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
1. [1]
  Richette, P.; Bardin, T. Lancet 2010, 375, 318. doi: 10.1016/S0140-6736(09)60883-7
2. [2]
  Punzi, L.; Scanu, A.; Ramonda, R.; Oliviero, F. Autoimmun. Rev. 2012, 12, 66. doi: 10.1016/j.autrev.2012.07.024
3. [3]
  Dalbeth, N.; Merriman, T. R.; Stamp, L. K. Lacent 2016, 388, 2039.
4. [4]
  Kuo, C, F.; Grainge, M. J.; Zhang, W. Y.; Doherty, M. Nat. Rev. Rheumatol. 2015, 11, 649. doi: 10.1038/nrrheum.2015.91
5. [5]
  Hyndman, D.; Liu, S.; Miner, J. N. Curr. Rheumatol. Rep. 2016, 18, 34. doi: 10.1007/s11926-016-0587-7
6. [6]
  Enomoto, A.; Kimura, H.; Chairoungdua, A.; Shigeta, Y.; Jutabha, P.; Cha, S. H.; Hosoyamada, M.; Takeda, M.; Sekine, T.; Igarashi, T.; Matsuo, H.; Kikuchi, Y.; Oda, T.; Ichida, K.; Hosoya, T.; Shimokata, K.; Niwa, T.; Kanai, Y.; Endou, H. Nature 2002, 417, 447. doi: 10.1038/nature742
7. [7]
  Cai, W.; Liu, W.; Liu, C.; Wang, J.; Zhao, G. Chin. J. Struct. Chem. 2017, 36, 897.
8. [8]
  Tian, H.; Wu, J.; Liu, Y.; Xie, Y.; Wang, J.; Zhao, G. Chin. J. Org. Chem. 2017, 37, 1748(in Chinese).
9. [9]
  Hoy, S. M. Drugs 2016, 76, 509. doi: 10.1007/s40265-016-0550-y
10. [10]
  Shen, Z.; Yeh, L. T.; Wallach, K.; Zhu, N.; Kerr, B.; Gillen, M. Clin. Drug Invest. 2016, 36, 443. doi: 10.1007/s40261-016-0386-y
11. [11]
  Zhang, X.; Wu, J.; Liu, W.; Liu, Y.; Xie, Y.; Shang, Q.; Zhou, Z.; Xu, W.; Tang, L.; Wang, J.; Zhao, G. Med. Chem. 2017, 13, 260. doi: 10.2174/1573406412666160915163002
12. [12]
  Miyake, H.; Nakao, Y.; Sasaki, M. Chem. Lett. 2006, 11, 1262.
13. [13]
  Miyake, H.; Nakao, Y.; Sasaki, M. Tetrahedron 2007, 63, 10433. doi: 10.1016/j.tet.2007.08.014
14. [14]
  Zhang, X.; Liu, Y.; Xie, Y.; Li, C.; Xin, X.; Xu, W.; Tang, L.; Zhao, G. Drugs Clin. 2015, 30, 1179(in Chinese).
15. [15]
  Bertus, P.; Szymoniak, J. J. Org. Chem. 2003, 68, 7133. doi: 10.1021/jo034710+
16. [16]
  Michailidis, F. R.; Pupier, M.; Besnard, C.; Burgi, T.; Alexakis, A. Org. Lett. 2014, 16, 4988. doi: 10.1021/ol5022355
17. [17]
  Li, W. J.; Gao, J, J.; Lorenz, J. C.; Xu, J. H.; Johnson, J.; Ma, S. L.; Lee, H.; Grinberg, N.; Busacca, C. A.; Lu, B.; Senanayake, C. H. Org. Process Res. Dev. 2012, 16, 836. doi: 10.1021/op300059b
18. [18]
  Haudrechy, A.; Chassaing, C.; Riche, C.; Langlois, Y. Tetrahedron 2000, 56, 3181. doi: 10.1016/S0040-4020(00)00227-1
19. [19]
  Murayama, K.; Yoshioka, T. Tetrahedron Lett. 1968, 11, 1363.
20. [20]
  Glaser, R.; Hillebrand, R.; Wycoff, W.; Camasta, C.; Gates, K, S. J. Org. Chem. 2015, 80, 4360. doi: 10.1021/acs.joc.5b00080
21. [21]
  Cakmak, O.; Kahveci, I.; Demirta, I.; Hokelek, T.; Smith, K. Collect. Czech. Chem. Commun. 2000, 65, 791.
1. [1]
  Ruizhi Duan , Xiaomei Wang , Panwang Zhou , Yang Liu , Can Li . The role of hydroxyl species in the alkaline hydrogen evolution reaction over transition metal surfaces. Acta Physico-Chimica Sinica, 2025, 41(9): 100111-0. doi: 10.1016/j.actphy.2025.100111
2. [2]
  Xuejie Wang , Guoqing Cui , Congkai Wang , Yang Yang , Guiyuan Jiang , Chunming Xu . Research Progress on Carbon-based Catalysts for Catalytic Dehydrogenation of Liquid Organic Hydrogen Carriers. Acta Physico-Chimica Sinica, 2025, 41(5): 100044-0. doi: 10.1016/j.actphy.2024.100044
3. [3]
  Lei Feng , Ze-Min Zhu , Ying Yang , Zongbin He , Jiafeng Zou , Man-Bo Li , Yan Zhao , Zhikun Wu . Long-Pursued Structure of Au₂₃(S-Adm)₁₆ and the Unexpected Doping Effects. Acta Physico-Chimica Sinica, 2024, 40(5): 2305029-0. doi: 10.3866/PKU.WHXB202305029
4. [4]
  Haiying Jiang , Liuhong Song , Yangyang Cheng , Kefen Yue , Mingli Peng , Huilin Guo . Ph―C≡C―Cu_2.5的力致变色现象探究——推荐一个物理化学实验. University Chemistry, 2025, 40(8): 249-254. doi: 10.12461/PKU.DXHX202410003
5. [5]
  Xue-Peng Zhang , Yuchi Long , Yushu Pan , Jiding Wang , Baoyu Bai , Rui Ding . 定量构效关系方法学习探索：以钴卟啉活化氧气为例. University Chemistry, 2025, 40(8): 345-359. doi: 10.12461/PKU.DXHX202410107
6. [6]
  Yihui Song , Shangshang Qin , Kai Wu , Chengyun Jin , Bin Yu . 生物化学在高水平创新型药学人才培养中的交叉融合应用——以去甲基化酶LSD1抑制剂的活性评价为例. University Chemistry, 2025, 40(6): 341-352. doi: 10.12461/PKU.DXHX202406018
7. [7]
  Zongpei Zhang , Yanyang Li , Yanan Si , Kai Li , Shuangquan Zang . Developing a Chemistry Experiment Center Employing a Multifaceted Approach to Serve High-Quality Laboratory Education. University Chemistry, 2024, 39(7): 13-19. doi: 10.12461/PKU.DXHX202404041
8. [8]
  Hongyao Li , Youyan Liu , Luwei Dai , Min Yang , Qihui Wang . The Blessing of Indium Sulfide：Confronting the Narrow Path with Uric Acid. University Chemistry, 2024, 39(5): 325-335. doi: 10.3866/PKU.DXHX202311104
9. [9]
  Tianqi Bai , Kun Huang , Fachen Liu , Ruochen Shi , Wencai Ren , Songfeng Pei , Peng Gao , Zhongfan Liu . Nanoscale Mechanism of Microstructure-Dependent Thermal Diffusivity in Thick Graphene Sheets. Acta Physico-Chimica Sinica, 2025, 41(3): 2404024-0. doi: 10.3866/PKU.WHXB202404024
10. [10]
  Yang WANG , Xiaoqin ZHENG , Yang LIU , Kai ZHANG , Jiahui KOU , Linbing SUN . Mn single-atom catalysts based on confined space: Fabrication and the electrocatalytic oxygen evolution reaction performance. Chinese Journal of Inorganic Chemistry, 2024, 40(11): 2175-2185. doi: 10.11862/CJIC.20240165
11. [11]
  Junjie Zhang , Yue Wang , Qiuhan Wu , Ruquan Shen , Han Liu , Xinhua Duan . Preparation and Selective Separation of Lightweight Magnetic Molecularly Imprinted Polymers for Trace Tetracycline Detection in Milk. University Chemistry, 2024, 39(5): 251-257. doi: 10.3866/PKU.DXHX202311084
