Modulators of beta-amyloid peptide aggregation comprising D-amino acids

Abstract

Compounds that modulate natural β amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a β amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a β amyloid peptide, preferably a retro-inverso isomer of Aβ 17-21 . In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

1 . A compound having the structure:  
         A-(Xaa)-B  wherein (Xaa) is a peptidic structure selected from the group consisting of D-Leu-D-Val-D-Phe-D-Phe, D-Leu-D-Val-D-Phe-phenethylamide, D-Leu-D-Val-D-Tyr-D-Phe, D-Leu-D-Val-D-IodoTyr-D-Phe, D-Leu-D-Val-D-Phe-D-Tyr, D-Leu-D-Val-D-Phe-D-IodoTyr, D-Leu-D-Val-D-Phe-D-Ala, D-Leu-D-Val-D-Phe-D-Phe-D-Ala, D-Ala-D-Val-D-Phe-D-Phe-D-Leu, D-Leu-D-Val-D-Tyr-D-Phe-D-Ala, D-Leu-D-Val-D-IodoTyr-D-Phe-D-Ala, D-Leu-D-Val-D-Phe-D-Tyr-D-Ala, D-Leu-D-Val-D-Phe-D-IodoTyr-D-Ala, D-Phe-D-Phe-D-Val-D-Leu, D-Ala-D-Phe-D-Phe-D-Val, D-Ala-D-Phe-D-Phe-D-Val-D-Leu, D-Ala-D-Phe-D-Phe-D-Leu-D-Leu, D-Leu-D-Phe-D-Phe-D-Val-D-Leu, D-Phe-D-Phe-D-Phe-D-Val-D-Leu, D-Phe-D-Phe-D-Phe-D-Leu-D-Val, D-Phe-D-Phe-D-Phe-D-Phe-D-Leu and D-Ala-D-Phe-D-Phe-D-Phe-D-Leu.    A is an amino-terminal modifying group selected from the group consisting of phenylacetyl, diphenylacetyl, triphenylacetyl, butanoyl, isobutanoyl hexanoyl, propionyl, 3-hydroxybutanoyl, 4-hydroxybutanoyl, 3-hydroxypropionoyl, 2,4-dihydroxybutyroyl, 1-Adamantanecarbonyl, 4-methylvaleryl, 2-hydroxyphenylacetyl, 3-hydroxyphenylacetyl, 4-hydroxyphenylacetyl, 3,5-dihydroxy-2-naphthoyl, 3,7-dihydroxy-2-napthoyl, 2-hydroxycinnamoyl, 3-hydroxycinnamoyl, 4-hydroxycinnamoyl, hydrocinnamoyl, 4-formylcinnamoyl, 3-hydroxy-4-methoxycinnamoyl, 4-hydroxy-3-methoxycinnamoyl, 2-carboxycinnamoyl, 3,4,-dihydroxyhydrocinnamoyl, 3,4-dihydroxycinnamoyl, trans-Cinnamoyl, (±)-mandelyl, (±)-mandelyl-(±)-mandelyl, glycolyl, 3-formylbenzoyl, 4-formylbenzoyl, 2-formylphenoxyacetyl, 8-formyl-1-napthoyl, 4-(hydroxymethyl)benzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, 5-hydantoinacetyl, L-hydroorotyl, 2,4-dihydroxybenzoyl, 3-benzoylpropanoyl, (±)-2,4-dihydroxy-3,3-dimethylbutanoyl, DL-3-(4-hydroxyphenyl)lactyl, 3-(2-hydroxyphenyl)propionyl, 4-(2-hydroxyphenyl)propionyl, D-3-phenyllactyl, 3-(4-hydroxyphenyl)propionyl, L-3-phenyllactyl, 3-pyridylacetyl, 4-pyridylacetyl, isonicotinoyl, 4-quinolinecarboxyl, 1-isoquinolinecarboxyl and 3-isoquinolinecarboxyl.    and B is a carboxy-terminal modifying group selected from the group consisting of an amide group, an alkyl amide group, an aryl amide group and a hydroxy group.    
     
