BLOCKADE OF HUMAN NEUTROPHIL ACTIVATION BY 2-[2-PROPYL-3-[3-[2-ETHYL-4-(4-FLUOROPHENYL)-5-HYDROXYPHENOXY]PROPOXY]PHENOXY]BENZOIC ACID (LY293111), A NOVEL LEUKOTRIENE B-4 RECEPTOR ANTAGONIST

Leukotriene B-4 (LTB(4)), a naturally occurring pro-inflammatory product of arachidonic acid metabolism, has been associated with human inflammatory disease. This study compares the abilities of two LTB(4) receptor antagonists, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic acid (LY293111) and 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]- 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid (SC-41930), to displace LTB(4) binding and their functional blockade of human neutrophil activation. LY293111 inhibited the binding of [H-3]LTB(4) with a K-i of 25 nhl; SC-41930 displayed a similar potency (K-i = 17 nM). in contrast, LY293111 prevented LTB(4)-induced calcium mobilization with an IC50 = 20 nM, or 40 times more effectively than SC-41930 (IC50 = 808 nM). LY293111 was 300 times more potent than SC-41930 in blocking LTB(4)-induced CD11b up-regulation on isolated neutrophils. LY293111 also arrested LTB(4)-induced up-regulation of CD11b on neutrophils in whole human blood. LY293111 was not effective in blocking human neutrophil activation responses induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP), platelet-activating factor (PAF), human recombinant endothelial interleukin-8 (IL-8) or human recombinant complement component 5a (C5a).