Abstract
Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Structure-activity relationship studies led to the identification of benzylamine-substituted phthalazinones as potent PDE4 inhibitors that also suppressed TNF-alpha production by whole rat blood cells. The most potent of these, when topically administered, were effective in a mouse model of dermatitis.
MeSH terms
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Animals
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Anti-Inflammatory Agents
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Benzylamines
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Blood Cells / metabolism
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Dermatitis / drug therapy
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Ketones
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Mice
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Phosphodiesterase 4 Inhibitors*
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / pharmacology
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Phthalazines / chemical synthesis*
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Phthalazines / pharmacology
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Rats
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Anti-Inflammatory Agents
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Benzylamines
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Ketones
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors
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Phthalazines
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Tumor Necrosis Factor-alpha
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benzylamine