Pharmacological Characterization of SC-57461A (3-[Methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic Acid HCl), a Potent and Selective Inhibitor of Leukotriene A₄Hydrolase II: In Vivo Studies

Abstract

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...

The development of novel LTA4H modulators to selectively target LTB4 generation

“…1h) demonstrates that this compound fills both arms, again suggesting it will impede PGP binding. It has previously been demonstrated that oral administration of SC57461A or a JNJ-40929837 derivative to naïve mice resulted in a potent inhibition of LTB 4 generation in an ex vivo whole blood assay2531. Importantly, we demonstrate that a comparable protocol, whereby SC57461A or JNJ-40929837 are orally administered to naïve mice, also potently abrogates serum aminopeptidase PGP-degrading activity (Fig.…”

“…It is feasible that the lack of success of these compounds may be due to their failure to distinguish between the opposing roles of LTA 4 H and thus inadvertently prevent PGP degradation. Searle/Pharmacia developed the potent, orally active inhibitor SC567461A that entered clinical trials for inflammatory bowel disease, but was withdrawn owing to adverse outcomes252627. DeCODE pharmaceuticals subsequently utilized a fragment based drug discovery program to identify inhibitors of LTA 4 H, leading to the development of the potent, orally active compound DG-051 that entered phase IIa clinical trials for myocardial infarction and stroke before further development being precluded282930.…”

Binding of Pro-Gly-Pro at the active site of leukotriene A 4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor

“…Inasmuch as LTA4H catalyzes the final and committed step in the biosynthesis of the potent chemotactic agent LTB 4 , this enzyme has been an interesting target for development of anti-inflammatory drugs. Thus, several highly potent and selective inhibitors have been developed within academia as well as industry (13)(14)(15)(16). However, none of these compounds have met the expectations and demonstrated clinical usefulness.…”

Leukotriene B4mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

“…For SC57461A, dose-response studies were conducted using a range of doses surrounding 10 mg/kg (5, 10, and 20 mg/kg ip daily) based on equivalence of IC50 with zileuton and similar oral bioavailability (2). These studies demonstrated maximal inhibitory effect of SC57461A on lung LTB4 content at 10 mg/kg (data not shown), the same (orally administered) dose and dose interval reported to have inhibitory effects on inflammatory injury in adult rodents (22). Each litter was maintained at n ϭ 10 -12 pups to control for nutritional effects.…”