Abstract
To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor α-mangostin (IC50 = 1.31 μM). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor 4e (IC50 = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of 4e at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / metabolism
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Animals
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Benzamides / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
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Cyclopropanes / metabolism
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Dementia, Vascular / drug therapy*
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Dogs
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Drug Design
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Humans
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Male
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Mice, Inbred C57BL
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Molecular Structure
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Phosphodiesterase 4 Inhibitors / chemical synthesis
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Phosphodiesterase 4 Inhibitors / metabolism
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Phosphodiesterase 4 Inhibitors / pharmacokinetics
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Phosphodiesterase 4 Inhibitors / therapeutic use*
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Protein Binding
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Rolipram / metabolism
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Rolipram / therapeutic use
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Structure-Activity Relationship
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Vomiting / prevention & control
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Xanthones / chemical synthesis
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Xanthones / metabolism
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Xanthones / pharmacokinetics
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Xanthones / therapeutic use*
Substances
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Aminopyridines
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Benzamides
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Cyclopropanes
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Phosphodiesterase 4 Inhibitors
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Xanthones
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Roflumilast
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE4D protein, mouse
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Rolipram
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mangostin