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

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

doi:10.1016/j.bmc.2017.03.030

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

Bioorg Med Chem. 2017 Oct 1;25(19):5077-5083. doi: 10.1016/j.bmc.2017.03.030. Epub 2017 Mar 18.

Authors

Riccardo Innocenti¹, Elena Lenci¹, Gloria Menchi², Alberto Pupi³, Andrea Trabocchi⁴

Affiliations

¹ Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
² 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.
³ 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.
⁴ 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.

PMID: 28359674
DOI: 10.1016/j.bmc.2017.03.030

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 IC₅₀ 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.

Keywords: Alzheimer’s disease; Amino acids; Drug discovery; Enzyme inhibition; Peptidomimetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetals / chemical synthesis
Acetals / chemistry
Acetals / pharmacology
Amino Acid Sequence
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Aspartic Acid Endopeptidases / metabolism
Azabicyclo Compounds / chemical synthesis
Azabicyclo Compounds / chemistry*
Azabicyclo Compounds / pharmacology*
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
HIV Protease Inhibitors / chemistry
HIV Protease Inhibitors / pharmacology
Humans
Molecular Docking Simulation
Peptidomimetics / chemical synthesis
Peptidomimetics / chemistry*
Peptidomimetics / pharmacology*
Sequence Alignment

Substances

Acetals
Azabicyclo Compounds
Enzyme Inhibitors
HIV Protease Inhibitors
Peptidomimetics
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human