Inhibition of TNF-alpha-Initiated Response

Abstract

The impact of lipoxin A 4 (LXA 4 ) and aspirin-triggered-lipoxins (ATL) was investigated in tumor necrosis factor (TNFα)-initiated neutrophil (PMN) responses in vitro and in vivo using metabolically stable LX analogs. At concentrations as low as 1-10 nM, the LXA 4 and ATL analogs each inhibited TNFα-stimulated superoxide anion generation and IL-1β release by human PMN.

1 . A method for treating TNFα initiated polymorphoneutrophil (PMN)
 inflammation in a subject, comprising   administering to the subject a pharmaceutical composition comprising an effective anti-TNFα amount of a lipoxin analog having the formula   
     
       
         
         
             
             
         
       
       wherein X is R 1 , OR 1 , or SR 1 ; 
       wherein R 1  is
 (i) a hydrogen atom; 
 (ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched; 
 (iii) a cycloalkyl of 3 to 10 carbon atoms; 
 (iv) an aralkyl of 7 to 12 carbon atoms; 
 (v) phenyl; 
 (vi) substituted phenyl 
 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R T , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R X  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;
 (vii) a detectable label molecule; or 
 (viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive; 
 
       wherein R T  is
 (i) a hydrogen atom; 
 (ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched; 
 (iii) a cycloalkyl of 3 to 10 carbon atoms; 
 (iv) an aralkyl of 7 to 12 carbon atoms; 
 (v) phenyl; 
 (vi) substituted phenyl 
 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl; 
       wherein Q 1  is (C═O), SO 2  or (CN), provided when Q 1  is CN, then X is absent; 
       wherein R 4  is
 (a) H; 
 (b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched; 
 
       wherein R 5  is 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(—O)—R T , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group; 
       wherein R 6  is
 (a) H; 
 (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched; 
 
       wherein T is O or S; and 
       pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier, such that TNFα initiated polymorphoneutrophil (PMN) inflammation is treated in a subject. 
     
   
   
       2 . The method of  claim 1 , wherein said method is performed in vitro. 
   
   
       3 . The method of  claim 1 , wherein said method is performed in vivo. 
   
   
       4 . A method for treating TNFα initiated cytokine inflammation in a subject, comprising
 administering to the subject a pharmaceutical composition comprising an effective anti-TNFα amount of a lipoxin analog having the formula   
     
       
         
         
             
             
         
       
       wherein X is R 1 , OR 1 , or SR 1 ; 
       wherein R 1  is
 (i) a hydrogen atom; 
 (ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched; 
 (iii) a cycloalkyl of 3 to 10 carbon atoms; 
 (iv) an aralkyl of 7 to 12 carbon atoms; 
 (v) phenyl; 
 (vi) substituted phenyl 
 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R T , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;
 (vii) a detectable label molecule; or 
 (viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive; 
 
       wherein R T  is
 (i) a hydrogen atom; 
 (ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched; 
 (iii) a cycloalkyl of 3 to 10 carbon atoms; 
 (iv) an aralkyl of 7 to 12 carbon atoms; 
 (v) phenyl; 
 (vi) substituted phenyl 
 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl; 
       wherein Q 1  is (C═O), SO 2  or (CN), provided when Q 1  is CN, then X is absent; 
       wherein R 4  is
 (a) H; 
 (b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched; 
 
       wherein R 1  is 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R T , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group; 
       wherein R 6  is
 (a) H; 
 (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched; 
 
       wherein T is O or S; and 
       pharmaceutically acceptable salts thereof and a pharmaceutical carrier, such that TNFα initiated cytokine inflammation is treated in a subject. 
     
   
   
       5 . The method of  claim 4 , wherein said method is performed in vitro. 
   
   
       6 . The method of  claim 4 , wherein said method is performed in vivo. 
   
   
       7 . A method for treating TNFα initiated IL-1β inflammation in a subject, comprising
 administering to the subject a pharmaceutical composition comprising an effective anti-TNFα amount of a lipoxin analog having the formula   
     
       
         
         
             
             
         
       
       wherein X is R 1 , OR 1 , or SR 1 ; 
       wherein R 1  is
 (i) a hydrogen atom; 
 (ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched; 
 (iii) a cycloalkyl of 3 to 10 carbon atoms; 
 (iv) an aralkyl of 7 to 12 carbon atoms; 
 (v) phenyl; 
 (vi) substituted phenyl 
 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R T , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;
 (vii) a detectable label molecule; or 
 (viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive; 
 
       wherein R T  is
 (i) a hydrogen atom; 
 (ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched; 
 (iii) a cycloalkyl of 3 to 10 carbon atoms; 
 (iv) an aralkyl of 7 to 12 carbon atoms; 
 (v) phenyl; 
 (vi) substituted phenyl 
 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R X  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl; 
       wherein Q 1  is (C═O), SO 2  or (CN), provided when Q 1  is CN, then X is absent; 
       wherein R 4  is
 (a) H; 
 (b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched; 
 
       wherein R 5  is 
     
     
       
         
         
             
             
         
       
       wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R T , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group; 
       wherein R 6  is
 (a) H; 
 (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched; 
 
       wherein T is O or S; and 
       pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier, such that TNFα initiated IL-1β inflammation is treated in a subject. 
     
   
   
       8 . The method of  claim 7 , wherein said method is performed in vitro. 
   
   
       9 . The method of  claim 7 , wherein said method is performed in vivo.