Abstract
A solid-phase route for the preparation of 4a,5,8,8a-tetrahydrophthalazinon-1-ones employing the Diels-Alder reaction has been developed. Some of the new compounds have been tested for inhibition of LPS-stimulated TNF-alpha production in human whole blood from patients with chronic obstructive pulmonary disease (COPD). This evaluation revealed two compounds 17 and 18 of interest, incorporating an arylpiperazine moiety, which were found to inhibit LPS-induced TNF-alpha release like the well known anti-inflammatory PDE4 inhibitors, rolipram and roflumilast.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
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Aminopyridines / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Benzamides / pharmacology
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Cyclopropanes / pharmacology
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Drug Design
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Drug Evaluation, Preclinical
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Humans
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Molecular Structure
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / chemistry
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Phosphodiesterase Inhibitors / pharmacology*
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Phthalazines / chemical synthesis*
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Phthalazines / chemistry
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Phthalazines / pharmacology*
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Pulmonary Disease, Chronic Obstructive / blood*
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Rolipram / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / drug effects
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Aminopyridines
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Anti-Inflammatory Agents, Non-Steroidal
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Benzamides
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Cyclopropanes
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Lipopolysaccharides
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Phosphodiesterase Inhibitors
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Phthalazines
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Tumor Necrosis Factor-alpha
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Roflumilast
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Rolipram
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azelastine