Novel peptidomimetics as BACE-1 inhibitors: Synthesis, molecular modeling, and biological studies Stefania Butini a , Emanuele Gabellieri a , Margherita Brindisi a , Alice Casagni a , Egeria Guarino a , Paul B. Huleatt a , Nicola Relitti a , Valeria La Pietra a,b , Luciana Marinelli a,b , Mariateresa Giustiniano a,b , Ettore Novellino a,b , Giuseppe Campiani a,⇑ , Sandra Gemma a a European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy b Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli ‘Federico II’, Via D. Montesano 49, I-80131 Napoli, Italy article info Article history: Received 11 September 2012 Revised 31 October 2012 Accepted 6 November 2012 Available online 14 November 2012 Keywords: BACE-1 Benzodiazepines Alzheimer’s disease Memapsin 2 b-Secretase 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. Ó 2012 Elsevier Ltd. All rights reserved. Alzheimer’s disease (AD), one of the most prevalent neurode- generative disorders among the elderly, is pathologically charac- terized by the extracellular accumulation of amyloid-b (Ab) plaques and by intracellular neurofibrillary tangles. Considerable evidence indicates a central role of the Ab peptide and its aggrega- tion in the pathogenesis of AD. 1 High levels of soluble Ab peptides correlate to cognitive decline in AD 2,3 and the original amyloid cas- cade hypothesis has evolved to propose that soluble oligomeric Ab assemblies precede deposition and are the proximal cause of syn- aptic dysfunction and early impairment in AD. 4 Ab40 and Ab42 5 are the two major isoforms of Ab found in AD brains. Although the Ab40 is the most abundant isoform, Ab42 is enriched in AD brains as it progressively accumulates into extracellular senile pla- ques. 4 The proteolytic enzyme b-secretase (BACE-1) catalyzes the rate-limiting step of the Ab generation by cleaving the Met671– Asp672 peptide bond of amyloid precursor protein (APP) at the extracellular space. 6,7 Currently available therapies for AD only treat disease symptoms and do not address the underlying disease processes. 8 On the basis of a number of seminal in vitro and in vivo studies the aspartic protease BACE-1 has been recognized as a rel- evant drug target for the development of AD disease-modifying therapies. 9 BACE-1 potent inhibitors have been produced by aca- demic and industrial research. 10 However very few of them fulfill the requirements for in vivo biological and clinical studies and only recently, orally available highly efficient BACE-1 inhibitors became available. 11 To identify new scaffolds for BACE-1 inhibition to over- come the well-known pharmacokinetic drawbacks of peptide-like structures, we decided to search for novel peptidomimetic com- pounds based on the C 8 /C 9 -substituted 1,4-benzodiazepine (BDZ) structural system or on the seco-1,4-BDZ scaffold, represented by the core structures 1 and 2 depicted in Figure 1. The BDZ system has not been explored to date for developing BACE-1 inhibitors, and the BDZ system is one of the most impor- tant privileged pharmacogenic structures for drug discovery en- dowed with a high degree of druggability. This prompted us to develop compounds 1a–h. Furthermore, we recently discovered a versatile synthetic protocol for the synthesis of C 8 and C 9 modified 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.11.011 ⇑ Corresponding author. Tel.: +39 0577 234172; fax: +39 0577 234333. E-mail address: campiani@unisi.it (G. Campiani). N * H N O R 1 * = (R) or (S) config R and R 1 as defined in Table 1 O NH * NHCbz O R 1 R R 1a-h 2a-d Figure 1. Title compounds: benzodiazepines 1a–h and seco-analogues 2a–d. Bioorganic & Medicinal Chemistry Letters 23 (2013) 85–89 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl