Chinese Journal of Organic Chemistry >
Design, Synthesis and Bioactivity of Highly Sterically Congested Flexible Uric Acid Transporter 1 (URAT1) Inhibitors
Received date: 2017-04-24
Revised date: 2017-05-18
Online published: 2017-05-25
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.
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
[1] Richette, P.; Bardin, T. Lancet 2010, 375, 318.
[2] Punzi, L.; Scanu, A.; Ramonda, R.; Oliviero, F. Autoimmun. Rev. 2012, 12, 66.
[3] Dalbeth, N.; Merriman, T. R.; Stamp, L. K. Lacent 2016, 388, 2039.
[4] Kuo, C, F.; Grainge, M. J.; Zhang, W. Y.; Doherty, M. Nat. Rev. Rheumatol. 2015, 11, 649.
[5] Hyndman, D.; Liu, S.; Miner, J. N. Curr. Rheumatol. Rep. 2016, 18, 34.
[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.
[7] Cai, W.; Liu, W.; Liu, C.; Wang, J.; Zhao, G. Chin. J. Struct. Chem. 2017, 36, 897.
[8] Tian, H.; Wu, J.; Liu, Y.; Xie, Y.; Wang, J.; Zhao, G. Chin. J. Org. Chem. 2017, 37, 1748(in Chinese). (田禾, 吴景卫, 刘钰强, 谢亚非, 王建武, 赵桂龙, 有机化学, 2017, 37, 1748.)
[9] Hoy, S. M. Drugs 2016, 76, 509.
[10] Shen, Z.; Yeh, L. T.; Wallach, K.; Zhu, N.; Kerr, B.; Gillen, M. Clin. Drug Invest. 2016, 36, 443.
[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.
[12] Miyake, H.; Nakao, Y.; Sasaki, M. Chem. Lett. 2006, 11, 1262.
[13] Miyake, H.; Nakao, Y.; Sasaki, M. Tetrahedron 2007, 63, 10433.
[14] Zhang, X.; Liu, Y.; Xie, Y.; Li, C.; Xin, X.; Xu, W.; Tang, L.; Zhao, G. Drugs Clin. 2015, 30, 1179(in Chinese). (张宪生, 刘钰强, 谢亚非, 李川, 辛晓, 徐为人, 汤立达, 赵桂龙, 现代药物与临床, 2015, 30, 1179.)
[15] Bertus, P.; Szymoniak, J. J. Org. Chem. 2003, 68, 7133.
[16] Michailidis, F. R.; Pupier, M.; Besnard, C.; Burgi, T.; Alexakis, A. Org. Lett. 2014, 16, 4988.
[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.
[18] Haudrechy, A.; Chassaing, C.; Riche, C.; Langlois, Y. Tetrahedron 2000, 56, 3181.
[19] Murayama, K.; Yoshioka, T. Tetrahedron Lett. 1968, 11, 1363.
[20] Glaser, R.; Hillebrand, R.; Wycoff, W.; Camasta, C.; Gates, K, S. J. Org. Chem. 2015, 80, 4360.
[21] Cakmak, O.; Kahveci, I.; Demirta, I.; Hokelek, T.; Smith, K. Collect. Czech. Chem. Commun. 2000, 65, 791.
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