title: Design and synthesis of bicyclic acetals as Beta Secretase (BACE1) inhibitors.
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 IC50in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues.
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Innocenti
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Lenci
authors.affiliation: 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.
authors.forename: Gloria
authors.initials: G
authors.lastname: Menchi
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pupi
authors.affiliation: 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: andrea.trabocchi@unifi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Trabocchi
mesh_terms: D000080:Acetals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016415:Sequence Alignment
chemical_list: D000080:Acetals; D053961:Azabicyclo Compounds; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D057786:Peptidomimetics; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; Amino acids; Drug discovery; Enzyme inhibition; Peptidomimetics