Method for treating amyloidosis

Abstract

Therapeutic compounds and methods for inhibiting amyloid deposition in a subject, whatever its clinical setting, are described. Amyloid deposition is inhibited by the administration to a subject of an effective amount of a therapeutic compound comprising an anionic group and a carrier molecule, or a pharmaceutically acceptable salt thereof, such that an interaction between an amyloidogenic protein and a basement membrane constituent is inhibited. Preferred anionic groups are sulfonates and sulfates. Preferred carrier molecules include carbohydrates, polymers, peptides, peptide derivatives, aliphatic groups, alicyclic groups, heterocyclic groups, aromatic groups and combinations thereof.

1 . A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, the therapeutic compound comprising at least one anionic group attached to a carrier molecule, or a pharmaceutically acceptable salt thereof, such that the therapeutic compound inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to inhibit amyloid deposition.  
     
     
         2 . The method of  claim 1  further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.  
     
     
         3 . The method of  claim 1 , wherein the carrier molecule is selected from the group consisting of a carbohydrate, a polymer, a peptide, a peptide derivative, an aliphatic group, an alicyclic group, a heterocyclic group, an aromatic group and combinations thereof.  
     
     
         4 . The method of  claim 1 , wherein the anionic group is selected from the group consisting of a sulfonate group, a sulfate group, a carboxylate group, a phosphate group, a phosphonate group, and a heterocyclic group selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the carrier molecule is selected for delivery of the therapeutic compound to the brain.  
     
     
         6 . The method of  claim 1 , wherein the therapeutic compound is delivered liposomally.  
     
     
         7 . A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, the therapeutic compound comprising at least one sulfonate group covalently attached to a carrier molecule, or a pharmaceutically acceptable salt thereof, such that the therapeutic compound inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to inhibit amyloid deposition.  
     
     
         8 . A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, the therapeutic compound having the following formula:  
       Q-[—SO 3   − X + ] n    
       wherein Q is a carrier molecule; X +  is a cationic group; and n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound, wherein the therapeutic compound inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to inhibit amyloid deposition.  
     
     
         9 . The method of  claim 7 , wherein the therapeutic compound is administered orally.  
     
     
         10 . The method of  claim 7 , further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.  
     
     
         11 . The method of  claim 7 , wherein the carrier molecule is selected for delivery of the therapeutic compound to the brain.  
     
     
         12 . The method of  claim 7 , wherein the therapeutic compound is delivered liposomally.  
     
     
         13 . The method of  claim 7 , wherein the carrier molecule is selected from the group consisting of a carbohydrate, a polymer, a peptide, a peptide derivative, an aliphatic group, an alicyclic group, a heterocyclic group, an aromatic group and combinations thereof.  
     
     
         14 . The method of  claim 13 , wherein the carrier molecule is a carbohydrate.  
     
     
         15 . The method of  claim 13 , wherein the carrier molecule is a lower aliphatic group.  
     
     
         16 . The method of  claim 13 , wherein the carrier molecule is a polymer.  
     
     
         17 . The method of  claim 16 , wherein the polymer is selected from the group consisting of substituted and unsubstituted vinyl, acryl, styrene and carbohydrate-derived polymers and copolymers and pharmaceutically acceptable salts thereof.  
     
     
         18 . The method of  claim 13 , wherein the carrier molecule includes a heterocylic group.  
     
     
         19 . A method for inhibiting amyloid deposition in a subject comprising orally administering to the subject an effective amount of a therapeutic compound, the therapeutic compound comprising at least one sulfonate group covalently attached to a carrier molecule, or a pharmaceutically acceptable salt thereof.  
     
     
         20 . The method of  claim 19  further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.  
     
     
         21 . A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, the therapeutic compound comprising at least one sulfate group covalently attached to a carrier molecule, or a pharmaceutically acceptable salt thereof, such that the therapeutic compound inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to inhibit amyloid deposition.  
     
     
         22 . A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, the therapeutic compound having the following formula:  
       Q-[—OSO 3   − X + ] n    wherein Q is a carrier molecule; X +  is a cationic group; and n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound, wherein the therapeutic compound inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to inhibit amyloid deposition.    
     
     
         23 . The method of  claim 21 , wherein the therapeutic compound is administered orally.  
     
     
         24 . The method of  claim 21 , further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.  
     
     
         25 . The method of  claim 21 , wherein the carrier molecule is selected from the group consisting of a carbohydrate, a polymer, a peptide, a peptide derivative, an aliphatic group, an alicyclic group, a heterocyclic group, an aromatic group and combinations thereof.  
     
     
         26 . The method of  claim 25 , wherein the carrier molecule is a carbohydrate.  
     
     
         27 . The method of  claim 25 , wherein the carrier molecule is a lower aliphatic group.  
     
     
         28 . The method of  claim 25 , wherein the carrier molecule is a polymer.  
     
     
         29 . The method of  claim 28 , wherein the polymer is selected from the group consisting of substituted and unsubstituted vinyl, acryl, styrene and carbohydrate-derived polymers and copolymers and pharmaceutically acceptable salts thereof.  
     
     
         30 . The method of  claim 25 , wherein the carrier molecule includes a heterocyclic group.  
     
     
         31 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfonate group covalently attached to a lower aliphatic group, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         32 . The method of  claim 31 , wherein the therapeutic compound 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-hydroxybutane-1-sulfonic acid, and pharmaceutically acceptable salts thereof.  
     
     
         33 . The method of  claim 31 , wherein the therapeutic compound is administered orally.  
     
     
         34 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfonate group covalently attached to a disaccharide, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         35 . The method of  claim 34 , wherein the disaccharide is sucrose.  
     
