Abstract
The synthesis and biological activity of a novel series of 2, 2-disubstituted indan-1,3-dione-based PDE4 inhibitors are described. This structurally unique class of PDE4 inhibitors is markedly different from the known PDE4 inhibitors such as RP 73401 (2) and CDP 840 (3). Structure-activity relationship (SAR) studies led to the identification of inhibitors with nanomolar potency and oral activity in a murine endotoxemia model for TNF-alpha inhibition. Unlike other classical PDE4 inhibitors, several analogues were found to be nonemetic in a canine emesis model at intravenous doses of up to 3 mg/kg.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
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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 / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / toxicity
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / pharmacology
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Benzamides / toxicity
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Brain / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Dogs
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Endotoxemia / metabolism
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Female
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Guinea Pigs
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In Vitro Techniques
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Lipopolysaccharides / toxicity
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / enzymology
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Male
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Mice
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Mice, Inbred BALB C
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Models, Molecular
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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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Phosphodiesterase Inhibitors / toxicity
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Pyridines / toxicity
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Vomiting / chemically induced
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Benzamides
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Lipopolysaccharides
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Phosphodiesterase Inhibitors
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Pyridines
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Tumor Necrosis Factor-alpha
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CDP 840
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4
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piclamilast