ONO-4057, a novel, orally active leukotriene B4 antagonist: Effects on LTB₄-induced neutrophil functions

ONO-4057(5-[2-(2-Carboxyethyl)-3-{6-( 4-methoxyphenyl )-5E-hexenyl} oxyphenoxy ] valeric acid), an orally active leukotriene B₄(LTB₄) antagonist, displaced the binding of [³H] LTB₄ to the LTB₄ receptor in human neutrophil (Ki = 3.7±0.9 nM). ONO-4057 inhibited the LTB₄-induced rise in cytosolic free calcium (the concentration causing 50% inhibition (IC₅₀) = 0.7±0.3μM) and inhibited human neutrophil aggregation, chemotaxis or degranulation induced by LTB₄ (IC₅₀ = 3.0±0.1, 0.9±0.1 and 1.6±0.1μM) without showing any agonist activity at concentration up to 30μM. ONO-4057 did not inhibit fMLP or C5a-induced neutrophil activation at concentrations up to 30μM. In the in vivo study, ONO-4057 given orally, prevented LTB₄-induced transient neutropenia or intradermal neutrophil migration in guinea pig (the dose causing 50% efficacy (ED₅₀) = 25.6mg/kg or 5.3mg/kg). Furthermore, ONO-4057 given topically, suppressed phorbol-12-myristate-13-acetate (PMA)-induced neutrophil infiltration in guinea pig ear (the effective dose = 1 mg/ear). These results indicate that ONO-4057 is a selective and orally active LTB₄ antagonist and may be a potential candidate for the treatment of various inflammatory diseases.