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 . (canceled) 
     
     
         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 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the therapeutic compound is of 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. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 6 , 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. 
     
     
         10 . The method of  claim 9 , wherein the carrier molecule is a carbohydrate. 
     
     
         11 . The method of  claim 9 , wherein the carrier molecule is a lower aliphatic group. 
     
     
         12 . The method of  claim 9 , wherein the carrier molecule is a polymer. 
     
     
         13 . The method of  claim 12 , 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. 
     
     
         14 . The method of  claim 9 , wherein the carrier molecule includes a heterocyclic group. 
     
     
         15 . 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. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the therapeutic compound is of 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. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 18 , 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. 
     
     
         22 . The method of  claim 21 , wherein the carrier molecule is a carbohydrate. 
     
     
         23 . The method of  claim 21 , wherein the carrier molecule is a lower aliphatic group. 
     
     
         24 . The method of  claim 21 , wherein the carrier molecule is a polymer. 
     
     
         25 . The method of  claim 24 , 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. 
     
     
         26 . The method of  claim 21 , wherein the carrier molecule includes a heterocyclic group. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 11 , 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. 
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the therapeutic compound comprises at least one sulfonate group covalently attached to a disaccharide, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle. 
     
     
         31 . The method of  claim 30 , wherein the disaccharide is sucrose. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 12 , 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. 
     
     
         34 . The method of  claim 33 , wherein the therapeutic compound is poly(vinylsulfonic acid) or a pharmaceutically acceptable salt thereof. 
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 14 , 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. 
     
     
         37 . The method of  claim 1 , wherein the therapeutic compound comprises 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. 
     
     
         38 . (canceled) 
     
     
         39 . The method of  claim 23 , 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. 
     
     
         40 . The method of  claim 1 , wherein the therapeutic compound comprises at least one sulfate group covalently attached to a disaccharide, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable vehicle. 
     
     
         41 . The method of  claim 40 , wherein the therapeutic compound is sucrose octasulfate or a pharmaceutically acceptable salt thereof. 
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 24 , 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. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 26 , 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. 
     
     
         46 . The method of  claim 1 , wherein the therapeutic compound comprises 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. 
     
     
         47 .- 55 . (canceled)