| 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 I: in vitro studies. | |
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MedLine Citation:
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PMID: 11805219 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Leukotriene (LT) B(4) is an inflammatory mediator that has been implicated in the pathogenesis of various diseases, including inflammatory bowel disease and psoriasis. As the rate-limiting step for LTB(4) production, LTA(4) hydrolase represents an attractive target for therapeutic agents that interfere with LTB(4) production. In the present study we evaluated a chemically novel compound designated SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) as an inhibitor of LTA(4) hydrolase. Pharmacological comparisons are made to its free acid SC-57461. SC-57461A is a potent competitive inhibitor of recombinant human LTA(4) hydrolase when either LTA(4) (IC(50) = 2.5 nM, K(i) = 23 nM) or peptide substrates (IC(50) = 27 nM) are used. In human whole blood, the IC(50) for calcium ionophore-induced LTB(4) production was 49 nM, indicative of good cell penetration. Whole blood production of the cyclooxygenase metabolite thromboxane B(2) was not affected. SC-57461A was also active in several other species, including mouse, rat, dog, and rhesus monkey. The data indicate that SC-57461A is a potent and selective inhibitor of LTA(4) hydrolase. |
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Authors:
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Leslie J Askonas; James F Kachur; Doreen Villani-Price; Chi-Dean D Liang; Mark A Russell; Walter G Smith |
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Publication Detail:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 300 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2002 Feb |
Date Detail:
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Created Date: 2002-01-25 Completed Date: 2002-02-25 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 577-82 Citation Subset: IM |
Affiliation:
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Pharmacia Research and Development, Skokie, Illinois, USA. leslie.j.askonas@pharmacia.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aminopeptidases
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metabolism Animals Arachidonic Acid / metabolism Chromatography, High Pressure Liquid Dogs Eicosanoids / biosynthesis, blood Enzyme Inhibitors / pharmacology* Enzyme-Linked Immunosorbent Assay Epoxide Hydrolases / antagonists & inhibitors*, metabolism Humans Ionophores / pharmacology Kinetics Leukotriene A4 / metabolism Leukotriene Antagonists / pharmacology* Macaca mulatta Mice Rats Recombinant Proteins / metabolism Species Specificity Substrate Specificity beta-Alanine / analogs & derivatives*, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Eicosanoids; 0/Enzyme Inhibitors; 0/Ionophores; 0/Leukotriene A4; 0/Leukotriene Antagonists; 0/Recombinant Proteins; 0/SC 57461; 107-95-9/beta-Alanine; 506-32-1/Arachidonic Acid; EC 3.3.2.-/Epoxide Hydrolases; EC 3.3.2.-/leukotriene A4 hydrolase; EC 3.4.11.-/Aminopeptidases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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