Valproic acid and derivatives thereof as histone deacetylase inhibitors

Abstract

The present invention relates to the use of the drug valproic acid and derivatives thereof as inhibitors of enzymes having histone deacetylase activity. The invention also relates to the use of those compounds for the manufacture of a medicament for the treatment of diseases which are associated with hypoacetylation of histones or in which induction of hyperacetylation has a beneficial effect for example by induction of differentiation and/or apoptosis in transformed cells.

1 - 23 . (canceled)  
     
     
         24 . The use of a compound of Formula I as an inhibitor of an enzyme having histone deacetylase activity,  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  independently are a linear or branched, saturated or unsaturated, aliphatic C 2-25  hydrocarbon chain which may be substituted with a hydroxyl, amino, alkoxy, aryl or heterocyclic group, R 3  is hydroxyl, halogen, alkoxy or an optionally alkylated amino group; or a pharmaceutically acceptable salt of a compound of the Formula I; or a prodrug or pharmaceutically active metabolite of a compound of the Formula I, or a pharmaceutically acceptable salt of a prodrug or metabolite thereof.  
       
     
     
         25 . The use according to  claim 24 , wherein R 1  and R 2  independently are a linear or branched, saturated or unsaturated, C 2-10  hydrocarbon chain.  
     
     
         26 . The use according to  claim 24 , wherein the compound is selected from the group consisting of VPA, S-4-yn VPA, 2-ethyl hexanoic acid and pharmaceutically acceptable salts, prodrugs or pharmaceutically active metabolites thereof.  
     
     
         27 . The use according to anyone of  claims 24  to  26 , wherein the enzyme having histone deacetylase activity is mammalian, preferably human histone deacetylase.  
     
     
         28 . The use according to  claim 27 , wherein the human histone deacetylase is selected from the group consisting of histone deacetylases HDAC 1-3 (class I) and HDAC 4-8 (class II).  
     
     
         29 . The use according to  claim 24 , wherein the compound is used for the induction of differentiation of cells.  
     
     
         30 . The use according to  claim 29 , wherein the compound is used for the induction of differentiation of transformed cells.  
     
     
         31 . The use according to  claim 24 , wherein the compound is used for the induction of apoptosis of transformed cells.  
     
     
         32 - 49 . (canceled)  
     
     
         50 . A method of treating a disease or disorder associated with the hyperacetylation of histones, comprising administering to a subject in need of such treatment, an agent capable of inhibiting histone deacetylase, selected from the group consisting of valproic acid, S-4-yn valproic acid, and 2-ethyl-hexanoic acid or a pharmaceutically acceptable salt; or a prodrug or pharmaceutically active metabolite, or a pharmaceutically acceptable salt of a prodrug or metabolite thereof, wherein the disease is an endocrine disorder associated with induction of histone deacetylase.  
     
     
         51 . The method of  claim 50 , wherein the disease is thyroid resistance syndrome.