Compounds and methods for modulating cerebral amyloid angiopathy

Abstract

The invention provides methods of inhibiting cerebral amyloid angiopathy. The invention further provides methods of treating a disease state characterized by cerebral amyloid angiopathy in a subject.

1 . A method of inhibiting cerebral amyloid angiopathy, comprising contacting a blood vessel wall cell with an Aβ40 inhibitor, such that cerebral amyloid angiopathy is inhibited, provided said Aβ40 inhibitor is not 3-amino-1-propanesulfonic acid. 
     
     
         2 . The method of  claim 1 , wherein the Aβ40 inhibitor has the following structure:
   Q-[—Y − X + ] n      
     
     
         3 . The method of  claim 1 , wherein said Aβ40 inhibitor is selected from the group consisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4-hydroxy-1-butanesulfonic acid, and pharmaceutically acceptable salts thereof. 
     
     
         4 . The method of  claim 1 , wherein said Aβ40 inhibitor is selected from the group consisting of 1-butanesulfonic acid, 1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof. 
     
     
         5 . The method of  claim 1 , wherein said Aβ40 inhibitor is 1,7-dihydroxy-4-heptanesulfonic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 1 , wherein said blood vessel wall cell is selected from the group consisting of blood vessel wall smooth muscle cells, pericytes and endothelial cells. 
     
     
         7 . The method of  claim 1 , wherein said blood vessel wall cell is a blood vessel wall smooth muscle cell. 
     
     
         8 . The method of  claim 1 , wherein the death of said blood vessel wall cell is prevented. 
     
     
         9 . The method of  claim 1 , wherein structural changes to said blood vessel wall cell are prevented. 
     
     
         10 . The method of  claim 1 , wherein said Aβ40 inhibitor is a peptide or a peptidomimetic which interacts with specific regions of the Aβ peptide. 
     
     
         11 . The method of  claim 1 , wherein said Aβ40 inhibitor has the following structure: 
       
         
           
           
               
               
           
         
         wherein
 Z is XR 2  or R 4 ; 
 R 1  and R 2  are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; 
 R 3  is hydrogen, lower alkyl, aryl, or a salt-forming cation; 
 R 4  is hydrogen, lower alkyl, aryl or amino; 
 X is, independently for each occurrence, O or S; 
 Y 1  and Y 2  are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and 
 n is an integer from 0 to 12. 
 
       
     
     
         12 . The method of  claim 1 , wherein said Aβ40 inhibitor is administered in a pharmaceutically acceptable formulation. 
     
     
         13 . The method of  claim 1 , wherein said pharmaceutically acceptable formulation is a dispersion system. 
     
     
         14 . The method of  claim 13 , wherein said pharmaceutically acceptable formulation comprises a lipid-based formulation. 
     
     
         15 . The method of  claim 14 , wherein said pharmaceutically acceptable formulation comprises a liposome formulation. 
     
     
         16 . The method of  claim 15 , wherein said pharmaceutically acceptable formulation comprises a multivesicular liposome formulation. 
     
     
         17 . The method of  claim 12 , wherein said pharmaceutically acceptable formulation comprises a polymeric matrix. 
     
     
         18 . The method of  claim 17 , wherein said polymeric matrix is selected from the group consisting of naturally derived polymers, such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides. 
     
     
         19 . The method of  claim 17 , wherein said polymeric matrix is selected from the group consisting of synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics. 
     
     
         20 . The method of  claim 17 , wherein said polymeric matrix is in the form of microspheres. 
     
     
         21 . The method of  claim 12 , wherein the pharmaceutically acceptable formulation provides sustained delivery of said Aβ40 inhibitor to a subject. 
     
     
         22 . A method of treating a disease state characterized by cerebral amyloid angiopathy in a subject, comprising administering an Aβ40 inhibitor to said subject, such that said disease state characterized by cerebral amyloid angiopathy is treated, provided said Aβ40 inhibitor is not 3-amino-1-propanesulfonic acid. 
     
     
         23 . The method of  claim 22 , wherein said Aβ40 inhibitor has the structure:
   Q-[—Y − X + ] n      wherein Y −  is an anionic group at physiological pH; Q is a carrier group; X +  is a cationic group; and n is an integer selected such that the biodistribution of the Aβ40 inhibitor for an intended target site is not prevented while maintaining activity of the Aβ40 inhibitor, such that cerebral amyloid angiopathy is inhibited.   
     
     
         24 . The method of  claim 22 , wherein said Aβ40 inhibitor is selected from the group consisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4-hydroxy-1-butanesulfonic acid, and pharmaceutically acceptable salts thereof. 
     
     
         25 . The method of  claim 22 , wherein said Aβ40 inhibitor is selected from the group consisting of 1-butanesulfonic acid, 1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof. 
     
