Lo Monte Fabio, Kramer Thomas, Gu Jiamin, Brodrecht Martin, Pilakowski Johannes, Fuertes Ana, Dominguez Juan Manuel, Plotkin Batya, Eldar-Finkelman Hagit, Schmidt Boris
Clemens Schöpf - Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstrasse 22, 64287 Darmstadt, Germany.
Eur J Med Chem. 2013 Mar;61:26-40. doi: 10.1016/j.ejmech.2012.06.006. Epub 2012 Jun 12.
Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases β-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3α and β, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3α and 17 nM for GSK-3β. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3α over GSK-3β, with an IC50 of 35 nM for GSK-3α. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety.
抑制糖原合酶激酶-3（GSK-3）可诱导神经保护作用，例如减少β-淀粉样蛋白生成并降低tau蛋白过度磷酸化，这两者均与阿尔茨海默病（AD）相关。哺乳动物中的两种GSK-3同工型为GSK-3α和β，它们在催化结构域中具有98%的同源性。我们基于两种不同的骨架研究了GSK-3抑制剂，以阐明ATP结合口袋的需求[1]。特别是，恶二唑骨架提供了强效且选择性的GSK-3抑制剂。例如，本系列中最有效的抑制剂乙酰胺26d，对GSK-3α的IC50为2 nM，对GSK-3β的IC50为17 nM。此外，苯并二恶烷8g对GSK-3α的选择性比对GSK-3β高27倍，对GSK-3α的IC50为35 nM。进一步在野生型（wt）斑马鱼胚胎试验中对两种GSK-3抑制剂的功效和毒性进行了分析，以同时评估其通透性和安全性。
