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.
Leukotriene B4 (LTB4), a naturally occurring pro-inflammatory product of arachidonic acid metabolism, has been associated with human inflammatory disease. This study compares the abilities of two LTB4 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 LTB4 binding and their functional blockade of human neutrophil activation. LY293111 inhibited the binding of [3H]LTB4 with a Ki of 25 nM; SC-41930 displayed a similar potency (Ki = 17 nM). In contrast, LY293111 prevented LTB4-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 LTB4-induced CD11b up-regulation on isolated neutrophils. LY293111 also arrested LTB4-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).
Marder
P
P
Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Sawyer
J S
JS
Froelich
L L
LL
Mann
L L
LL
Spaethe
S M
SM
D001565:Benzoates / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D001667:Binding, Competitive; D018845:CD11 Antigens / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000187:drug effects
D001565:Benzoates; D001578:Benzopyrans; D018845:CD11 Antigens; C094099:LY 293111; D018102:Receptors, Leukotriene B4; C059950:SC 41930; D007975:Leukotriene B4; D002118:Calcium