Novel peptidomimetics as BACE-1 inhibitors: Synthesis,molecular modeling,and biological studies |
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Authors: | Stefania Butini Emanuele Gabellieri Margherita Brindisi Alice Casagni Egeria Guarino Paul B Huleatt Nicola Relitti Valeria La Pietra Luciana Marinelli Mariateresa Giustiniano Ettore Novellino Giuseppe Campiani Sandra Gemma |
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Institution: | 1. European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy;2. Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli ‘Federico II’, Via D. Montesano 49, I-80131 Napoli, Italy |
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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. |
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