Butyrylcholinesterase (BChE) has been more and more attractive for treating neurodegenerative diseases, especially Alzheimer's disease (AD). In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC₅₀ values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC₅₀ = 2.94 nM, hBChE IC₅₀ = 34.6 nM, and 20, eqBChE IC₅₀ = 0.15 nM, hBChE IC₅₀ = 45.2 nM) have been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments. Two candidates exhibited remarkable neuroprotective properties and cognition improving activity, by benefiting cholinergic system, reducing the total Aβ amount and increasing the ghrelin content. Simultaneous modulation in the center and periphery greatly improves the efficiency of BChE inhibitors. Considering the regulation on ghrelin level, BChE inhibition could improve not only symptoms but also nutritional status of AD patients.

丁酰胆碱酯酶 (BChE) 在治疗神经退行性疾病，尤其是阿尔茨海默病 (AD) 方面越来越有吸引力。在这项研究中，我们根据之前报道的结构进行了活性和成药性优化。大多数化合物表现出显着的 BChE 抑制能力，具有纳摩尔 IC ₅₀值。基于抑制活性和细胞安全性评估的结果，两种化合物（7，eq BChE IC ₅₀  = 2.94 nM，h BChE IC ₅₀  = 34.6 nM，和20，eq BChE IC ₅₀  = 0.15 nM，h BChE IC ₅₀ = 45.2 nM) 已被选为候选者。化合物20的高稳定性有助于显着改善血液浓度和组织暴露，从而降低药效学实验中的给药和有效剂量。两种候选药物通过有益于胆碱能系统、降低总 Aβ 量和增加生长素释放肽含量，表现出显着的神经保护特性和认知改善活性。中心和外围的同时调制大大提高了 BChE 抑制剂的效率。考虑到对生长素释放肽水平的调节，抑制 BChE 不仅可以改善 AD 患者的症状，还可以改善营养状况。