Abstract
To further explore the structure-activity relationship around the chromeno[2,3- c]pyrrol-9(2 H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC50 of 0.32 nM with remarkable selectivity and druglike profile. Oral administration of 3 (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 mg/kg) against pulmonary arterial hypertension. Further, different binding patterns from sildenafil were revealed in cocrystal structures, which provide structural templates for discovery of highly potent PDE5 inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Crystallography, X-Ray
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ERG1 Potassium Channel / antagonists & inhibitors
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Hypertension, Pulmonary / drug therapy*
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Hypertension, Pulmonary / metabolism
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Hypertension, Pulmonary / pathology
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Microsomes, Liver / drug effects*
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Microsomes, Liver / metabolism
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Microsomes, Liver / pathology
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Models, Molecular
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Molecular Structure
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Phosphodiesterase 5 Inhibitors / administration & dosage*
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Phosphodiesterase 5 Inhibitors / chemistry
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Phosphodiesterase 5 Inhibitors / pharmacology*
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Protein Conformation
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Pulmonary Artery / drug effects*
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Pulmonary Artery / metabolism
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Pulmonary Artery / pathology
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Structure-Activity Relationship
Substances
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ERG1 Potassium Channel
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Phosphodiesterase 5 Inhibitors