State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.
School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, People's Republic of China.
J Med Chem. 2021 Feb 25;64(4):1844-1855. doi: 10.1021/acs.jmedchem.0c01863. Epub 2021 Feb 11.
The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between and AChE. Besides, the data from the phase I trials demonstrated that had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
乙酰胆碱酯酶 (AChE) 抑制剂仍然是治疗阿尔茨海默病 (AD) 的关键治疗药物。然而，安全性窗口低限制了它们的最大治疗效果。在这里，采用了一种新的基于动力学的药物设计策略来发现具有更长药物靶标停留时间和更大安全性窗口的新一代 AChE 抑制剂。经过详细研究，确定化合物 为一种高效、高选择性、可口服和优先分布于脑内的 AChE 抑制剂。此外，它以比多奈哌齐更低的有效剂量显著改善了不同小鼠模型的认知障碍。该复合物的 X 射线结构提供了 与 AChE 之间的精确结合模式。此外，I 期临床试验数据表明， 在健康志愿者的所有预设剂量下均具有良好的安全性、耐受性和药代动力学特征，为其在 AD 治疗的 II 期临床试验中进一步研究提供了坚实的基础。