12. [12]
  Mingjie Lei , Wenting Hu , Kexin Lin , Xiujuan Sun , Haoshen Zhang , Ye Qian , Tongyue Kang , Xiulin Wu , Hailong Liao , Yuan Pan , Yuwei Zhang , Diye Wei , Ping Gao . Accelerating the reconstruction of NiSe₂ by Co/Mn/Mo doping for enhanced urea electrolysis. Acta Physico-Chimica Sinica, 2025, 41(8): 100083-0. doi: 10.1016/j.actphy.2025.100083
13. [13]
  Zihao Guo , Shichen Ma , Kin Shing Chan . 烯烃环化反应中6电子试剂的等瓣相似性和等电子关系. University Chemistry, 2025, 40(6): 160-166. doi: 10.12461/PKU.DXHX202408038
14. [14]
  Da Wang , Xiaobin Yin , Jianfang Wu , Yaqiao Luo , Siqi Shi . All-Solid-State Lithium Cathode/Electrolyte Interfacial Resistance: From Space-Charge Layer Model to Characterization and Simulation. Acta Physico-Chimica Sinica, 2024, 40(7): 2307029-0. doi: 10.3866/PKU.WHXB202307029
15. [15]
  Hao BAI , Weizhi JI , Jinyan CHEN , Hongji LI , Mingji LI . Preparation of Cu₂O/Cu-vertical graphene microelectrode and detection of uric acid/electroencephalogram. Chinese Journal of Inorganic Chemistry, 2024, 40(7): 1309-1319. doi: 10.11862/CJIC.20240001
16. [16]
  Bo YANG , Gongxuan LÜ , Jiantai MA . Corrosion inhibition of nickel-cobalt-phosphide in water by coating TiO₂ layer. Chinese Journal of Inorganic Chemistry, 2025, 41(2): 365-384. doi: 10.11862/CJIC.20240063
17. [17]
  Xiaotian ZHU , Fangding HUANG , Wenchang ZHU , Jianqing ZHAO . Layered oxide cathode for sodium-ion batteries: Surface and interface modification and suppressed gas generation effect. Chinese Journal of Inorganic Chemistry, 2025, 41(2): 254-266. doi: 10.11862/CJIC.20240260
18. [18]
  Zilin Hu , Yaoshen Niu , Xiaohui Rong , Yongsheng Hu . Suppression of Voltage Decay through Ni³⁺ Barrier in Anionic-Redox Active Cathode for Na-Ion Batteries. Acta Physico-Chimica Sinica, 2024, 40(6): 2306005-0. doi: 10.3866/PKU.WHXB202306005
19. [19]
  Xinyu ZENG , Guhua TANG , Jianming OUYANG . Inhibitory effect of Desmodium styracifolium polysaccharides with different content of carboxyl groups on the growth, aggregation and cell adhesion of calcium oxalate crystals. Chinese Journal of Inorganic Chemistry, 2024, 40(8): 1563-1576. doi: 10.11862/CJIC.20230374
20. [20]
  Yajie Li , Bin Chen , Yiping Wang , Hui Xing , Wei Zhao , Geng Zhang , Siqi Shi . Inhibiting Dendrite Growth by Customizing Electrolyte or Separator to Achieve Anisotropic Lithium-Ion Transport: A Phase-Field Study. Acta Physico-Chimica Sinica, 2024, 40(3): 2305053-0. doi: 10.3866/PKU.WHXB202305053

Get Citation

PDF

XML

Metrics

PDF Downloads(4)
Abstract views(1283)
HTML views(135)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142