Pharmacological profile of a novel, orally active leukotriene B4 antagonist, SM-15178

SM-15178, a new hydroxyacetophenone derivative, was evaluated to determine its antiinflammatory activity and antagonistic activity against leukotriene B4 (LTB4). SM-15178 inhibited [3H]LTB4 binding to its receptors on human neutrophils (IC50 = 0.30 microM). It inhibited LTB4-induced chemotaxis of human neutrophils (IC50 = 0.72 microM) with little inhibitory effect against C5a or FMLP-induced chemotaxis at concentrations up to 30 microM. The compound alone did not cause human neutrophil chemotaxis at concentrations up to 10 microM. LTB4-induced chemotaxis of mouse and rat neutrophils and guinea pig eosinophils was also inhibited by the compound, with IC50 values of 0.55, 0.52, and 0.58 microM, respectively. In an in vivo study, SM-15178, given orally, significantly prevented LTB4-induced transient leukopenia. It also suppressed LTB4-induced bronchoconstriction in the guinea pig almost completely when given orally at a dose of 40 mg/kg. Furthermore, orally given SM-15178 suppressed arachidonic acid-induced neutrophil infiltration in mouse ears and Arthus reaction-induced paw edema in the mouse in a dose-dependent manner. These results suggest that SM-15178 is a selective and orally active LTB4 antagonist and that it might be effective for the treatment of some types of inflammatory diseases.