Abstract
The (E)-[2-(4-Methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden](methyloxy)amine (5) and (arylmethyloxy)amines (6-12) were designed in order to verify the effects on the biological properties of the substitution of an aryl of selective diarylcyclopentenyl cyclooxygenase-2 (COX-2) inhibitors of type 3 with a methyleneaminoxymethyl moiety (MAOMM). Compounds 5-12 were tested in vitro for their inhibitory activity towards COX-1 and COX-2 by measuring prostaglandin E2 (PGE2) production in U937 cell lines and activated J774.2 macrophages, respectively. The compound with the highest in vitro activity towards COX-2 (9) was also assayed in vivo for its antiinflammatory activity by means of the carrageenan-induced paw edema test in rats. Some of the new compounds showed an appreciable in vitro COX-2 inhibitory activity, with IC(50) values in the microM (6,7,9,10,11) range. Compound 9 also exhibited an appreciable in vivo activity (29% inhibition at a dose of 30 mg kg(-1)) when administered intraperitoneally. The structural parameters of 9 were determined by X-ray crystallographic analysis.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Carrageenan
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Cell Line
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Crystallography, X-Ray
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Cyclooxygenase 1
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / chemical synthesis*
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Cyclooxygenase Inhibitors / pharmacology
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Cyclooxygenase Inhibitors / therapeutic use
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / pharmacology
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Edema / chemically induced
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Edema / drug therapy
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Heterocyclic Compounds, 2-Ring / chemical synthesis*
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Heterocyclic Compounds, 2-Ring / pharmacology
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Heterocyclic Compounds, 2-Ring / therapeutic use
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Isoenzymes / antagonists & inhibitors*
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Macrophages / drug effects
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Macrophages / metabolism
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Membrane Proteins
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Models, Molecular
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Prostaglandin-Endoperoxide Synthases
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Rats
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Sulfhydryl Compounds / chemical synthesis*
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Sulfhydryl Compounds / pharmacology
Substances
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(2-(4-methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden)(methyloxy)amine
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Cyclopentanes
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Heterocyclic Compounds, 2-Ring
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Isoenzymes
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Membrane Proteins
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Sulfhydryl Compounds
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Carrageenan
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Cyclooxygenase 1
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Ptgs1 protein, rat