Abstract

Leukotriene (LT) A₄ hydrolase is a dual function enzyme that is essential for the conversion of LTA₄ to LTB₄ and also possesses an aminopeptidase activity. SC-57461A (3-[methyl[3-[4-phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) is a potent inhibitor of human recombinant LTA₄hydrolase (epoxide hydrolase and aminopeptidase activities,K_i values = 23 and 27 nM, respectively) as well as calcium ionophore-induced LTB₄ production in human whole blood (IC₅₀ = 49 nM). In the present study, we investigated its action in several animal models. Oral activity was evident from the ability of the compound to inhibit mouse ex vivo calcium ionophore-stimulated blood LTB₄ production with ED₅₀ values at 1.0 and 3.0 h of 0.2 and 0.8 mg/kg, respectively. A single oral dose of 10 mg/kg SC-57461A blocked mouse ex vivo LTB₄ production 67% at 18 h and 44% at 24 h, suggesting a long pharmacodynamic half-life. In a rat model of ionophore-induced peritoneal eicosanoid production, SC-57461 inhibited LTB₄ production in a dose-dependent manner (ED₅₀ = 0.3–1 mg/kg) without affecting LTC₄ or 6-keto-prostaglandin F_1αproduction. Oral pretreatment with SC-57461 in a rat reversed passive dermal Arthus model blocked LTB₄ production with an ED₉₀ value of 3 to 10 mg/kg, demonstrating good penetration of drug into skin. Plasma level of intact SC-57461 (3 h after oral gavage dosing with 3 mg/kg) was 0.4 μg/ml, which corresponds to >80% inhibition of dermal LTB₄ production. Oral or topical pretreatment with SC-57461A 1 h before challenge with arachidonic acid blocked ear edema in the mouse. SC-57461A is a competitive, selective, and orally active inhibitor of LTA₄hydrolase in vivo, making it useful to explore the contribution of LTB₄ to a number of inflammatory diseases.