新型基于苯并咪唑的拟不可逆丁酰胆碱酯酶抑制剂，在阿尔茨海默病小鼠模型中具有神经保护活性。
Novel benzimidazole-based pseudo-irreversible butyrylcholinesterase inhibitors with neuroprotective activity in an Alzheimer's disease mouse model.
作者信息
Spatz Philipp, Zimmermann Thomas, Steinmüller Sophie, Hofmann Julian, Maurice Tangui, Decker Michael
机构信息
Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg Am Hubland D-97074 Germany
MMDN, University of Montpellier, EPHE, INSERM F-34095 Montpellier France.
出版信息
RSC Med Chem. 2022 Jun 20;13(8):944-954. doi: 10.1039/d2md00087c. eCollection 2022 Aug 17.
Abstract
As levels of acetylcholinesterase (AChE) decrease while levels of butyrylcholinesterase (BChE) increase in later stages of Alzheimer's disease (AD), BChE stands out as a promising target for treatment of AD. Therefore, several benzimidazole-carbamates were designed based on docking studies to inhibit BChE selectively over AChE, while retaining a reasonable solubility. Synthesized molecules exhibit IC values from 2.4 μM down to 3.7 nM with an overall highly hBChE-selective profile of the designed compound class. After evaluation of potential neurotoxicity, the most promising compound was further investigated . Compound 11d attenuates Aβ-induced learning impairments in both spontaneous alternation and passive avoidance responses at a very low dosage of 0.03 mg kg, proving selective BChE inhibition to lead to effective neuroprotectivity in AD.
摘要
在阿尔茨海默病（AD）后期，随着乙酰胆碱酯酶（AChE）水平下降而丁酰胆碱酯酶（BChE）水平上升，BChE成为AD治疗的一个有前景的靶点。因此，基于对接研究设计了几种苯并咪唑氨基甲酸酯，以选择性抑制BChE而非AChE，同时保持合理的溶解度。合成的分子表现出2.4 μM至3.7 nM的IC值，所设计的化合物类别总体上具有高度的hBChE选择性特征。在评估潜在神经毒性后，对最有前景的化合物进行了进一步研究。化合物11d在0.03 mg/kg的极低剂量下，可减轻Aβ诱导的自发交替和被动回避反应中的学习障碍，证明选择性抑制BChE可在AD中产生有效的神经保护作用。
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