     
         26 . The method of  claim 22 , wherein said Aβ40 inhibitor is 1,7-dihydroxy-4-heptane sulfonic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method of  claim 22 , wherein said blood vessel wall cell is selected from the group consisting of blood vessel wall smooth muscle cells, pericytes and endothelial cells. 
     
     
         28 . The method of  claim 22 , wherein said blood vessel wall cell is a blood vessel wall smooth muscle cell. 
     
     
         29 . The method of  claim 22 , wherein the death of said blood vessel wall cell is prevented. 
     
     
         30 . The method of  claim 22 , wherein structural changes to said blood vessel wall cell are prevented. 
     
     
         31 . The method of  claim 22 , wherein said Aβ40 inhibitor is a peptide or a peptidomimetic which interacts with specific regions of the Aβ peptide. 
     
     
         32 . The method of  claim 22 , wherein said Aβ40 inhibitor has the following structure: 
       
         
           
           
               
               
           
         
         wherein
 Z is XR 2  or R 4 ; 
 R 1  and R 2  are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; 
 R 3  is hydrogen, lower alkyl, aryl, or a salt-forming cation; 
 R 4  is hydrogen, lower alkyl, aryl or amino; 
 X is, independently for each occurrence, O or S; 
 Y 1  and Y 2  are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and 
 n is an integer from 0 to 12. 
 
       
     
     
         33 . The method of  claim 22 , wherein said Aβ40 inhibitor is administered in a pharmaceutically acceptable formulation. 
     
     
         34 . The method of  claim 33 , wherein said pharmaceutically acceptable formulation is a dispersion system. 
     
     
         35 . The method of  claim 34 , wherein said pharmaceutically acceptable formulation comprises a lipid-based formulation. 
     
     
         36 . The method of  claim 35 , wherein said pharmaceutically acceptable formulation comprises a liposome formulation. 
     
     
         37 . The method of  claim 36 , wherein said pharmaceutically acceptable formulation comprises a multivesicular liposome formulation. 
     
     
         38 . The method of  claim 33 , wherein said pharmaceutically acceptable formulation comprises a polymeric matrix. 
     
     
         39 . The method of  claim 38 , wherein said polymeric matrix is selected from the group consisting of naturally derived polymers, such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides. 
     
     
         40 . The method of  claim 38 , wherein said polymeric matrix is selected from the group consisting of synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics. 
     
     
         41 . The method of  claim 38 , wherein said polymeric matrix is in the form of microspheres. 
     
     
         42 . The method of  claim 33 , wherein the pharmaceutically acceptable formulation provides sustained delivery of said Aβ40 inhibitor to a subject. 
     
     
         43 . A method of inhibiting cerebral amyloid angiopathy in a subject, comprising administering an Aβ40 inhibitor to said patient in an effective amount and manner such that said Aβ40 inhibitor contacts a blood vessel wall cell in said patient and that cerebral amyloid angiopathy is inhibited, provided said Aβ40 inhibitor is not 3-amino-1-propanesulfonic acid. 
     
     
         44 . The method of  claim 43 , wherein the Aβ40 inhibitor has the following structure:
   Q-[—Y − X + ] n      wherein Y −  is an anionic group at physiological pH; Q is a carrier group; X +  is a cationic group; and n is an integer selected such that the biodistribution of the Aβ40 inhibitor for an intended target site is not prevented while maintaining activity of the Aβ40 inhibitor, such that cerebral amyloid angiopathy is inhibited.   
     
     
         45 . The method of  claim 43 , wherein said Aβ40 inhibitor is selected from the group consisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4-hydroxy-1-butanesulfonic acid, and pharmaceutically acceptable salts thereof. 
     
     
         46 . The method of  claim 43 , wherein said Aβ40 inhibitor is selected from the group consisting of 1-butanesulfonic acid, 1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof. 
     
     
         47 . The method of  claim 43 , wherein said Aβ40 inhibitor is 1,7-dihydroxy-4-heptanesulfonic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The method of  claim 43 , wherein said blood vessel wall cell is selected from the group consisting of blood vessel wall smooth muscle cells, pericytes and endothelial cells. 
     
     
         49 . The method of  claim 43 , wherein said blood vessel wall cell is a blood vessel wall smooth muscle cell. 
     
     
         50 . The method of  claim 43 , wherein the death of said blood vessel wall cell is prevented. 
     
     
         51 . The method of  claim 43 , wherein structural changes to said blood vessel wall cell are prevented. 
     
     
         52 . The method of  claim 43 , wherein said Aβ40 inhibitor is a peptide or a peptidomimetic which interacts with specific regions of the Aβ peptide. 
     
