Design and synthesis of bicyclic acetals as Beta Secretase (BACE1) inhibitors.

Riccardo Innocenti, Elena Lenci, Gloria Menchi, Alberto Pupi, Andrea Trabocchi

Journal: Bioorganic & medicinal chemistry 2017;25(19):5077-5083

PMID: 28359674

Full Text on Elsevier Science View on PubMed

Abstract

Taking advantage of the structural similarity between aspartic proteases, small-molecule peptidomimetic inhibitors that already showed activity towards Secreted Aspartic Protease 2 as anti-Candida agents and HIV protease inhibitors were exploited as potential BACE1 inhibitors. A focused library of 6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetic scaffolds was synthesized and assayed towards BACE1 enzyme, resulting in the identification of a thiolactam-containing hit compound possessing IC in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues.

Address: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.; Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy; Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy.; Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy; Department of Clinical and Experimental Biomedical Science "Mario Serio", University of Florence, Largo Brambilla 3, 50134 Florence, Italy; Azienda Ospedaliera Universitaria Careggi (AOUC), Largo Brambilla 3, 50134 Florence, Italy.; Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy; Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy. Electronic address: [email protected].

DOI: 10.1016/j.bmc.2017.03.030

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MeSH Terms: Acetals, Amino Acid Sequence, Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases, Azabicyclo Compounds, Drug Design, Enzyme Inhibitors, HIV Protease Inhibitors, Humans, Molecular Docking Simulation, Peptidomimetics, Sequence Alignment