Abstract
Starting from tadalafil as a template, a series of functionalized tetrahydro-β-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4-methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC(50) = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carbolines / chemical synthesis
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Carbolines / chemistry
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Carbolines / pharmacology*
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Cyclic AMP / metabolism
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Cyclic GMP / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 5 / drug effects*
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Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
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Drug Design
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Humans
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Inhibitory Concentration 50
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Phosphodiesterase 5 Inhibitors / chemical synthesis
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Phosphodiesterase 5 Inhibitors / chemistry
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Phosphodiesterase 5 Inhibitors / pharmacology*
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Structure-Activity Relationship
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Tadalafil
Substances
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Carbolines
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Phosphodiesterase 5 Inhibitors
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tryptoline
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Tadalafil
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Cyclic AMP
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Cyclic GMP