Citation: 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]. Chinese Journal of Organic Chemistry, ;2017, 37(9): 2303-2314. doi: 10.6023/cjoc201704038 shu

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

Corresponding author: Wang Jianwu, jwwang@sdu.edu.cn Zhao Guilong, zhao_guilong@126.com
Received Date: 24 April 2017
Revised Date: 18 May 2017
Available Online: 24 September 2017
Fund Project: Project supported by the Natural Science Foundation of Shandong Province (No. ZR2015BM028)Natural Science Foundation of Shandong Province ZR2015BM028

Figures(4)

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.
- gout,
- hyperuricemia,
- URAT1 inhibitor,
- structure-activity relationship,
- lesinurad,
- steric congestion
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