Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE-1 and GSK-3β Inhibitors
Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE-1 and GSK-3β Inhibitors
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DOI：
10.1002/anie.201410456
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发表时间：
2015-01-26
影响因子：
16.6
通讯作者：
Cavalli, Andrea
中科院分区：
文献类型：
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作者：
Prati, Federica;De Simone, Angela;Cavalli, Andrea
累积的证据强烈支持淀粉样蛋白和tau蛋白假说不是相互排斥的，而是伴随着阿尔茨海默病（AD）中的神经变性。因此，参与这两种途径的多靶点药物的开发可能是一个有前途的治疗策略。因此，本文报道了6-氨基-4-苯基-3，4-二氢-1，3，5-三嗪-2（1H）-酮作为能够同时调节BACE-1和GSK-3 β的第一类分子的发现。值得注意的是，一种三嗪酮显示出对两种酶的良好平衡的体外效力（对BACE-1和GSK-3 β的IC 50分别为（18.03 +/- 0.01）μ m和（14.67 +/- 0.78）μ m）。在基于细胞的测定中，它显示出有效的神经保护和神经原活性，并且没有神经毒性。在小鼠中的初步药代动力学评估中，它还显示出良好的脑渗透性。总的来说，三嗪酮可能是一个有前途的起点，高品质的铅化合物与AD修改的潜力。
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.