Pharmacological Characterization of SC-57461A (3-[Methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic Acid HCl), a Potent and Selective Inhibitor of Leukotriene A4Hydrolase I: In Vitro Studies
| Autor: | Leslie J Askonas, Mark A Russell, Walter G. Smith, James F. Kachur, Chi-Dean D. Liang, D Villani-Price |
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| Rok vydání: | 2002 |
| Předmět: |
beta-Alanine
Enzyme-Linked Immunosorbent Assay In Vitro Techniques Pharmacology Aminopeptidases Substrate Specificity Mice chemistry.chemical_compound Dogs Species Specificity In vivo Hydrolase Animals Humans Enzyme Inhibitors Epoxide hydrolase Chromatography High Pressure Liquid Epoxide Hydrolases Leukotriene Arachidonic Acid Ionophores Leukotriene A4 Macaca mulatta Recombinant Proteins Rats Kinetics chemistry Biochemistry Eicosanoids Leukotriene Antagonists Molecular Medicine Arachidonic acid Ex vivo |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 300:577-582 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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. SC-57461A (3-[methyl[3-[4-phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) is a potent inhibitor of human recombinant LTA(4) hydrolase (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 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) = 0.3-1 mg/kg) without affecting LTC(4) or 6-keto-prostaglandin F(1alpha) 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 microg/ml, which corresponds to >80% 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. |
| Databáze: | OpenAIRE |
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