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 B4 receptor antagonist

Abstract 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-2 H -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 [ 3 H]LTB 4 with a K i , of 25 nM; SC-41930 displayed a similar potency ( K i = 17 nM). In contrast, LY293111 prevented LTB 4 -induced calcium mobilization with an IC 50 = 20 nM, or 40 times more effectively than SC-41930 (IC 50 = 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).