Leukotriene (LT) A 4 hydrolase is a dual function enzyme that is essential for the conversion of LTA 4 to LTB 4 and also possesses an aminopeptidase activity. phenoxy]propyl]amino]propanoic acid HCl) is a potent inhibitor of human recombinant LTA 4 hydrolase (epoxide hydrolase and aminopeptidase activities, K i values ϭ 23 and 27 nM, respectively) as well as calcium ionophore-induced LTB 4 production in human whole blood (IC 50 ϭ 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 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 blocked mouse ex vivo 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 ϭ 0.3-1 mg/kg) without affecting LTC 4 or 6-ketoprostaglandin F 1␣ 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 g/ml, which corresponds to Ͼ80% inhibition of dermal LTB 4 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 LTA 4 hydrolase in vivo, making it useful to explore the contribution of LTB 4 to a number of inflammatory diseases. -57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) is a potent and competitive inhibitor of recombinant human leukotriene A 4 hydrolase in vitro (Askonas et al., 2002). It inhibits recombinant human leukotriene A 4 at nanomolar concentrations when either LTA 4 (epoxide hydrolase, K i ϭ 23 nM) or peptide substrates (aminopeptidase, K i ϭ 27 nM) are used. SC-57461A is selective for LTA 4 hydrolase and does not inhibit other enzymes involved in the metabolism of arachidonic acid (AA) [e.g., 5-lipoxygenase (5-LO), LTC 4 synthase, or various isoforms of cyclooxygenase] as well as other zinccontaining aminopeptidases (e.g., human leukocyte elastase, rabbit lung angiotensin-converting enzyme) (Askonas et al., 2002).
SCSC-57461A is also active in mammalian whole blood under conditions in which both 5-LO and cyclooxygenase pathways were simultaneously stimulated with calcium ionophore A23187. The IC 50 values for inhibition of LTB 4 are less than 0.5 M in the blood of several species (Askonas et al., 2002), suggesting that SC-57461A is metabolically stable and can penetrate cells to inhibit the cytosolic enzyme.To characterize SC-57461A in vivo, we used several rodent models to assess oral activity, selectivity for inhibiting LTB 4 synthesis, and efficacy in several mode...