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



蔡文卿a, 刘巍b, 张硕c, 王建武a, 赵桂龙bb   

  1. 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;
  • 基金资助:


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

Cai Wenqinga, Liu Weib, Zhang Shuoc, Wang Jianwua, Zhao Guilongb   

  1. 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;
  • Supported by:

    Project supported by the Natural Science Foundation of Shandong Province (No. ZR2015BM028).

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