Abstract
A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases
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Animals
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Cattle
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Dogs
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Drug Evaluation, Preclinical
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Humans
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In Vitro Techniques
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Male
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Muscles
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Penis / drug effects
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Penis / physiology
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Phosphodiesterase Inhibitors / chemical synthesis*
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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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Phosphoric Diester Hydrolases / metabolism*
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Quinazolines / chemical synthesis*
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Quinazolines / chemistry
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Quinazolines / pharmacokinetics
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Quinazolines / pharmacology
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Rabbits
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Rats
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Structure-Activity Relationship
Substances
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Phosphodiesterase Inhibitors
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Quinazolines
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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, human
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Pde5a protein, rat