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Design, Synthesis and Structure–Activity Relationship of Functionalized Tetrahydro-β-carboline Derivatives as Novel PDE5 Inhibitors

Authors

  • Nermin S. Ahmed,

    Corresponding author
    1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
    • Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. Fax: +20227581041.
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  • Bernard D. Gary,

    1. Division of Drug Discovery, Department of Biochemistry and Molecular Biology, Southern Research Institute, The University of Alabama at Birmingham, Birmingham, AL, USA
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  • Hethar N. Tinsley,

    1. Division of Drug Discovery, Department of Biochemistry and Molecular Biology, Southern Research Institute, The University of Alabama at Birmingham, Birmingham, AL, USA
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  • Gary A. Piazza,

    1. Division of Drug Discovery, Department of Biochemistry and Molecular Biology, Southern Research Institute, The University of Alabama at Birmingham, Birmingham, AL, USA
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  • Stefan Laufer,

    1. Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
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  • Ashraf H. Abadi

    1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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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 (IC50 = 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.

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