First non-ATP competitive glycogen synthase kinase 3 β (GSK-3β) inhibitors:: Thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease
First non-ATP competitive glycogen synthase kinase 3 β (GSK-3β) inhibitors:: Thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease
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DOI：
10.1021/jm011020u
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发表时间：
2002-03-14
影响因子：
7.3
通讯作者：
Moreno, FJ
中科院分区：
文献类型：
--
作者：
Martinez, A;Alonso, M;Moreno, FJ
糖原合成酶激酶3 β (gsk -3 β)在阿尔茨海默病（AD）中起核心作用。避免tau蛋白过度磷酸化的选择性抑制剂可能是治疗AD药物治疗和其他神经退行性疾病的有效方法。在这里，我们描述了小杂环噻二唑烷酮（TDZD）作为gsk -3 β的第一个非atp竞争性抑制剂的合成，生物学评价和SAR。它们的合成是基于亚砜酰氯的反应性。在gsk -3 β测定中，TDZD衍生物显示IC50值在微摩尔范围内，而在其他蛋白激酶测定中，它们没有任何抑制活性。SAR研究允许识别关键的结构特征。最后，提出了一种可能的酶结合模式。
Glycogen synthase kinase 3beta (GSK-3beta) has a central role in Alzheimer's disease (AD). Selective inhibitors which avoid tau hyperphosphorylation may represent an effective therapeutical approach to the AD pharmacotherapy and other neurodegenerative disorders. Here, we describe the synthesis, biological evaluation, and SAR of the small heterocyclic thiadiazolidinones (TDZD) as the first non-ATP competitive inhibitor of GSK-3beta. Their synthesis is based on the reactivity of sulfenyl chlorides. In GSK-3beta assays, TDZD derivatives showed IC50 values in the micromolar range, whereas in other protein kinases assays they were devoid of any inhibitory activity. SAR studies allowed the identification of the key structural features. Finally, a possible enzymatic binding mode is proposed.