     
         2 . A compound having the structure:  
         A-(Xaa)-B  wherein (Xaa) is a peptidic structure selected from the group consisting of D-Leu-D-Val-D-Phe-D-Phe, D-Leu-D-Val-D-Phe-phenethylamide, D-Leu-D-Val-D-Tyr-D-Phe, D-Leu-D-Val-D-IodoTyr-D-Phe, D-Leu-D-Val-D-Phe-D-Tyr, D-Leu-D-Val-D-Phe-D-IodoTyr, D-Leu-D-Val-D-Phe-D-Ala, D-Ala-D-Val-D-Phe-D-Phe-D-Leu, D-Leu-D-Val-D-Tyr-D-Phe-D-Ala, D-Leu-D-Val-D-IodoTyr-D-Phe-D-Ala, D-Leu-D-Val-D-Phe-D-Tyr-D-Ala, D-Leu-D-Val-D-Phe-D-IodoTyr-D-Ala, D-Phe-D-Phe-D-Val-D-Leu, D-Ala-D-Phe-D-Phe-D-Val, D-Ala-D-Phe-D-Phe-D-Val-D-Leu, D-Ala-D-Phe-D-Phe-D-Leu-D-Leu, D-Leu-D-Phe-D-Phe-D-Val-D-Leu, D-Phe-D-Phe-D-Phe-D-Val-D-Leu, D-Phe-D-Phe-D-Phe-D-Leu-D-Val, D-Phe-D-Phe-D-Phe-D-Phe-D-Leu and D-Ala-D-Phe-D-Phe-D-Phe-D-Leu.    A is an amino-terminal modifying group selected from the group consisting of cholyl, lithocholyl, hyodeoxycholyl, chenodeoxycholyl and ursodeoxycholyl; and    B is a carboxy-terminal modifying group selected from the group consisting of an amide group, an alkyl amide group, an aryl amide group and a hydroxy group.    
     
     
         3 . The compound of  claim 2 , wherein A is selected from the group consisting of lithocholyl, hyodeoxycholyl, chenodeoxycholyl and ursodeoxycholyl.  
     
     
         4 - 7 . (canceled)  
     
