Abstract
To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound 3a (IC50 = 0.010 μM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, 3a bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 Å with Tyr748, which possibly interprets the 220-fold selectivity of 3a against PDE2A. Additionally, oral administration of compound 3a achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.
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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Adenine / analogs & derivatives*
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Adenine / chemistry
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Adenine / metabolism
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Adenine / pharmacology
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Adenine / therapeutic use
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Administration, Oral
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Animals
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Behavior, Animal / drug effects
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Binding Sites
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Crystallography, X-Ray
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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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Half-Life
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Humans
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Inhibitory Concentration 50
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Mice
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Molecular Dynamics Simulation
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / metabolism
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Phosphodiesterase Inhibitors / pharmacology
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Phosphodiesterase Inhibitors / 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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Isoenzymes
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Phosphodiesterase Inhibitors
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2-chloroadenine
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3',5'-Cyclic-AMP Phosphodiesterases
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PDE8A protein, human
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Adenine