Novel peptidomimetics as BACE-1 inhibitors: Synthesis, molecular modeling, and biological studies

• Published in: Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (1), p.85-89
• Main Authors: Butini, Stefania, Gabellieri, Emanuele, Brindisi, Margherita, Casagni, Alice, Guarino, Egeria, Huleatt, Paul B., Relitti, Nicola, La Pietra, Valeria, Marinelli, Luciana, Giustiniano, Mariateresa, Novellino, Ettore, Campiani, Giuseppe, Gemma, Sandra
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; BACE-1; Benzodiazepines; Benzodiazepines - chemistry; Binding Sites; Catalytic Domain; chemistry; HEK293 Cells; Humans; in vitro studies; Memapsin 2; Models, Chemical; Molecular Docking Simulation; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - metabolism; pharmacokinetics; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Protein Binding; Stereoisomerism; Structure-Activity Relationship; Transfection; β-Secretase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.011

Aiming at identifying new scaffolds for BACE-1 inhibition devoid of the pharmacokinetic drawbacks of peptide-like structures, we investigated a series of novel peptidomimetics based on a 1,4-benzodiazepine (BDZ) core 1a–h and their seco-analogues 2a–d. We herein discuss synthesis, molecular modeling and in vitro studies which, starting from 1a, led to the seco-analogues (R)-2c and (S)-2d endowed with BACE-1 inhibition properties in the micromolar range both on the isolated enzyme and in cellular studies. These data can encourage to pursue these analogues as hits for the development of a new series of BACE-1 inhibitors active on whole-cells.