Abstract
Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases
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Animals
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Genitalia, Male / drug effects
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In Vitro Techniques
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Indicators and Reagents
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Isoenzymes / antagonists & inhibitors
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Male
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Muscle Relaxation / drug effects
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Muscle, Smooth / drug effects
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Naphthyridines / chemical synthesis*
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Naphthyridines / pharmacology*
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphoric Diester Hydrolases / drug effects*
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Piperazines / pharmacology
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Purines
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Rabbits
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Sildenafil Citrate
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Structure-Activity Relationship
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Sulfones
Substances
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Indicators and Reagents
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Isoenzymes
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Naphthyridines
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Phosphodiesterase Inhibitors
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Piperazines
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Purines
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Sulfones
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Sildenafil Citrate
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Phosphoric Diester Hydrolases
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3',5'-Cyclic-GMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 5