidic or a basic amino acid; 
 X 9  is Leu (L) or Gly (G); 
 X 10  is Leu (L), Trp (W) or Gly (G); 
 X 11  is a hydrophilic amino acid; 
 X 12  is a hydrophilic amino acid; 
 X 13  is Gly (G) or an aliphatic amino acid; 
 X 14  is Leu (L), Trp (W), Gly (G) or Nal; 
 X 15  is a hydrophilic amino acid; 
 X 16  is a hydrophobic amino acid; 
 X 17  is a hydrophobic amino acid; 
 X 18  is Gln (Q), Asn (N) or a basic amino acid; 
 X 19  is Gln (Q), Asn (N) or a basic amino acid; 
 X 20  is a basic amino acid; 
 X 21  is an aliphatic amino acid; and 
 X 22  is a basic amino acid. 
 
     
     
         39 . The method of  claim 38 , wherein:
 X 1  is Pro (P), Gly (G), Ala (A), Gln (Q), Asn (N), Asp (D) or D-Pro (p);   X 2  is Ala (A), Val (V) or Leu (L);   X 4  is Asp (D) or Glu (E);   X 7  is Lys (K), Arg (R), Orn, Asn (N) or Glu (E);   X 8  is Asp (D), Arg (R) or Glu (E);   X 11  is Asn (N), Gln (Q), Glu (E) or Arg (R);   X 12  is Asp (D), Glu (E) or Asn (N);   X 13  is Leu (L), Gly (G) or Aib;   X 15  is Asp (D), Glu (E), Gln (Q) or Lys (K);   X 16  is Ala (A), Trp (W), Gly (G), Leu (L), Phe (F) or Nal;   X 17  is Leu (L), Gly (G) or Nal;   X 18  is Lys (K), Orn, Gln (Q) or Asn (N);   X 19  is Lys (K), Orn, Gln (Q) or Asn (N);   X 20  is Lys (K) or Orn;   X 21  is Leu (L); and/or   X 22  is Lys (K) or Orn.   
     
     
         40 . The method of  claim 38 , wherein:
 X 2  is Val (V);   X 3  is Leu (L);   X 5  is Leu (L);   X 6  is Phe (F);   X 7  is Arg (R) or Lys (K);   X 8  is Glu (E);   X 9  is Leu (L);   X 10  is Leu (L);   X ii  is Asn (N) or Glu (O);   X 12  is Glu (E); and/or   X 15  is Glu (E).   
     
     
         41 . The method of  claim 38 , wherein:
 X 1  is Pro (P), Gly (G) or D-Pro (p);   X 2  is Val (V);   X 3  is Leu (L);   X 4  is Asp (D) or Glu (E);   X 5  is L (Leu) or Phe (F);   X 6  is Phe (F);   X 7  is Arg (R);   X 8  is Glu (E);   X 9  is Leu (L);   X 10  is Leu (L) or Trp (W);   X 11  is Asn (N);   X 12  is Glu (E);   X 13  is Gly (G);   X 14  is Leu (L);   X 15  is Glu (E);   X 16  is Ala (A) or Trp (W);   X 17  is Leu (L) or Nal;   X 18  is Lys (K) or Orn;   X 19  is Gln (Q);   X 20  is Lys (K) or Orn;   X 21  is Leu (L); and   X 22  is Lys (K) or Orn.   
     
     
         42 . The method of  claim 38 , wherein:
 X i  is Pro (P), Gly (G), Ala (A) or D-Pro (p);   X 2  is Val (V) or Leu (L);   X 3  is Leu (L);   X 4  is Asp (D) or Glu (E);   X 5  is Leu (L) or Phe (F);   X 6  is Leu (L) or Phe (F);   X 7  is Arg (R) or Lys (K);   X 8  is Glu (E);   X 9  is Leu (L);   X 10  is Leu (L) or Trp (W);   X 11  is Asn (N) or Gln (Q);   X 12  is Glu (E);   X 13  is Leu (L) or Aib;   X 14  is Leu (L), Trp (W) or Nal;   X 15  is Glu (E);   X 16  is Ala (A), Leu (L), Trp (W) or Nal;   X 17  is Leu (L) or Nal;   one of X 18  or X 19  is Gln (Q) and the other is Lys (K) or Orn;   X 20  is Lys (K) or Orn;   X 21  is Leu (L); and   X 22  is Lys (K) or Orn.   
     
