Abstract
To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism
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Administration, Oral
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Animals
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Binding Sites
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Catalytic Domain
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Dementia, Vascular / drug therapy
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Dementia, Vascular / pathology
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Disease Models, Animal
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Drug Design*
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Drug Evaluation, Preclinical
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Half-Life
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Humans
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Maze Learning / drug effects
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Mice
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Molecular Docking Simulation
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacology
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Phosphodiesterase Inhibitors / therapeutic use
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Pyrazoles / chemistry
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Pyrazoles / metabolism
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Pyrazoles / pharmacology
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Pyrazoles / therapeutic use
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Pyridines / chemistry
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Pyridines / metabolism
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Pyridines / pharmacology
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Pyridines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Phosphodiesterase Inhibitors
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Protein Isoforms
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Pyrazoles
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Pyridines
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pyrazolopyridine
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3',5'-Cyclic-AMP Phosphodiesterases
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PDE9A protein, human