Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE-1 and GSK-3β Inhibitors

被引：114

作者：

Prati, Federica ^{[1
,2
]}

De Simone, Angela ^{[1
,3
]}

Bisignano, Paola ^{[1
]}

Armirotti, Andrea ^{[1
]}

Summa, Maria ^{[1
]}

Pizzirani, Daniela ^{[1
]}

Scarpelli, Rita ^{[1
]}

Perez, Daniel I. ^{[4
]}

Andrisano, Vincenza ^{[3
]}

Perez-Castillo, Ana ^{[5
,6
]}

Monti, Barbara ^{[2
]}

Massenzio, Francesca ^{[2
]}

Polito, Letizia ^{[7
]}

Racchi, Marco ^{[8
]}

Favia, Angelo D. ^{[1
]}

Bottegoni, Giovanni ^{[1
]}

Martinez, Ana ^{[4
]}

Bolognesi, Maria Laura ^{[2
]}

Cavalli, Andrea ^{[1
,2
]}

机构：

[1] Ist Italiano Tecnol, I-16163 Genoa, Italy

[2] Univ Bologna, Dept Pharm & Biotechonol, I-40126 Bologna, Italy

[3] Univ Bologna, Dept Life Qual Studies, I-47921 Rimini, Italy

[4] CSIC, Ctr Invest Biol, Madrid 28040, Spain

[5] CSIC UAM, Inst Invest Biomed, Madrid 28029, Spain

[6] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain

[7] Fdn Golgi Cenci, I-20081 Milan, Italy

[8] Univ Pavia, Dept Drug Sci Pharmacol, I-27100 Pavia, Italy

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2015年 / 54卷 / 05期

关键词：

drug design; drug discovery; enzymes; heterocycles; neurochemistry; GLYCOGEN-SYNTHASE KINASE-3; DERIVATIVES; ACID;

D O I：

10.1002/anie.201410456

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3 beta. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03 +/- 0.01) mu m and (14.67 +/- 0.78) mu m for BACE-1 and GSK-3 beta, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.

引用

页码：1578 / 1582

页数：5

共 34 条

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