A stereoselective approach to peptidomimetic BACE1 inhibitors

• Published in: European journal of medicinal chemistry 2013-12, Vol.70, p.233-247
• Main Authors: Butini, Stefania, Gabellieri, Emanuele, Brindisi, Margherita, Giovani, Simone, Maramai, Samuele, Kshirsagar, Giridhar, Guarino, Egeria, Brogi, Simone, La Pietra, Valeria, Giustiniano, Mariateresa, Marinelli, Luciana, Novellino, Ettore, Campiani, Giuseppe, Cappelli, Andrea, Gemma, Sandra
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE1; Benzodiazepines; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HEK293 Cells; Humans; Inhibitors; Models, Molecular; Molecular Structure; Peptidomimetics; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Recombinant Proteins - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.09.056

Aiming at identifying new scaffolds to generate beta-secretase (BACE1) inhibitors we developed peptidomimetics based on a 1,4-benzodiazepine core (3a–d), their seco-analogs (4a–b), and linear analogs (5a–h), by stereoselective approaches. We herein discuss the synthesis, molecular modeling and in vitro studies for the newly developed ligands. Compounds 5c and 5h behaved as BACE1 inhibitors on the isolated enzyme and in cellular studies. Particularly, for its low molecular weight, inhibitor 5h is a prototypic hit to develop a series of BACE1 inhibitors more potent and active on whole-cells. [Display omitted] •Stereoselective synthesis of peptidomimetics.•Novel BACE1 inhibitors.•Inhibitors active on enzyme and cell-based assays.