Pharmacological Characterization of SC-57461A (3-[Methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic Acid HCl), a Potent and Selective Inhibitor of Leukotriene A_4 Hydrolase II: In Vivo Studies

摘要

Leukotriene (LT) A_4 hydrolase is a dual function enzyme that is essential for the conversion of LTA)4 to LTB_4 and also possess an aminopeptidase activity. SC-57461A (3-[methyl-[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) is a potent inhibitor of human recombinant LTA_4 hyrolase (epoxide hydrolase and aminopeptidase activities, K_i values = 23 and 27 nM, respectively) as well as calcium ionophore-induced LTB_4 production in human whole blood (IC_50 = 49 nM). In the present study, we invstigated its action in severa lanimal models. Oral activity was evident from the ability of the compound to inhibit mouse ex vivo calcium ionophore-stimulated blood LTB_4 production with ED_50 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 blockid mouse ex civo LTB_4 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 LTB_4 production in a dose-dependent manner (ED_50 = 0.3-1 mg/kg) without affecting LTC_4 or 6-keto-prostglandin F_1#alpha# production. Oral pretreatment with SC-57461 in a rat reversed passive dermal Arthus model blocked LTB_4 production with an ED_90 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 #mu#g/mlo, which correspondings to > 80% inhibition of dermal LTB_4 production. Oral or topical pretreatment with SC-57461A 1h before challenge with arachidonic acid blcoked ear edema in the mouse. SC-57461A is a competitive, selective, and orally active inhibitor of LTA_4 hydrolase in vivo, making it useful to explore the contribution of LTB_4 to a numgber of inflammatory diseases.