     
         53 . The method of  claim 43 , wherein said Aβ40 inhibitor has the following structure: 
       
         
           
           
               
               
           
         
         wherein
 Z is XR 2  or R 4 ; 
 R 1  and R 2  are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; 
 R 3  is hydrogen, lower alkyl, aryl, or a salt-forming cation; 
 R 4  is hydrogen, lower alkyl, aryl or amino; 
 X is, independently for each occurrence, O or S; 
 Y 1  and Y 2  are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and 
 n is an integer from 0 to 12. 
 
       
     
     
         54 . The method of  claim 43 , wherein said Aβ40 inhibitor is administered in a pharmaceutically acceptable formulation. 
     
     
         55 . The method of  claim 54 , wherein said pharmaceutically acceptable formulation is a dispersion system. 
     
     
         56 . The method of  claim 55 , wherein said pharmaceutically acceptable formulation comprises a lipid-based formulation. 
     
     
         57 . The method of  claim 56 , wherein said pharmaceutically acceptable formulation comprises a liposome formulation. 
     
     
         58 . The method of  claim 57 , wherein said pharmaceutically acceptable formulation comprises a multivesicular liposome formulation. 
     
     
         59 . The method of  claim 54 , wherein said pharmaceutically acceptable formulation comprises a polymeric matrix. 
     
     
         60 . The method of  claim 59 , wherein said polymeric matrix is selected from the group consisting of naturally derived polymers, such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides. 
     
     
         61 . The method of  claim 59 , wherein said polymeric matrix is selected from the group consisting of synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics. 
     
     
         62 . The method of  claim 59 , wherein said polymeric matrix is in the form of microspheres. 
     
     
         63 . The method of  claim 54 , wherein the pharmaceutically acceptable formulation provides sustained delivery of said Aβ40 inhibitor to a subject. 
     
     
         64 . A method of inhibiting cerebral amyloid angiopathy, comprising contacting a blood vessel wall cell with a Aβ40 inhibitor having the structure: 
       
         
           
           
               
               
           
         
         wherein
 Z is XR 2  or R 4 ; 
 R 1  and R 2  are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; 
 R 3  is hydrogen, lower alkyl, aryl, or a salt-forming cation; 
 R 4  is hydrogen, lower alkyl, aryl or amino; 
 X is, independently for each occurrence, O or S; 
 Y 1  and Y 2  are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and 
 n is an integer from 0 to 12, such that cerebral amyloid angiopathy is inhibited. 
 
       
     
     
         65 . A method of inhibiting cerebral amyloid angiopathy in a subject, comprising administering an Aβ40 inhibitor to said patient in an effective amount and manner such that said Aβ40 inhibitor contacts a blood vessel wall cell in said patient, said Aβ40 inhibitor having the structure: 
       
         
           
           
               
               
           
         
         wherein
 Z is XR 2  or R 4 ; 
 R 1  and R 2  are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; 
 R 3  is hydrogen, lower alkyl, aryl, or a salt-forming cation; 
 R 4  is hydrogen, lower alkyl, aryl or amino; 
 X is, independently for each occurrence, O or S; 
 Y 1  and Y 2  are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and 
 n is an integer from 0 to 12, 
 
         such that cerebral amyloid angiopathy is inhibited. 
       
     
     
         66 . The method of  claim 65 , wherein said Aβ40 inhibitor has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         67 . The method of  claim 65 , wherein said Aβ40 inhibitor has the structure: 
       
         
           
           
               
               
           
         
         wherein R a  and R b  are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R a  and R b , taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring, and n is an integer from 0 to 6. 
       
     
     
         68 . The method of  claim 67 , wherein R a  and R b  are each hydrogen. 
     
     
         69 . The method of  claim 65 , wherein said Aβ40 inhibitor has the structure: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R 3  is hydrogen, lower alkyl, aryl, or a salt-forming cation; Y 1  and Y 2  are each independently hydrogen, halogen, lower alkyl, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12. 
       
     
     
         70 . The method of  claim 65 , wherein R 1  and R 2  are an aliphatic group selected from the group consisting of a branched or straight-chain aliphatic moiety having from about 1 to 24 carbon atoms or a branched or straight-chain aliphatic moiety having from about 10 to 24 carbon atoms, in the chain; and an unsubstituted or substituted cyclic aliphatic moiety having from 4 to 7 carbon atoms in the aliphatic ring. 
     
     
         71 . A method of inhibiting cerebral amyloid angiopathy in a subject, comprising administering an Aβ40 inhibitor to said patient in an effective amount and manner such that said Aβ40 inhibitor contacts a blood vessel wall cell in said patient, said Aβ40 inhibitor having the structure: 
       
         
           
           
               
               
           
         
         wherein G represents hydrogen or one or more substituents on the aryl ring and L is a substituted alkyl group, and M +  is a counter ion, such that cerebral amyloid angiopathy is inhibited. 
       
     
     
         72 . The method of  claim 71 , where G is hydrogen or an electron-donating group. 
     
     
         73 . The method of  claim 71 , where G is an electron-withdrawing group at the meta position.