Methods and formulations for treatment of spinobulbar muscular atrophy

Abstract

Methods and formulations are provided for treating spinobulbar muscular atrophy in a subject in need thereof. By administering a therapeutically effective amount of a selective androgen receptor modulator or a small molecule such as 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole or a derivative, prodrug, or pharmaceutically acceptable salt thereof, one or more symptoms of spinobulbar muscular atrophy can be ameliorated. The effective amount can be effective to prevent or delay loss of body weight, a loss of mobility, and/or a loss of physical strength in the subject; to prevent or delay neurogenic atrophy and/or to prevent a loss of spinal cord motor neurons in the subject; to restore the frequency of type I myofibers to normal levels for a healthy subject; and/or to reverse testicular atrophy in the subject.

1 . A pharmaceutical formulation for treating spinobulbar muscular atrophy in a subject in need thereof, the pharmaceutical formulation comprising:
 a therapeutically effective amount of a small molecule having a structure according to the following formula   
       
         
           
           
               
               
           
         
         or a derivative thereof, a prodrug thereof, or a salt thereof; 
         wherein each occurrence of R 1 , R 2 , R 3 , and R 4  is independently a hydrogen, a hydroxyl, a halogen, or a substituted or unsubstituted C 1 -C 6  alkyl or alkoxy; 
         wherein each occurrence of X 1  and X 2  is independently O or S; 
         wherein each occurrence of A 1  is independently none or a substituted or unsubstituted C 1 -C 6  alkyl diradical; and 
         wherein the therapeutically effective amount is effective to ameliorate one or more symptoms of spinobulbar muscular atrophy in the subject. 
       
     
     
         2 . The pharmaceutical formulation according to  claim 1 , wherein each occurrence of R 1  is a hydrogen. 
     
     
         3 . The pharmaceutical formulation according to  claim 1 , wherein each occurrence of R 2  is a hydrogen. 
     
     
         4 . The pharmaceutical formulation according to  claim 1 , wherein each occurrence of R 3  is a hydrogen. 
     
     
         5 . The pharmaceutical formulation according to  claim 1 , wherein R 4  is a hydrogen, methyl, ethyl, isopropyl, or t-butyl. 
     
     
         6 . The pharmaceutical formulation according to  claim 5 , wherein X 1  is S. 
     
     
         7 . The pharmaceutical formulation according to  claim 6 , wherein each occurrence of X 2  is O. 
     
     
         8 . The pharmaceutical formulation according to  claim 1 , wherein each occurrence of A 1  is an unsubstituted C 1 -C 3  alkyl diradical. 
     
     
         9 . (canceled) 
     
     
         10 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation comprises the derivative of the small molecule; and
 wherein the derivative is selected from the group consisting of ester and amide derivatives of the small molecule, pegylated derivatives of the small molecule, and N-oxides of the small molecule.   
     
     
         11 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation comprises the prodrug of the small molecule; and
 wherein the prodrug is an amide, carbamate, imide, ester, anhydride, thioester, or thioanhydride of the small molecule.   
     
     
         12 - 23 . (canceled) 
     
     
         24 . A method of treating spinobulbar muscular atrophy in a subject in need thereof, the method comprising administering a therapeutically effective amount of a small molecule having a structure according to the following formula: 
       
         
           
           
               
               
           
         
         or a derivative thereof, a prodrug thereof, or a salt thereof; 
         wherein each occurrence of R 1 , R 2 , R 3 , and R 4  is independently a hydrogen, a hydroxyl, a halogen, or a substituted or unsubstituted C 1 -C 6  alkyl or alkoxy; 
         wherein each occurrence of X 1  and X 2  is independently O or S; 
         wherein each occurrence of A 1  is independently none or a substituted or unsubstituted C 1 -C 6  alkyl diradical; and 
         wherein the therapeutically effective amount is effective to ameliorate one or more symptoms of spinobulbar muscular atrophy in the subject. 
       
     
     
         25 . A method of treating spinobulbar muscular atrophy in a subject in need thereof, the method comprising administering a therapeutically effective amount of a selective androgen receptor modulator to the subject,
 wherein the therapeutically effective amount is effective to ameliorate one or more symptoms of spinobulbar muscular atrophy in the subject.   
     
     
         26 . The method according to  claim 25 , wherein the selective androgen receptor modulator alters a co-regulator binding to the activation function-2 (AF2) domain of the androgen receptor. 
     
     
         27 . The method according to  claim 25 , wherein the selective androgen receptor selectively binds to the binding function-3 (BF3) domain of the androgen receptor. 
     
     
         28 . The method according to  claim 25 , wherein the selective androgen receptor modulator is selected from the group consisting of 17α-methyl-17β-hydroxy-2-oxa-5α-androstan-3-one and derivatives thereof, testosterone and derivatives thereof, 4,5α-dihydrotestosterone and derivatives thereof, ((2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide) and a derivative thereof, and a combination thereof. 
     
     
         29 . The method according to  claim 24 , wherein the method comprises administering a pharmaceutical formulation according to  claim 1 . 
     
     
         30 . The method according to  claim 24 , wherein the effective amount is effective to prevent or delay loss of body weight, a loss of mobility, and/or a loss of physical strength in the subject. 
     
     
         31 . The method according to  claim 24 , wherein the effective amount is effective to prevent or delay neurogenic atrophy and/or to prevent a loss of spinal cord motor neurons in the subject. 
     
     
         32 . The method according to  claim 24 , wherein the effective amount is effective to restore the frequency of type I myofibers to normal levels for a healthy subject. 
     
     
         33 - 35 . (canceled)