Korea Institute of Science and Technology, 39-1 Hawolgog-dong, Seoul 136-791, Republic of Korea.
Bioorg Med Chem. 2012 Aug 15;20(16):4921-35. doi: 10.1016/j.bmc.2012.06.045. Epub 2012 Jul 3.
Aggregated β-amyloid (Aβ) plays crucial roles in Alzheimer's disease (AD) pathogenesis, therefore blockade of Aβ aggregation is considered as a potential therapeutic target. We designed and synthesized small molecules to reduce Aβ-induced cytotoxicity by inhibiting Aβ aggregation. The small molecules were screened via ThT, MTT, and cell-based cytotoxicity assay (Aβ burden assay). Selected compounds 1c, 1d, 1e, and 1f were then investigated by evaluating their effects on cognitive impairment of acute AD mice model. Learning and memory dysfunction by injection of Aβ(1-42) was recovered by administration of these molecules. Especially, 1d showed the best recovery activity in Y-maze task, object recognition task, and passive avoidance task with dose dependent manner. These results suggest that 1d has high potential as a therapeutic agent for AD.
聚集态的β-淀粉样蛋白（Aβ）在阿尔茨海默病（AD）的发病机制中起着关键作用，因此抑制 Aβ聚集被认为是一种有潜力的治疗靶点。我们设计并合成了小分子，通过抑制 Aβ聚集来降低 Aβ 诱导的细胞毒性。通过 ThT、MTT 和基于细胞的细胞毒性测定（Aβ负担测定）筛选小分子。然后通过评估它们对急性 AD 小鼠模型认知障碍的影响来研究选定的化合物 1c、1d、1e 和 1f。通过注射 Aβ（1-42）引起的学习和记忆功能障碍，通过给予这些分子得到了恢复。特别是，化合物 1d 在 Y 迷宫任务、物体识别任务和被动回避任务中表现出最佳的恢复活性，具有剂量依赖性。这些结果表明，1d 具有作为 AD 治疗剂的高潜力。
