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基于晶体结构的抑制剂优化的魔力:具有皮摩尔亲和力和体内活性的丁酰胆碱酯酶抑制剂的开发。

The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity.

机构信息

Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.

Institute of Pathological Physiology, Faculty of Medicine, University of Ljubljana , Vrazov trg 2, 1000 Ljubljana, Slovenia.

出版信息

J Med Chem. 2018 Jan 11;61(1):119-139. doi: 10.1021/acs.jmedchem.7b01086. Epub 2017 Dec 22.

Abstract

The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-π interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.

摘要

脑内丁酰胆碱酯酶(BChE)的酶活性随着阿尔茨海默病的进展而增加,因此 BChE 被归类为晚期阿尔茨海默病有前途的药物靶点。我们使用基于结构的药物发现方法来开发高效、选择性和可逆的人 BChE 抑制剂。最有效的化合物 3 对 BChE 的抑制常数为皮摩尔级,这是由于其与人 BChE 的复合物的晶体结构揭示的强阳离子-π 相互作用。此外,化合物 3 抑制 BChE 的体外和非细胞毒性。体外药代动力学实验表明,化合物 3 具有高蛋白结合率、高渗透性和代谢稳定性。最后,化合物 3 可穿透血脑屏障,并可改善东莨菪碱诱导痴呆小鼠的记忆、认知功能和学习能力。因此,化合物 3 是一种很有前途的晚期先导化合物,可用于开发治疗晚期阿尔茨海默病患者胆碱能功能低下症状的药物。

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