Inhibition of TNF-α-initiated neutrophil response
View Patent ↗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 an effective anti-TNFα amount of a lipoxin analog having the formula
where X is R 1 , OR 1 , 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, 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 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, —S 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, 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 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 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.