Antiinflammatory effects of second-generation leukotriene B sub(4) receptor antagonist, SC-53228: Impact upon leukotriene B sub(4)- and 12(R)-HETE-mediated events

• Published in: Inflammation Vol. 19; no. 2; pp. 193 - 206
• Main Authors: Fretland, D J, Anglin, C P, Bremer, M, Isakson, P, Widomski, D L, Paulson, S K, Docter, SH, Djuric, S W, Penning, T D, Yu, S, McKearn, J P
• Format: Journal Article
• Language: English
• Published: 01-01-1995
• ISSN: 0360-3997

Leukotriene B sub(4) (LTB sub(4)) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB sub(4) and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 {7-[3-(4-acetyl-3-methoxy-2-phenoxy)propoxyl]-3,4-dihydro-8-propyl -2 H-1-benzopyran-2-carboxylic acid} , a first-generation LTB sub(4) receptor antagonist, inhibited the chemotactic actions of LTB sub(4) when given orally with an ED sub(50) value of 1.7 mg/kg. The second-generation LTB sub(4) receptor antagonist, SC-53228 inhibited LTB sub(4)-induced chemotaxis when given intragastrically with an ED sub(50) value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED sub(50) value of 5.8 mg/kg. When dosed orally over a range of 0.03-100 mg/kg, SC-53228 gave C sub(max) plasma concentrations of 0.015-41.1 mu g/ml. SC-53228 inhibited LTB sub(4)-primed membrane depolarization of human neutrophils with an IC sub(50) value of 34 nM. As a potent LTB sub(4) receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB sub(4) and/or 12(R)-HETE are implicated as inflammatory mediators.