     
         43 . The method of  claim 38 , wherein:
 X 2  is Val (V);   X 4  is Asp (D);   X 5  is Leu (L);   X 6  is Phe (F);   X 7  is Arg R);   X 10  is Leu (L);   X ii  is Asn (N);   X 13  is Leu (L);   X 14  is Leu (L);   X 16  is Ala (A);   X 17  is Leu (L);   X 18  is Lys (K);   X 19  is Gln (Q);   X 20  is Lys (K) and/or   X 22  is Lys (K).   
     
     
         44 . The method of  claim 24 , wherein the phospholipid of the complex is egg sphingomyelin or 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine. 
     
     
         45 . The method of  claim 24 , wherein the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine. 
     
     
         46 . The method of  claim 45 , wherein the egg sphingomyelin and the 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine are present in a weight ratio of 1:1. 
     
     
         47 . The method of  claim 36 , wherein the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine. 
     
     
         48 . The method of  claim 47 , wherein the peptide of SEQ. ID. NO: 1 or pharmaceutically acceptable salt thereof, the egg sphingomyelin, and the 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine are present in a weight ratio of 1:1:1. 
     
     
         49 . A method for preventing or treating a valvular calcification in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide/phospholipid complex, wherein the peptide of the complex is an Apolipoprotein A-1 mimetic peptide. 
     
     
         50 . The method of  claim 49 , wherein administering said peptide/phospholipid complex includes injecting said peptide/lipid complex in said subject. 
     
     
         51 . The method of  claim 50 , wherein said peptide/phospholipid complex is injected at a dosage of from about 1 μg to about 10 g of peptide per kg body weight of said subject. 
     
     
         52 . The method of  claim 51 , wherein said peptide/phospholipid complex is injected at a dosage of from about 1 mg to about 0.5 g of peptide per kg body weight of said subject. 
     
     
         53 . The method of  claim 52 , wherein said peptide/phospholipid complex is injected at a dosage of about 25 mg of peptide per kg body weight of said subject. 
     
     
         54 . The method of  claim 49 , wherein said subject is a mammal. 
     
     
         55 . The method of  claim 54 , wherein said subject is a human. 
     
     
         56 . The method of  claim 49 , wherein the valvular calcification is prevented. 
     
     
         57 . The method of  claim 49 , wherein the valvular calcification is treated. 
     
     
         58 . The method of  claim 49 , wherein treating said valvular calcification includes reducing a rate of progression of said valvular calcification. 
     
     
         59 . The method of  claim 49 , wherein the Apolipoprotein A-1 mimetic peptide has the sequence set forth in SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. 
     
     
         60 . The method of  claim 49 , wherein the Apolipoprotein A-1 mimetic peptide has a sequence set forth in one of SEQ ID NOS: 3 to 51 or a pharmaceutically acceptable salt thereof. 
     
     
         61 . The method of  claim 49 , wherein the Apolipoprotein A-1 mimetic peptide is a peptide of the following Formula (I))
   X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22      
       or a pharmaceutically acceptable salt thereof, wherein:
 X i  is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p); 
 X 2  is an aliphatic amino acid; 
 X 3  is Leu (L) or Phe (F); 
 X 4  is an acidic amino acid; 
 X 5  is Leu (L) or Phe (F); 
 X 6  is Leu (L) or Phe (F); 
 X 7  is a hydrophilic amino acid; 
 X 8  is an acidic or a basic amino acid; 
 X 9  is Leu (L) or Gly (G); 
 X 10  is Leu (L), Trp (W) or Gly (G); 
 X 11  is a hydrophilic amino acid; 
 X 12  is a hydrophilic amino acid; 
 X 13  is Gly (G) or an aliphatic amino acid; 
 X 14  is Leu (L), Trp (W), Gly (G) or Nal; 
 X 15  is a hydrophilic amino acid; 
 X 16  is a hydrophobic amino acid; 
 X 17  is a hydrophobic amino acid; 
 X 18  is Gln (Q), Asn (N) or a basic amino acid; 
 X 19  is Gln (Q), Asn (N) or a basic amino acid; 
 X 20  is a basic amino acid; 
 X 21  is an aliphatic amino acid; and 
 X 22  is a basic amino acid. 
 
