Acetylcholinesterase (AChE) inhibitors are currently the first-line drugs approved by the FDA for the treatment of Alzheimer's disease (AD). However, a short effective-window limits their therapeutic benefits. Clinical studies have confirmed that the combination of AChE inhibitors and neuroprotective agents exhibits better anti-AD effects. We have previously reported that the dual AChE/GSK3β (Glycogen synthase kinase 3β) modulators have both neuroprotective effects and cognitive impairment-improvement effects. In this study, we characterized a new backbone of the AChE/GSK3β inhibitor 11c. It was identified as a highly potent AChE inhibitor and was found superior to donepezil, the first-line drug for the treatment of AD. In vivo studies confirmed that 11c significantly inhibited the activity of AChE in the brain but had little effect on the activity of AChE in the intestine. This advantage of 11c was expected to reduce the peripheral side effects caused by donepezil. Furthermore, biomarker studies have shown that 11c also improved the levels of acetylcholine and synaptophysin in the brain and exhibited neuroprotective effects. Preliminary in vivo and in vitro research results underline the exciting potential of compound 11c in the treatment of AD.

乙酰胆碱酯酶（AChE）抑制剂是目前 FDA 批准用于治疗阿尔茨海默病（AD）的一线药物。然而，较短的有效窗口限制了它们的治疗效果。临床研究证实，AChE 抑制剂和神经保护剂的组合表现出更好的抗 AD 作用。我们之前曾报道过双重 AChE/GSK3β（糖原合酶激酶 3β）调节剂具有神经保护作用和认知障碍改善作用。在这项研究中，我们表征了 AChE/GSK3β 抑制剂11c的新骨架。它被确定为一种高效的 AChE 抑制剂，并且优于多奈哌齐，后者是治疗 AD 的一线药物。体内研究证实，11c显着抑制脑内 AChE 的活性，但对肠内 AChE 的活性影响不大。预计11c 的这一优势将减少多奈哌齐引起的外周副作用。此外，生物标志物研究表明，11c还提高了大脑中乙酰胆碱和突触素的水平，并表现出神经保护作用。初步的体内和体外研究结果强调化合物的励磁潜在11C在AD的治疗。