Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection

被引：56

作者：

Li, Qi ^{[1
,3
]}

Chen, Ying ^{[4
]}

Xing, Shuaishuai ^{[1
]}

Liao, Qinghong ^{[4
]}

Xiong, Baichen ^{[1
]}

Wang, Yuanyuan ^{[1
]}

Lu, Weixuan ^{[1
]}

He, Siyu ^{[5
]}

Feng, Feng ^{[4
,6
]}

Liu, Wenyuan ^{[1
]}

Chen, Yao ^{[2
]}

Sun, Haopeng ^{[1
]}

机构：

[1] China Pharmaceut Univ, Sch Pharm, Nanjing 211198, Peoples R China

[2] Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210023, Peoples R China

[3] Qingdao Univ, Sch Basic Med, Qingdao 266071, Peoples R China

[4] China Pharmaceut Univ, Dept Nat Med Chem, Nanjing 211198, Peoples R China

[5] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, State Key Lab Nat Med, Jiangsu Key Lab Carcinogenesis & Intervent, Nanjing 210009, Peoples R China

[6] Jiangsu Food & Pharmaceut Sci Coll, Huaian 223003, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 10期

基金：

中国国家自然科学基金;

关键词：

ALZHEIMERS-DISEASE PATIENTS; NONTRANSGENIC MOUSE MODEL; TAU HYPERPHOSPHORYLATION; BIOLOGICAL EVALUATION; CELLULAR MECHANISMS; AMYLOID PEPTIDES; ACETYLCHOLINESTERASE; GHRELIN; PROTEIN; PHOSPHORYLATION;

D O I：

10.1021/acs.jmedchem.1c00167

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with A beta deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and A beta(1-42) peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.

引用

页码：6856 / 6876

页数：21

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