     
     
         62 . The method of  claim 61 , wherein:
 X 1  is Pro (P), Gly (G), Ala (A), Gln (Q), Asn (N), Asp (D) or D-Pro (p);   X 2  is Ala (A), Val (V) or Leu (L);   X 4  is Asp (D) or Glu (E);   X 7  is Lys (K), Arg (R), Orn, Asn (N) or Glu (E);   X 8  is Asp (D), Arg (R) or Glu (E);   X 11  is Asn (N), Gln (Q), Glu (E) or Arg (R);   X 12  is Asp (D), Glu (E) or Asn (N);   X 13  is Leu (L), Gly (G) or Aib;   X 15  is Asp (D), Glu (E), Gln (Q) or Lys (K);   X 16  is Ala (A), Trp (W), Gly (G), Leu (L), Phe (F) or Nal;   X 17  is Leu (L), Gly (G) or Nal;   X 18  is Lys (K), Orn, Gln (Q) or Asn (N);   X 19  is Lys (K), Orn, Gln (Q) or Asn (N);   X 20  is Lys (K) or Orn;   X 21  is Leu (L); and/or   X 22  is Lys (K) or Orn.   
     
     
         63 . The method of  claim 61 , wherein:
 X 2  is Val (V);   X 3  is Leu (L);   X 5  is Leu (L);   X 6  is Phe (F);   X 7  is Arg (R) or Lys (K);   X 8  is Glu (E);   X 9  is Leu (L);   X 10  is Leu (L);   X ii  is Asn (N) or Glu (Q);   X 12  is Glu (E); and/or   X 15  is Glu (E).   
     
     
         64 . The method of  claim 61 , wherein:
 X 1  is Pro (P), Gly (G) or D-Pro (p);   X 2  is Val (V);   X 3  is Leu (L);   X 4  is Asp (D) or Glu (E);   X 5  is L (Leu) or Phe (F);   X 6  is Phe (F);   X 7  is Arg (R);   X 8  is Glu (E);   X 9  is Leu (L);   X 10  is Leu (L) or Trp (W);   X 11  is Asn (N);   X 12  is Glu (E);   X 13  is Gly (G);   X 14  is Leu (L);   X 15  is Glu (E);   X 16  is Ala (A) or Trp (W);   X 17  is Leu (L) or Nal;   X 18  is Lys (K) or Orn;   X 19  is Gln (Q);   X 20  is Lys (K) or Orn;   X 21  is Leu (L); and   X 22  is Lys (K) or Orn.   
     
     
         65 . The method of  claim 61 , wherein:
 X i  is Pro (P), Gly (G), Ala (A) or D-Pro (p);   X 2  is Val (V) or Leu (L);   X 3  is Leu (L);   X 4  is Asp (D) or Glu (E);   X 5  is Leu (L) or Phe (F);   X 6  is Leu (L) or Phe (F);   X 7  is Arg (R) or Lys (K);   X 8  is Glu (E);   X 9  is Leu (L);   X 10  is Leu (L) or Trp (W);   X 11  is Asn (N) or Gln (Q);   X 12  is Glu (E);   X 13  is Leu (L) or Aib;   X 14  is Leu (L), Trp (W) or Nal;   X 15  is Glu (E);   X 16  is Ala (A), Leu (L), Trp (W) or Nal;   X 17  is Leu (L) or Nal;   one of X 18  or X 19  is Gln (Q) and the other is Lys (K) or Orn;   X 20  is Lys (K) or Orn;   X 21  is Leu (L); and   X 22  is Lys (K) or Orn.   
     
     
         66 . The method of  claim 61 , wherein:
 X 2  is Val (V);   X 4  is Asp (D);   X 5  is Leu (L);   X 6  is Phe (F);   X 7  is Arg R);   X 10  is Leu (L);   X ii  is Asn (N);   X 13  is Leu (L);   X 14  is Leu (L);   X 16  is Ala (A);   X 17  is Leu (L);   X 18  is Lys (K);   X 19  is Gln (Q);   X 20  is Lys (K) and/or   X 22  is Lys (K).   
     
     
         67 . The method of  claim 49 , wherein the phospholipid of the complex is egg sphingomyelin or 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine. 
     
     
         68 . The method of  claim 49 , wherein the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine. 
     
     
         69 . The method of  claim 49 , wherein the egg sphingomyelin and the 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine are present in a weight ratio of 1:1. 
     
     
         70 . The method of  claim 59 , wherein the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine. 
     
     
         71 . The method of  claim 70 , wherein the peptide of SEQ. ID. NO: 1 or pharmaceutically acceptable salt thereof, the egg sphingomyelin, and the 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine are present in a weight ratio of 1:1:1.