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,Ki 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 F1αproduction. 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.
Footnotes
- Abbreviations:
- SC-57461A
- 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl
- LT
- leukotriene
- AA
- arachidonic acid
- 5-LO
- 5-lipoxygenase
- DMSO
- dimethyl sulfoxide
- ELISA
- enzyme-linked immunoassay
- PGF1α
- prostaglandin F1α
- RPA
- reversed passive Arthus
- PBS
- phosphate-buffered saline
- TxB2
- thromboxane B2
- A23187
- calcium ionophore A23187(Calcimycin)
- RP64966
- omega-[(omega-arylalkyl)aryl]alkanoic acid
- Received July 17, 2001.
- Accepted November 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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