title: A stereoselective approach to peptidomimetic BACE1 inhibitors.
abstract: 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.
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Emanuele
authors.initials: E
authors.lastname: Gabellieri
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Simone
authors.initials: S
authors.lastname: Giovani
authors.forename: Samuele
authors.initials: S
authors.lastname: Maramai
authors.forename: Giridhar
authors.initials: G
authors.lastname: Kshirsagar
authors.forename: Egeria
authors.initials: E
authors.lastname: Guarino
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Giustiniano
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D057786:Peptidomimetics; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: 1,4-benzodiazepine; AD; APP; Alzheimer's disease; BACE1; BDZ; Benzodiazepines; HEA; Inhibitors; Peptidomimetics; amyloid precursor protein; hydroxyethylamine; β-Secretase