Abstract
The design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors, which possess new templates instead of a cyclohexane ring, are described. The mode of interaction with the enzyme is discussed based on the structure-activity relationship (SAR) data obtained for the synthesized inhibitors. Furthermore, the roles of three pharmacophores, a catechol moiety, a nitrile moiety, and acidic moieties, are discussed using in silico docking studies. More detailed biological evaluations of selected compounds are also presented.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
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Animals
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Binding Sites
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Bronchoconstriction / drug effects
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Computer Simulation
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Ferrets
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Gastric Emptying / drug effects
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Guinea Pigs
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Male
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Rats
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Rats, Sprague-Dawley
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Rolipram / chemistry
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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
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Vomiting / drug therapy
Substances
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Enzyme Inhibitors
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Heterocyclic Compounds, 4 or More Rings
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Tumor Necrosis Factor-alpha
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Rolipram