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

Publication date: Available online 18 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Riccardo Innocenti, Elena Lenci, Gloria Menchi, Alberto Pupi, Andrea Trabocchi
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

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