Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5610-5. doi: 10.1016/j.bmcl.2011.06.131. Epub 2011 Jul 18.
The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer's disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure-activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC(50)=140 nM) and the pyridylurea 62 (IC(50)=98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC(50)=330 nM) in our assays.
糖原合酶激酶 3（GSK-3）参与多种细胞过程，并与阿尔茨海默病（AD）的发病机制有关。在我们的研究课题中，我们合成了一系列有效的 GSK-3 抑制剂文库。我们利用了强效且高度选择性的 GSK-3 抑制剂 AR-A014418（阿斯利康）中存在的脲骨架。该部分既适合（a）利用易得的构建块的收敛方法，也适合（b）基于微波加热辅助 Suzuki 偶联的发散方法。我们建立了一种无色谱纯化方法，以生成具有足够纯度的产物，用于生物测定。文库的构效关系为合成苯并噻唑基脲 66（IC50=140 nM）和吡啶基脲 62（IC50=98 nM）提供了依据，与我们的测定中参考化合物 18（AR-A014418：IC50=330 nM）相比，这两种化合物的活性提高了两到三倍。
