Leukotriene B4-induced granulocyte trafficking in guinea pig dermis

Leukotriene B₄ (LTB₄) is a proinflammatory product of arachidonic acid metabolism that has teen 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 inhibitedthe 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 secondgeneration 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-benzopyran2-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.