Abstract
A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
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Animals
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Blood Pressure / drug effects
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Carbolines / chemical synthesis*
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Carbolines / pharmacology*
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Combinatorial Chemistry Techniques / methods
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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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Erectile Dysfunction / drug therapy
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Humans
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Isoenzymes
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Male
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Penis / drug effects
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Piperazines
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Purines
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Sildenafil Citrate
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Solubility
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Structure-Activity Relationship
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Sulfones
Substances
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Carbolines
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Isoenzymes
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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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3',5'-Cyclic-GMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 5
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PDE5A protein, human