     
         8 . A compound having a structure selected from the group consisting of: Diphenylacetyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-NH 2 ; 
 Triiphenylacetyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-NH 2 ;    Isobutanoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-phenylalanine-NH 2 ;    4-Methylvaleryl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-phenylalanine-NH 2 ;    3-Hydroxyphenylacetyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-NH 2 ;    3,5-Dihydroxy-2-naphthoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-NH 2 ;    3,5-Dihydroxy-2-naphthoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    2-Hydroxyphenylacetyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-NH 2 ;    3,4-Dihydroxycinnamoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-NH 2 ;    (±)-Mandelyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-NH 2 ;    (±)-Mandelyl-(±)-Mandelyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    Glycolyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    Glycolyl-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-valine-D -leucine-NH 2 ;    D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    D-leucine-D-valine-D-iodotyrosine-D-phenylalanine-D-alanine-NH 2 ;    D-alanine-D-phenylalanine-D-phenylalanine-D-leucine-D-leucine-NH 2 ;    D-leucine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    D-phenylalanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    D-phenylalanine-D-phenylalanine-D-phenylalanine-D-leucine-D-valine-NH 2 ;    D-phenylalanine-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-leucine-NH 2 ;    D-alanine-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-leucine-NH 2 ;    D-alanine-D-homophenylalanine-D-homophenylalanine-D-valine-D-leucine-NH 2 ;    D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    D-leucine-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-leucine-NH 2 ;    D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-leucine-NH 2 ;    D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-phenylalanine-NH 2 ;    D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-valine-NH 2 ;    Hyodeoxycholyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    Chenodeoxycholyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    Ursodeoxycholyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    2,4-Dihydroxybenzoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    2-Hydroxycinnamoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    3-Hydroxy cinnamoyl -D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    4-Hydroxycinnamoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    5-Hydantoinacetyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    3,4-Dihydroxycinnamoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    3-Formylbenzoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    2-Formylphenoxyacetyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    4-Hydroxy-3-methoxycinnamoyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    3,5-Dihydroxy-2-naphthoyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3,4-Dihydroxycinnamoyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    (±)-Mandelyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Hydroxycinnamoyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    Glycolyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3,4-Dihydroxycinnamoyl-D-leucine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    Glycolyl-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    DL-3-(-4-Hydroxyphenyl)Lactyl-D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ;    D-3-Phenyllactyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    L-3-Phenyllactyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3-(2-Hydroxyphenyl)propionyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-(2-Hydroxyphenyl)propionyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    D-3-Phenyllactyl-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3-(2-Hydroxyphenyl)propionyl-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3-(4-Hydroxyphenyl)propionyl-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    Hydocinnamoyl-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Hydroxybenzoyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    D-3-Phenyllactyl-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    Hydrocinnamoyl-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Hydroxybenzoyl-D-leucine-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-leucine-NH 2 ;    Acetyl-D-leucine-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-leucine-NH 2 ;    3,7-Dihydroxy-2-naphthoyl-D-leucine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Hydroxyphenylacetyl-D-leucine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3,7-Dihydroxy-2-naphthoyl-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Hydroxyphenylacetyl-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3,7-Dihydroxy-2-naphthoyl-D-phenylalanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Hydroxybenzoyl-D-Pyridylalanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3-Pyridylacetyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    Isonicotinoyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    H-Glycyl-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    H-Glycyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Pyridylacetyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Quinolinecarboxyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    1-Isoquinolinecarboxyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    3-Isoquinolinecarboxyl-D-alanine-D-phenylalanine-D-phenylalanine-D-valine-D-leucine-NH 2 ;    4-Hydroxybenzoyl-D-leucine-D-valine-D-phenylalanine-D-tyrosine-D-alanine-NH 2 ;    4-Hydroxybenzoyl-D-leucine-D-valine-D-tyrosine-D-phenylalanine-D-alanine-NH 2 ;    4-Hydroxybenzoyl-D-leucine-D-valine-D-tyrosine-D-tyrosine-D-alanine-NH 2 ;    3,5-Dihydroxy-2-Napthoyl-(D-leucine-D-valine-D-phenylalanine-D-phenvylalanine-D-alanine)-NH 2 ;    3,7-Dihydroxy-2-Napthoyl-(D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine)-NH 2 ;    4-Hydroxybenzoyl-(D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine-NH 2 ; and    4-Hydroxyphenylacetyl-(D-leucine-D-valine-D-phenylalanine-D-phenylalanine-D-alanine)-NH 2 .    
     
     
         9 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim  1 - 8  and a pharmaceutically acceptable carrier.  
     
     
         10 . A method for inhibiting aggregation of natural β-amyloid peptides, comprising contacting the natural β-amyloid peptides with the compound of  claim 1  such that aggregation of the natural β-amyloid peptides is inhibited.  
     
     
         11 . A method for detecting the presence or absence of natural β-amyloid peptides in a biological sample, comprising: 
 contacting a biological sample with the compound of  claim 1 , wherein the compound is labeled with a detectable substance; and    detecting the compound bound to natural β-amyloid peptides to thereby detect the presence or absence of natural β-amyloid peptides in the biological sample.    
     
     
         12 . The method of  claim 11 , wherein the β-amyloid modulator compound and the biological sample are contacted in vitro.  
     
     
         13 . The method of  claim 11 , wherein the β-amyloid modulator compound is contacted with the biological sample by administering the β-amyloid modulator compound to a subject.  
     
     
         14 . The method of  claim 11 , wherein the compound is labeled with radioactive technetium or radioactive iodine.  
     
     
         15 . A method for treating a subject for a disorder associated with β-amyloidosis, comprising: 
 administering to the subject a therapeutically effective amount of the compound of  claim 1  such that the subject is treated for a disorder associated with β-amyloidosis.    
     
     
         16 . The method of  claim 15 , wherein the disorder is Alzheimer's disease.