Inhibition of TNF-alpha-Initiated Neutrophil 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 modulating a disease or condition associated with TNFα initiated polymorphoneutrophil (PMN) inflammation, TNFα initiated cytokine activity or TNFα initiated IL-1β in a subject, comprising 
 administering to the subject 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 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 one of R 2  and R 3 , if present, is a hydrogen atom and the other is 
 (a) H;  
 (b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched;  
 (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;  
 (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or  
 (e) R a Q 2 R b  wherein Q 2  is —O— or —S—; wherein R a  is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein R b  is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b  is 0, then R b  is a hydrogen atom;  
 
 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 iii , 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, if present, is O or S, and pharmaceutically acceptable salts thereof excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4, such that TNFα initiated polymorphoneutrophil (PMN) inflammation, TNFα initiated cytokine activity or TNFα initiated IL-1β in a subject is modulated.  
   
     
     
         2 . A method for modulating a disease or condition associated with TNFα initiated polymorphoneutrophil (PMN) inflammation, TNFα initiated cytokine activity or TNFα initiated IL-1β in a subject, comprising 
 administering to the subject 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 Q 3  and Q 4 , if present, are each independently O, S or NH;    wherein one of R 2  and R 3 , if present, is a hydrogen atom and the other is 
 (a) H;  
 (b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched;  
 (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;  
 (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or  
 (e) R a Q 2 R b  wherein Q 2  is —O— or —S—; wherein R a  is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein R b  is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b  is 0, then R b  is a hydrogen atom;  
   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 Y 1 , if present, is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CH a Z b  where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;    wherein R 6  is 
 (a) H;  
 (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;  
   wherein T, if present, is O or S, and pharmaceutically acceptable salts thereof excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4; and    a pharmaceutically acceptable carrier, such that TNFα initiated polymorphoneutrophil (PMN) inflammation, TNFα initiated cytokine activity or TNFα initiated IL-1β in a subject is modulated.    
     
     
         3 . A method for modulating a disease or condition associated with TNFα initiated polymorphoneutrophil (PMN) inflammation, TNFα initiated cytokine activity or TNFα initiated IL-1β in a subject, comprising 
 administering to the subject an effective anti-TNFα amount of a lipoxin analog having the formula                          a pharmaceutically acceptable carrier, wherein said pharmaceutical carrier is not a ketone, such that TNFα initiated polymorphoneutrophil (PMN) inflammation, TNFα initiated cytokine activity or TNFα initiated IL-1β in a subject is modulated.