Abstract
A new series of catechol hydrazines was synthesized and their structure-activity relationship (SAR) was analyzed for developing an effective phosphodiesterase 4 (PDE4) inhibitor as an anti-asthmatic drug candidate. Among the (E)-Analogues tested using in vitro assays, 5CC showed a strong PDE4 inhibitory activity and a significantly improved rolipram binding profile compared with rolipram, a prototype PDE4 inhibitor. Moreover, from in-vivo asthma model, we observed that (E)-Analogue 5CC had a good efficacy against guinea-pig respiratory tract inflammation and bronchoconstriction, along with a remarkably reduced emetic side effect, compared with rolipram. Conclusively, (E)-Analogue 5CC seems to be a promising candidate for the development of anti-asthmatic PDE4 inhibitors.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
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Animals
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Anti-Asthmatic Agents / adverse effects
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Anti-Asthmatic Agents / chemical synthesis*
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Anti-Asthmatic Agents / therapeutic use*
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Binding Sites / drug effects
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Brain / drug effects
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Brain / metabolism
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Bronchoalveolar Lavage Fluid / cytology
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Bronchoconstriction / drug effects
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Ferrets
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Guinea Pigs
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Hydrazines / chemical synthesis
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Hydrazines / therapeutic use
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In Vitro Techniques
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Inflammation / drug therapy
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Inflammation / pathology
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Models, Molecular
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Muscle Relaxation / drug effects
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Phosphodiesterase Inhibitors / adverse effects
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / metabolism
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Phosphodiesterase Inhibitors / therapeutic use*
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Rolipram / adverse effects
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Rolipram / metabolism
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Rolipram / therapeutic use
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Structure-Activity Relationship
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Trachea / drug effects
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Vomiting / chemically induced
Substances
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Anti-Asthmatic Agents
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Hydrazines
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Phosphodiesterase Inhibitors
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Rolipram