Abstract
The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases
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Administration, Oral
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Animals
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Biological Availability
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Cell Line
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Dioxoles / chemical synthesis
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Dioxoles / chemistry*
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Dioxoles / pharmacology
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Dogs
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Injections, Intravenous
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Male
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Penile Erection / drug effects
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacology
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Phosphoric Diester Hydrolases / chemistry
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Phosphoric Diester Hydrolases / metabolism*
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Pyrroles / chemical synthesis
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Pyrroles / chemistry*
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Pyrroles / pharmacology
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Quinolones / chemical synthesis
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Quinolones / chemistry*
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Quinolones / pharmacology
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Rats
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Stereoisomerism
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Structure-Activity Relationship
Substances
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3-benzo(1,3)dioxol-5-yl-9-oxo-1,3,4,9-tetrahydropyrrolo(3,4-b)quinoline-2-carboxylic acid pyridin-4-ylmethyl ester
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Dioxoles
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Phosphodiesterase Inhibitors
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Pyrroles
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Quinolones
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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
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Pde5a protein, rat