LEUKOTRIENE-B4-INDUCED GRANULOCYTE TRAFFICKING IN GUINEA-PIG DERMIS - EFFECT OF 2ND-GENERATION LEUKOTRIENE-B4 RECEPTOR ANTAGONISTS, SC-50605 AND SC-51146

Leukotriene B4 (LTB4) is a proinflammatory product of arachidonic acid metabolism that has been implicated as a mediator in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB4 elicits 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-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid}, a first-generation LTB4 receptor antagonist inhibited the chemotactic actions of LTB4 when coadministered into the dermal site and when given orally with ED50 values of 340 ng and 1.7 mg/kg, respectively. The second-generation LTB4 receptor antagonists SC-50605 {7-[3-[2(cyclopropylmethyl)-3-methoxy-4-(4-thiazolyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid} and SC-51146 {7-[3-[2(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid} inhibited LTB4-induced chemotaxis when coadministered with ED50 values of 70 ng and 32 ng, respectively, and when given intragastrically with ED50 values of 0.10 and 0.09 mg/kg, respectively. SC-41930, SC-50605, and SC-51146 had oral durations of action of 5.5, 15, and 21 h, respectively. These potent, LTB4 receptor antagonists may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, where LTB4 is implicated as an inflammatory mediator.