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

doi:10.5246/jcps.2018.03.016

Journal of Chinese Pharmaceutical Sciences ›› 2018, Vol. 27 ›› Issue (3): 143-158.DOI: 10.5246/jcps.2018.03.016

• Original articles • Next Articles

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).

Abstract

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

CLC Number:

R916

Supporting:

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

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