COMPOUNDS THAT INHIBIT NFkB AND BACE1 ACTIVITY

Abstract

The present invention relates to compounds with activity as BACE1 and NFκB modulators, and methods for treating, preventing, or ameliorating neurodegenerative diseases, such as Alzheimer's disease. The present invention is also directed to the treatment of diseases related to dysfunction of cell proliferation, the immune system and/or inflammation using such compounds or pharmaceutical compositions containing such candidate compounds.

1 . A composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , and R 5  are independently selected for each occurrence from the group consisting of hydrogen, halogen, alkyl, aryl, alkoxy, aryloxy, alkylthiol, arylthiol, CN, and NO 2 ; and 
         wherein R 10  is selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl and alkenyl. 
       
     
     
         2 . The composition of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5  are independently selected for each occurrence from the group consisting of:
 hydrogen, methyl, Cl, OCH 3 , CF 3  and F.   
     
     
         3 . The composition of  claim 1 , wherein R 10  is selected from the group consisting of phenyl, 2-Nitrophenyl, 3-Nitrophenyl, 4-Nitrophenyl, 4-Methyl-2-nitrophenyl, 2-Methyl-5-nitrophenyl, 2-Nitro-4-(trifluoromethyl)phenyl, 4-Methoxy-2-nitrophenyl, 2-Methyl-5-nitrophenyl, 4-Methyl-2-nitrophenyl, 4-Methylphenyl, 2-Aminophenyl, 2-Amino-4-methyl phenyl, Thiophen-2-yl, 5-Chlorothiophen-2-yl, 5-Bromothiophen-2-yl. 
     
     
         4 - 9 . (canceled) 
     
     
         10 . A method for inhibiting the activity of a β-site APP cleavage enzyme 1 (BACE1) in a cell which comprises contacting the cell with a compound of  claim 1  in an amount effective to inhibit β-site APP cleavage enzyme 1 activity. 
     
     
         11 . The method of  claim 10 , wherein the inhibition of β-site APP cleavage enzyme 1 activity reduces the metabolism of an amyloid precursor protein (APP). 
     
     
         12 . The method of  claim 10 , wherein the cell is a mammalian cell. 
     
     
         13 . The method of  claim 10 , wherein the cell is contacted in vitro. 
     
     
         14 . A method for treating Alzheimer's disease in an individual, which method comprises administering to the individual an effective amount of a compound according to  claim 1 . 
     
     
         15 . A method for inhibiting the activity of a Nuclear factor-κ B (NFκB) in a cell which comprises contacting the cell with a compound of  claim 1  in an amount effective to inhibit Nuclear factor-κ B (NFκB) activity. 
     
     
         16 . The method of  claim 15 , wherein the inhibition of Nuclear factor-κ B (NFκB) activity reduces nuclear translocation of the Nuclear factor-κ B (NFκB). 
     
     
         17 . The method of  claim 15 , wherein the cell is a mammalian cell. 
     
     
         18 . The method of  claim 15 , wherein the cell is contacted in vitro. 
     
     
         19 . A method for treating a disease related to dysfunction of cell proliferation, the immune system, and/or inflammation in an individual, which method comprises administering to the individual an effective amount of a compound according to  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein the disease is cancer. 
     
     
         21 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         22 . The composition of  claim 1 , wherein R 10  is a substituted phenyl, and wherein the substituents are selected from the group consisting of hydrogen, halogen and combinations thereof. 
     
     
         23 . The composition of  claim 22 , wherein the substituents are selected from the group consisting of hydrogen, fluorine, chlorine and combinations thereof.