Abstract
Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer's disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.
Publication types
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Research Support, N.I.H., Extramural
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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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Animals
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Blotting, Western
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Body Fluids / chemistry
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Catalytic Domain
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Crystallography, X-Ray
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Drug Discovery
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Gene Expression Regulation, Neoplastic / drug effects*
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Glucose-6-Phosphatase / antagonists & inhibitors*
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Hep G2 Cells
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Humans
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Hydrogen Bonding
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology*
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Mice
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Microsomes, Liver / drug effects*
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Phosphodiesterase Inhibitors / chemistry
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Phosphodiesterase Inhibitors / pharmacokinetics
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Phosphodiesterase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyrazoles / chemistry
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology*
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Pyrimidinones / chemistry
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Pyrimidinones / pharmacokinetics
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Pyrimidinones / pharmacology*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Structure-Activity Relationship
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Tissue Distribution
Substances
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2-((1-cyclopentyl-4-hydroxy-1H-pyrazolo(3,4-d)pyrimidin-6-yl)amino)-N-(4-methoxyphenyl)propanamide
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Hypoglycemic Agents
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Phosphodiesterase Inhibitors
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Pyrazoles
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Pyrimidinones
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RNA, Messenger
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phosphoenolpyruvate carboxylase kinase
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Protein Serine-Threonine Kinases
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Glucose-6-Phosphatase
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3',5'-Cyclic-AMP Phosphodiesterases
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PDE9A protein, human