Abstract
A series of potent chiral PDE5 inhibitors are described that are based on the sildenafil architecture but exhibit much greater selectivity over PDE6. Eudismic analysis of the SAR in this series provided a clear illustration of Pfeiffer's rule and indicated that the chiral motif was involved in a highly-stereoselective interaction with PDE5. This PDE5 specificity translated to levels of selectivity over PDE6 that were hitherto unprecedented in the sildenafil scaffold. UK-371,800 (compound 8) was identified as a development candidate from this series that married sildenafil-like molecular properties with high selectivity over PDE6. Clinical data confirm that UK-371,800 has markedly superior human pharmacokinetics to a previously-described higher molecular weight achiral analogue in this template (compound 1).
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors
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Combinatorial Chemistry Techniques
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Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors
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Dose-Response Relationship, Drug
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Erectile Dysfunction / drug therapy*
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Humans
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Male
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Molecular Structure
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Phosphodiesterase 5 Inhibitors*
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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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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacokinetics*
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Piperazines / pharmacology
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Purines / chemical synthesis
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Purines / chemistry
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Purines / pharmacokinetics
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Purines / pharmacology
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Sildenafil Citrate
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacokinetics*
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Sulfones / pharmacology
Substances
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Phosphodiesterase 5 Inhibitors
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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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UK-371,800
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Sildenafil Citrate
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3',5'-Cyclic-GMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 6