Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
Eur J Pharm Sci. 2013 Jul 16;49(4):603-13. doi: 10.1016/j.ejps.2013.04.024. Epub 2013 May 2.
Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid β fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC₅₀=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.
鉴于阿尔茨海默病（AD）的多因素性质，预计针对多个疾病修饰或治疗靶点进行治疗将具有极大优势。在这里，根据胆碱能假说，我们旨在同时抑制乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE），以增加突触间隙中的乙酰胆碱浓度。此外，还应抑制淀粉样β纤维的形成并破坏已形成的纤维。基于最近发现的一种具有 1,4-取代的 4-(1H)-吡啶亚基肼骨架的 AChE 抑制剂，我们生成了一个化合物库，并对其抑制 AChE、BuChE 和纤维形成的活性进行了测试。通过 Transwell 测定确保了血脑屏障的通透性。虽然带正硝基取代的化合物 18C 在纳摩尔浓度范围内显示出抗 AChE 活性（IC₅₀=90 nM），但双萘基取代的化合物 20L 被发现是 AChE/BuChE 的最佳抑制剂，并增强了纤维的破坏。
