title: Novel peptidomimetics as BACE-1 inhibitors: synthesis, molecular modeling, and biological studies.
abstract: 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.
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di 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: Alice
authors.initials: A
authors.lastname: Casagni
authors.forename: Egeria
authors.initials: E
authors.lastname: Guarino
authors.forename: Paul B
authors.initials: PB
authors.lastname: Huleatt
authors.forename: Nicola
authors.initials: N
authors.lastname: Relitti
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Giustiniano
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001569:Benzodiazepines / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D057809:HEK293 Cells; D006801:Humans; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D057786:Peptidomimetics; D011480:Protease Inhibitors; D001569:Benzodiazepines; D053829:Amyloid Precursor Protein Secretases