Journal of Medicinal Chemistry p. 10829 - 10854 (2020)
Update date:2022-08-15
Topics:
Zhao, Tong
Meng, Qing
Sun, Zhuosen
Chen, Yanyu
Ai, Wei
Zhao, Zean
Kang, Dongwei
Dong, Yue
Liang, Ruipeng
Wu, Ting
Pang, Jianxin
Liu, Xinyong
Zhan, Peng
Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of acute hyperuricemia, 21 of the synthesized compounds showed increased serum uric acid (SUA)-reducing activity; SUA was about 4-fold lower in animals treated with 44, 54, and 83 compared with lesinurad or benzbromarone. In the URAT1 inhibition assay, 44 was over 8-fold more potent than lesinurad (IC50: 1.57 μM vs 13.21 μM). Notably, 83 also displayed potent inhibitory activity (IC50 = 31.73 μM) against GLUT9. Furthermore, we also preliminarily explored the effect of chirality on the potency of the promising derivatives 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear to be promising candidates for the treatment of hyperuricemia and gout.
View MoreShandong Jiulong Hisince Pharmaceutical Co.,Ltd.
Contact:+86-15853188990
Address:Huadian Pioneer Park, Huadian Township, Qihe County, Dezhou City, Shandong, P.R.China
Contact:
Address:ROOM 1715, No#345 Jin Xiang Road, Pudong District
wuxi huabin bio-tech Co.,Ltd(expird)
Contact:86-0510-85133006
Address:hubin road NO157
Landz International Company Ltd.
Contact:0086-21-58891610
Address:985 Dongfang Road, Pudong, Shanghai 200122 China
TIANJIN DONGRUXIANG MINERALS MARKETING CO.,LTD(expird)
Contact:22-58516360
Address:tianjin
Doi:10.1021/ol026159t
(2002)Doi:10.1016/j.bmcl.2005.01.028
(2005)Doi:10.1021/ol026196k
(2002)Doi:10.1016/S0040-4039(02)00159-4
(2002)Doi:10.1016/j.bmc.2010.05.055
(2010)Doi:10.1016/S0040-4020(01)87185-4
(1993)