     
         36 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfonate group covalently attached to a polymer, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         37 . The method of  claim 36 , wherein the therapeutic compound is selected from the group consisting of poly(2-acrylamido-2-methyl-1-propanesulfonic acid); poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-acrylonitrile); poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-styrene); poly(vinylsulfonic acid); poly(sodium 4-styrenesulfonic acid); a sulfonate derivative of poly(acrylic acid); a sulfonate derivative of poly(methyl acrylate); a sulfonate derivative of poly(methyl methacrylate); and pharmaceutically acceptable salts thereof.  
     
     
         38 . The method of  claim 37 , wherein the therapeutic compound is poly(vinylsulfonic acid) or a pharmaceutically acceptable salt thereof.  
     
     
         39 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfonate group covalently attached to carrier molecule that includes a heterocyclic group, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         40 . The method of  claim 39 , wherein the compound is selected from the group consisting of 3-(N-morpholino)propanesulfonic acid, tetrahydrothiophene-1,1-dioxide-3,4-disulfonic acid, and pharmaceutically acceptable salts thereof.  
     
     
         41 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfonate group covalently attached to a peptide and a peptide derivative, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         42 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfate group covalently attached to a lower aliphatic group, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         43 . The method of  claim 42 , wherein the therapeutic compound is selected from the group consisting of ethyl sulfuric acid, 1,2-ethanediol disulfuric acid, 1-propyl sulfuric acid, 1,3-propanediol disulfuric acid, 1,4-butanediol disulfuric acid, 1,5-pentanediol disulfuric acid, 2-amino-ethanesulfuric acid, 1,4-butanediol monosulfuric acid, and pharmaceutically acceptable salts thereof.  
     
     
         44 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfate group covalently attached to a disaccharide, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         45 . The method of  claim 44 , wherein the therapeutic compound is sucrose octasulfate or a pharmaceutically acceptable salt thereof.  
     
     
         46 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfate group covalently attached to a polymer, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         47 . The method of  claim 46 , wherein the therapeutic compound is selected from the group consisting of poly(2-acrylamido-2-methyl-1-propanesulfuric acid); poly(2-acrylamido-2-methyl-1-propanesulfuric acid-co-acrylonitrile); poly(2-acrylamido-2-methyl-1-propanesulfuric acid-co-styrene); poly(vinylsulfuric acid); poly(sodium 4-styrenesulfuric acid); a sulfate derivative of poly(acrylic acid); a sulfate derivative of poly(methyl acrylate); a sulfate derivative of poly(methyl methacrylate); and pharmaceutically acceptable salts thereof.  
     
     
         48 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfate group covalently attached to a carrier molecule that includes a heterocyclic group, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         49 . The method of  claim 48 , wherein the compound is selected from the group consisting of 3-(N-morpholino)propanesulfuric acid, tetrahydrothiophene-1,1-dioxide-3,4-diol disulfuric acid, and pharmaceutically acceptable salts thereof.  
     
     
         50 . A method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound comprising at least one sulfate group covalently attached to a peptide and a peptide derivative, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle.  
     
     
         51 . A pharmaceutical composition for treating amyloidosis comprising a therapeutic compound comprising at least one sulfonate group covalently attached to a carrier molecule, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit amyloid deposition in a subject, and a pharmaceutically acceptable vehicle.  
     
     
         52 . The pharmaceutical composition of  claim 51 , wherein the carrier molecule is selected from the group consisting of a carbohydrate, a polymer, a peptide, a peptide derivative, an aliphatic group, an alicyclic group, a heterocyclic group, an aromatic group and combinations thereof.  
     
     
         53 . The pharmaceutical composition of  claim 51 , wherein the therapeutic compound is poly(vinylsulfonic acid) or a pharmaceutically acceptable salt thereof.  
     
     
         54 . The pharmaceutical composition of  claim 51 , wherein the therapeutic compound 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-amino-ethanesulfonic acid, 4-hydroxybutane-1-sulfonic acid, and pharmaceutically acceptable salts thereof.  
     
     
         55 . The pharmaceutical composition of  claim 51 , wherein the therapeutic compound is selected from the group consisting of 3-(N-morpholino)propanesulfonic acid, tetrahydrothiophene-1,1-dioxide-3,4-disulfonic acid, and pharmaceutically acceptable salts thereof.  
     
     
         56 . A pharmaceutical composition for treating amyloidosis comprising a therapeutic compound comprising at least one sulfate group covalently attached to a carrier molecule, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit amyloid deposition in a subject, and a pharmaceutically acceptable vehicle.  
     
     
         57 . The pharmaceutical composition of  claim 56 , wherein the carrier molecule is selected from the group consisting of a carbohydrate, a polymer, a peptide, a peptide derivative, an aliphatic group, an alicyclic group, a heterocyclic group, an aromatic group and combinations thereof.  
     
     
         58 . The pharmaceutical composition of  claim 56 , wherein the therapeutic compound is sucrose octasulfate or a pharmaceutically acceptable salt thereof.  
     
     
         59 . The pharmaceutical composition of  claim 56 , wherein the therapeutic compound is selected from the group consisting of ethyl sulfuric acid, 1,2-ethanediol disulfuric acid, 1-propanesulfuric acid, 1,3-propanediol disulfuric acid, 1,4-butanediol disulfuric acid, 1,5-pentanediol disulfuric acid, 2-amino-ethanesulfuric acid, 1,4-butanediol monosulfuric acid, and pharmaceutically acceptable salts thereof.  
     
     
         60 . The pharmaceutical composition of  claim 51 , wherein the therapeutuc compound is encapsulated in a liposome.  
     
     
         61 . The pharmaceutical composition of  claim 56 , wherein the therapeutuc compound is encapsulated in a liposome.