Novel ligands for prevention of neurotoxicity of the alzheimer's disease related amyloid-beta peptide

Abstract

The present invention relates to the field of molecular biochemistry and medicine, and in particular to ligands comprising modified amino acid residues, targeting the amyloid-β peptide associated with Alzheimer's disease for prevention of aggregation, neurotoxicity and use thereof as drugs for treatment of Alzheimer's disease.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R1 is a substituted or non-substituted, aromatic or heteroaromatic moiety; 
         R2 is H or a substituted or non-substituted, saturated or unsaturated alkyl or acyl group; 
         R3 is H or a substituted or non-substituted, saturated or unsaturated alkyl group optionally containing an aromatic moiety or a substituted or non-substituted, saturated or unsaturated acyl group; 
         R4 is a carboxylate, phosphonate or phosphate group; 
         R5 is a carboxylate, sulphonate or phosphonate group; 
         R6 is H or a substituted alkyl or acyl group; 
         p and q independently represent an integer of 1, 2, 3 or 4; 
         r and v independently represent an integer of 1 or 2; 
         s represents an integer of 0, 1 or 2; and 
         t represents an integer of 1, 2, 3 or 4; 
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein R2 is a substituted or non-substituted, saturated or unsaturated acyl group and R3 is H. 
     
     
         3 . The compound according to  claim 1 , wherein R2 is H and R3 is a substituted or non-substituted, saturated or unsaturated alkyl or acyl group containing an aromatic moiety. 
     
     
         4 . The compound according to  claim 1 , wherein R2 is H, R3 is H and R6 is a substituted alkyl or acyl group. 
     
     
         5 . The compound according to  claim 1 , wherein at least one of R2, R3 and R6 is other than H. 
     
     
         6 . The compound according to  claim 1 , wherein at least one of R2 and R3 is other than H. 
     
     
         7 . The compound according to  claim 1 , wherein said alkyl group containing an aromatic moiety in R3 represents an arylalkyl. 
     
     
         8 . The compound according to  claim 1 , wherein R1 is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , wherein p and q independently represent an integer of 2 or 3; r represents an integer of 1; t represents an integer of 1 or 2 or 3; and s represents an integer of 0 or 1 or 2. 
     
     
         10 . The compound according to  claim 9 , wherein t represents an integer of 2 or 3 and/or wherein s represents an integer of 0 or 1. 
     
     
         11 . The compound according to  claim 1 , wherein R2, when being a substituted or non-substituted, saturated or unsaturated alkyl or acyl group, comprises from 6 to 16 carbon atoms. 
     
     
         12 . The compound according to  claim 1 , wherein R3, when being a substituted or non-substituted, saturated or unsaturated alkyl or acyl group, comprises from 4 to 16 carbon atoms. 
     
     
         13 . The compound according to  claim 1 , wherein R4 is a carboxylate group. 
     
     
         14 . The compound according to  claim 1 , wherein R5 is a carboxylate group. 
     
     
         15 . The compound according to  claim 1 , wherein R6 is a substituted alkyl or acyl group selected from the group consisting of 2-acetamidoacetamido)eth-1-yl, 2-(2-benzylamino)eth-1-yl, 2-(2-acetamido-3-hydroxypropanamido)eth-1-yl, 2-(2-acetamido-4-amino-4-oxobutanamido)eth-1-yl, 2-(2-(2-acetamido-3-hydroxypropanamido)acetamido)eth-1-yl and 2-(2-(2-acetamido-4-amino-4-oxobutanamido)acetamido)eth-1-yl. 
     
     
         16 - 22 . (canceled) 
     
     
         23 . The compound according to  claim 1 , said compound being able to interact with at least two, three, four or five of
 the side chain of Lysl6 of an Aβ peptide;   the side chain of His 13 of an Aβ peptide;   the side-chain of Glu23 of an Aβ peptide;   the side chain of Phel9 of an Aβ peptide;   the side chain of Phe20 or an Aβ peptide;   the side-chain of Asp22 of an Aβ peptide; or   the side-chain of Val18 of an Aβ peptide.   
     
     
         24 . The compound according to  claim 1 , said compound being able to decrease the loss of an α-helix in an Aβ peptide. 
     
     
         25 - 26 . (canceled) 
     
     
         27 . A medicament for the treatment of Alzheimer's disease manufactured from a compound according to  claim 1 . 
     
     
         28 . A method of identifying a compound that is a candidate compound for treating an Aβ peptide-related disorder, the method comprising:
 providing a compound according to  claim 1 ; 
 contacting an Aβ peptide with the compound, thereby providing a sample; 
 determining the amount of Aβ peptide in α-helical form or β form in the sample; 
 comparing the amount of Aβ peptide in α-helical form or β form compared to a reference, wherein a compound that increases the amount of Aβ peptide in α-helical form or decreases the amount of Aβ peptide in β form in the sample compared to the reference is a candidate compound. 
 
     
     
         29 . The method according to  claim 28 , which is performed in vitro or in an animal model. 
     
     
         30 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         R2 a substituted or non-substituted, saturated or unsaturated alkyl or acyl group or an amino protecting group; 
         R1 is a substituted or non-substituted, aromatic or heteroaromatic moiety; 
         R3 is H or a substituted or non-substituted, saturated or unsaturated alkyl group optionally containing an aromatic moiety or a substituted or non-substituted, saturated or unsaturated acyl group; 
         R4 is a carboxylate, phosphonate or phosphate group; 
         R5 is a carboxylate, sulphonate or phosphonate group; 
         R6 is H or a substituted alkyl or acyl group; 
         p and q independently represent an integer of 1, 2, 3 or 4; 
         r and v independently represent an integer of 1 or 2; 
         s represents an integer of 0, 1 or 2; 
         t represents an integer of 1, 2, 3 or 4; 
         R7 is H or an amino protecting group; 
         R8 is OH, O—, or a substituted or non-substituted O-alkyl group or attachment to a solid support; and 
         R9 is H, N-dimethylamino, N-acetamido or O-alkyl. 
       
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . A process of synthesizing a compound of formula I according to  claim 1 , comprising the following steps:
 a) providing one or more precursors selected from   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         R1 is a substituted or non-substituted, aromatic or heteroaromatic moiety; 
         R2 is H, a substituted or non-substituted, saturated or unsaturated alkyl or acyl group or an amino protecting group; 
         R3 is H or a substituted or non-substituted, saturated or unsaturated alkyl group optionally containing an aromatic moiety or a substituted or non-substituted, saturated or unsaturated acyl group; 
         R4 is a carboxylate, phosphonate or phosphate group; 
         R5 is a carboxylate, sulphonate or phosphonate group; 
         R6 is H or a substituted alkyl or acyl group; 
         p and q independently represent an integer of 1, 2, 3 or 4; 
         r and v independently represent an integer of 1 or 2; 
         s represents an integer of 0, 1 or 2; 
         t represents an integer of 1, 2, 3 or 4; 
         R7 is H or an amino protecting group; 
         R8 is OH, O—, or a substituted or non-substituted O-alkyl group or attachment to a solid support; and 
         R9 is H, N-dimethylamino, N-acetamido or O-alkyl; 
         b) synthesizing the compound of formula I from said one or more precursors, wherein said process involves amide bond formation between specific precursors and other modular building blocks. 
       
     
     
         34 . (canceled) 
     
     
         35 . A method of treating a subject at risk for or having Alzheimer's disease, the method comprising administering a therapeutically effective amount of a compound according to  claim 1  to said subject.