Abstract
Starting from ethyl beta-carboline-3-carboxylate (beta-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-beta-carboline derivatives has been identified as a novel chemical class of potent and selective PDE5 inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compound 2 and of the aromatic ring on position 5 led to the identification of compound 6e, a highly potent and selective PDE5 inhibitor, with greater selectivity for PDE5 vs PDE1-4 than sildenafil. Compound 6e demonstrated a long-lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy.
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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Cattle
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Cyclic GMP / biosynthesis
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Drug Design
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Hydantoins / chemical synthesis
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Hydantoins / pharmacology
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Indicators and Reagents
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Isomerism
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / pharmacology*
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Rats
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Rats, Inbred SHR
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Structure-Activity Relationship
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Tadalafil
Substances
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Carbolines
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Hydantoins
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Indicators and Reagents
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Phosphodiesterase Inhibitors
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Tadalafil
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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
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Cyclic GMP