Tacrines for Alzheimer's disease therapy. III. The PyridoTacrines
Tacrines for Alzheimer's disease therapy. III. The PyridoTacrines
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DOI：
10.1016/j.ejmech.2019.02.005
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发表时间：
2019-03-15
影响因子：
6.7
通讯作者：
Marco-Contelles, Jose
中科院分区：
文献类型：
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作者：
de los Rios, Cristobal;Marco-Contelles, Jose
他克林是1993年批准用于治疗阿尔茨海默病（AD）的第一种药物，由于其肝毒性，于2013年被撤回。然而，新的，非肝毒性的他克林衍生物一直在寻找。在这种情况下，自1997年以来，我们已经制备了一些双硫醚官能化的他克林通过改变他克林中存在的苯环的五元或六元芳环的核心，可以呈现抗胆碱酯酶活性和额外的药理学性质。这些新化合物被设计为他克林和众所周知的钙离子拮抗剂1，4-二氢吡啶之间的并置结构，目的是获得多靶点定向的AD配体。在这个帐户中，我们提出了我们的研究结果的PyridoTacrine（PyrTac）家庭的他克林类似物，从取代的苯环由吡啶。我们强调他们的药理学概况，并在文献中回顾类似物。第一组PyrTac显示胆碱酯酶（ChE）的抑制活性和电压门控Ca 2+通道（VGCC）的阻断特性。具有改善的胆碱酯酶抑制的第二个家族失去了VGCC阻断活性。然而，该家族的先导化合物（5 f）呈现磷酸酶2A（PP 2A）的活化特征，并在AD和中风的实验性体内模型中显示出有趣的结果。我们已经鉴定了PyrTac 5-氨基-2-甲基-6，7，8，9-四氢苯并[B] [1，8]萘啶-3-羧酸乙酯（5 f），其表现出除了单纯的胆碱能改善之外的其他药理学性质。这些新的性质值得关注的5 f和其进一步发展作为一个新的潜在的治疗剂，用于AD治疗。(C)2019 Elsevier Masson SAS。All rights reserved.
Tacrine was the first drug approved for the treatment of Alzheimer's disease (AD) in 1993, which was withdrawn in 2013 due to its hepatotoxicity. However, new, non-hepatotoxic tacrine derivatives have been constantly searched for. In this context, since 1997, we have prepared a number of diversely functionalized tacrines by changing the benzene ring present in tacrine to five- or six-membered aromatic ring cores that could present anticholinesterasic activity and additional pharmacological properties. The new compounds were designed as juxtaposed structures between tacrine and the well-known Ca2+ antagonists 1,4-dihydropyridines, with the goal of obtaining multi-target directed ligands for AD. In this account, we present our results on the PyridoTacrine (PyrTac) family of tacrine analogues, resulting from the substitution of the benzene ring by a pyridine. We highlight their pharmacological profile and review similar analogues in the literature. A first set of PyrTac showed inhibitory activity of cholines-terases (ChE) and a blocking profile of voltage-gated Ca2+ channels (VGCC). A second family with improved ChE inhibition lost VGCC blocking activity. However, the lead compound of this family (5f) presented an activating profile of the phosphatase 2A (PP2A) and showed interesting outcomes in experimental in vivo models of AD and stroke. We have identified the PyrTac ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b] [1,8]naphthyridine-3-carboxylate (5f), which presents additional pharmacological properties beyond the mere cholinergic improvement. These new properties warrant attention to 5f and its further development as a new potential therapeutic agent for AD therapy. (C) 2019 Elsevier Masson SAS. All rights reserved.