Abstract
A series of analogues of pentoxifylline metabolites were prepared in the purine, pteridine, [1,2,5]-thiadiazolo[3,4-d]pyrimidine, and quinazoline ring systems and evaluated for their ability to inhibit the production of tumor necrosis factor-alpha (TNF alpha) in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). The more active compounds were also tested for inhibition of cyclic AMP phosphodiesterase type IV (PDE IV) from human neutrophils in order to help determine their mechanism of action. Selected compounds which showed good activity in the in vitro TNF alpha assay were evaluated in an in vivo LPS-induced leukopenia model in mice. The most potent compounds in the TNF alpha assay, 6, 31, and 58, inhibited TNF alpha production at an IC50 of approximately 5 microM for each. Compound 58 was a very poor inhibitor of PDE IV but was the most active at preventing the leukopenia induced by TNF alpha in mice, providing more than 60% protection at 50 mg/kg. Thus, compounds such as 58, which are good inhibitors of TNF alpha production but are devoid of PDE IV inhibitory properties, may have potential as new antiinflammatory agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases*
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4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / pharmacology
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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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Cyclic Nucleotide Phosphodiesterases, Type 4
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Disease Models, Animal
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Female
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Humans
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Leukopenia / prevention & control
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Lipopolysaccharides / pharmacology
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Mice
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Mice, Inbred Strains
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Molecular Structure
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Monocytes / drug effects
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Monocytes / metabolism
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Neutrophils / drug effects
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Neutrophils / metabolism
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Pentoxifylline / analogs & derivatives
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / pharmacology
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Phosphoric Diester Hydrolases / metabolism
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Pteridines / chemical synthesis*
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Pteridines / pharmacology
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Tumor Necrosis Factor-alpha / analysis
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Xanthines / chemical synthesis*
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Xanthines / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Lipopolysaccharides
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Phosphodiesterase Inhibitors
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Pteridines
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Tumor Necrosis Factor-alpha
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Xanthines
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4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone
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Phosphoric Diester Hydrolases
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Pentoxifylline