Design, Synthesis and Bioactivity of Highly Sterically Congested Flexible Uric Acid Transporter 1 (URAT1) Inhibitors

doi:10.6023/cjoc201704038

Chin. J. Org. Chem. ›› 2017, Vol. 37 ›› Issue (9): 2303-2314.DOI: 10.6023/cjoc201704038 Previous Articles Next Articles

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含大位阻结构的柔性尿酸转运体1(URAT1)抑制剂的设计、合成和生物活性研究

蔡文卿^a, 刘巍^b, 张硕^c, 王建武^a, 赵桂龙b^b

a 山东大学化学与化工学院济南 250100;
b 天津药物研究院天津市新药设计与发现重点实验室天津 300193;
c 山东省科学院新材料研究所山东省特种含硅新材料重点实验室济南 250014

收稿日期:2017-04-24 修回日期:2017-05-18 发布日期:2017-05-25
通讯作者: 赵桂龙, 王建武 E-mail:zhao_guilong@126.com;jwwang@sdu.edu.cn
基金资助:
山东省自然科学基金（No.ZR2015BM028）资助项目.

Design, Synthesis and Bioactivity of Highly Sterically Congested Flexible Uric Acid Transporter 1 (URAT1) Inhibitors

Cai Wenqing^a, Liu Wei^b, Zhang Shuo^c, Wang Jianwu^a, Zhao Guilong^b

a School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100;
b Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193;
c Shandong Key Laboratory for Special Silicon-Containing Materials, Advanced Materials Institute, Shandong Academy of Sciences, Jinan 250014

Received:2017-04-24 Revised:2017-05-18 Published:2017-05-25
Contact: 10.6023/cjoc201704038 E-mail:zhao_guilong@126.com;jwwang@sdu.edu.cn
Supported by:
Project supported by the Natural Science Foundation of Shandong Province (No. ZR2015BM028).

1. Design, Synthesis and Bioactivity of Highly Sterically Congested Flexible Uric Acid Transporter 1 (URAT1) Inhibitors.PDF(3101KB)

Abstract

The flexible naphthyltriazolylmethane-bearing uric acid transporter 1 (URAT1) inhibitor 1 is a novel, highly potent drug candidate for the treatment of hyperuricemia and gout. In order to understand the effect of substituents at the CH₂ linker between naphthalene and triazole rings on the bioactivity, 7 highly congested compounds 2a~2g were designed and synthesized. All the synthesized compounds were characterized by ¹H NMR, ¹³C NMR and HRMS, and their in vitro URAT1 inhibitory assay was studied. The results showed that the bioactivity decreased dramatically after the introduction of substituents to the CH₂ linker, and among the synthesized compounds the bioactivity dropped as the flexibility of the molecules decreased, strongly indicating that any substituents at the CH₂ linker were intolerable. The structure-activity relationship discovered here will be valuable to the design of URAT1 inhibitors.

Key words: gout, hyperuricemia, URAT1 inhibitor, structure-activity relationship, lesinurad, steric congestion

Cite this article

Cai Wenqing, Liu Wei, Zhang Shuo, Wang Jianwu, Zhao Guilong. Design, Synthesis and Bioactivity of Highly Sterically Congested Flexible Uric Acid Transporter 1 (URAT1) Inhibitors[J]. Chin. J. Org. Chem., 2017, 37(9): 2303-2314.

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含大位阻结构的柔性尿酸转运体1(URAT1)抑制剂的设计、合成和生物活性研究

Design, Synthesis and Bioactivity of Highly Sterically Congested Flexible Uric Acid Transporter 1 (URAT1) Inhibitors

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