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Design, synthesis and structure-activity relationship of functionalized tetrahydro-?-carboline derivatives as novel PDE5 inhibitors.

ABSTRACT: Starting from tadalafil as a template, a series of functionalized tetrahydro-?-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.

SUBMITTER: Ahmed NS

PROVIDER: S-EPMC4980839 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Design, synthesis and structure-activity relationship of functionalized tetrahydro-β-carboline derivatives as novel PDE5 inhibitors.

Ahmed Nermin S NS Gary Bernard D BD Tinsley Hethar N HN Piazza Gary A GA Laufer Stefan S Abadi Ashraf H AH

Archiv der Pharmazie 20101222 3

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 sel ...[more]

PMID: 21384413

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