甲基异噁唑/异噻唑酰胺衍生物类BACE1抑制剂的设计, 合成和体外生物评价

doi:10.5246/jcps.2018.03.016

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (3): 143-158.DOI: 10.5246/jcps.2018.03.016

• 【研究论文】 • 下一篇

甲基异噁唑/异噻唑酰胺衍生物类BACE1抑制剂的设计, 合成和体外生物评价

吕鹏, 李灿, 牛彦^*, 李宏月, 周童亮, 许凤荣, 梁磊, 王超, 徐萍^*

北京大学医学部药学院药物化学系, 北京 100191

收稿日期:2017-11-30 修回日期:2018-02-03 出版日期:2018-03-31 发布日期:2018-02-28
通讯作者: Tel.: +86-010-82801558; +86-010-82802632, E-mail: yanniu@bjmu.edu.cn; pingxu@bjmu.edu.cn
基金资助:
The National Natural Science Foundationof China (Grant No. 21002002) and the Beijing Natural Science Foundation (Grant No. 7162110).

Design, synthesis, and in vitro activity of methylisoxazole/isothiazole amides as BACE1 inhibitors

Peng Lv, Can Li, Yan Niu^*, Hongyue Li, Tongliang Zhou, Fengrong Xu, Lei Liang, Chao Wang, Ping Xu^*

Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2017-11-30 Revised:2018-02-03 Online:2018-03-31 Published:2018-02-28
Contact: Tel.: +86-010-82801558; +86-010-82802632, E-mail: yanniu@bjmu.edu.cn; pingxu@bjmu.edu.cn
Supported by:
The National Natural Science Foundationof China (Grant No. 21002002) and the Beijing Natural Science Foundation (Grant No. 7162110).

摘要/Abstract

摘要：

本文在先前的虚拟筛选发现的命中化合物B51(IC₅₀ =37.4 μM)的结构基础上,设计并合成了一系列新型甲基异噁唑/异噻唑衍生物类BACE1抑制剂。分子对接结果显示,将B51结构中的氰基嘧啶酮片段转化为甲基异恶唑/异噻唑,同时缩短连接氰基嘧啶酮环和酰胺键另一侧咪唑环之间的连接链长度,可以使分子与BACE1的S1'和S2'口袋的契合程度更好,从而提高活性。因此本文设计合成了20个甲基异噁唑/异噻唑类衍生物并对其抑制BACE1酶活性进行了初步构效关系研究。在这些化合物中,5t显示出比B51提高了近10倍的效力。SPR实验结果显示,其与BACE1结合动力学呈现“快结合,慢解离”的特征。所获得的活性甲基异噻唑类化合物分子量小,对正常细胞安全无毒,经PAMPA实验测试具有透过BBB的可能,可作为BACE1抑制剂类抗AD药物设计的新结构骨架。

关键词: 阿尔茨海默氏病, BACE1抑制剂, 甲基异噁唑/异噻唑

Abstract:

Based on the structure of compound B51 (IC₅₀ = 37.4 μM), which was discovered as hit in a previous virtual screen, a series of methylisoxazole/isothiazole amide derivatives were designed and synthesized as BACE1 inhibitors. The methoxyphenylpyrimidone fragment of B51 was transformed into a methoxyphenylmethylisoxazole/isothiazole moiety to reduce the molecular weight while retaining the ability to fit into the S₁' and S₂' subpocket of BACE1 as predicted by docking studies. The effects of BACE1 inhibition and the structure-activity relationships were analyzed. Among all 20 designed compounds, 5t exhibited almost 10-fold improved potency (IC₅₀ = 5.33 μM) compared to B51 in the BACE1 inhibition assay. Additionally, it has exhibited “rapid binding, slow dissociation” kinetics in SPR analysis, suggesting a longer inhibitory effect than B51. All acquired methylisoxazole/isothiazole derivatives were small in size and safe to normal cells, which allow them represent a novel scaffold for BACE1 inhibitor design.

Key words: Alzheimer’s disease, BACE1 inhibitor, Methylisoxazole/isothiazole amides

中图分类号:

R916

Supporting:

吕鹏, 李灿, 牛彦, 李宏月, 周童亮, 许凤荣, 梁磊, 王超, 徐萍. 甲基异噁唑/异噻唑酰胺衍生物类BACE1抑制剂的设计, 合成和体外生物评价[J]. 中国药学(英文版), 2018, 27(3): 143-158.

Peng Lv, Can Li, Yan Niu, Hongyue Li, Tongliang Zhou, Fengrong Xu, Lei Liang, Chao Wang, Ping Xu. Design, synthesis, and in vitro activity of methylisoxazole/isothiazole amides as BACE1 inhibitors[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(3): 143-158.

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甲基异噁唑/异噻唑酰胺衍生物类BACE1抑制剂的设计, 合成和体外生物评价

Design, synthesis, and in vitro activity of methylisoxazole/isothiazole amides as BACE1 inhibitors

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