化学
运输机
可药性
药理学
葡萄糖转运蛋白
对偶(语法数字)
药物发现
生物化学
内科学
基因
医学
艺术
文学类
胰岛素
作者
Xiaoyu Shi,Tong Zhao,Shuo Wang,Peng Zhan,Hui Liao,Shenghua Gao,Zhen Gao,Jian Zhang,Danhui Qi,Zhijiao Zhang,Fengxin Zheng,Youzhao Wang,Zhenqian Wang,Mingyu Yang,Qian Yang,Yi Fan,Jianxin Pang,Xinyong Liu,Peng Zhan
标识
DOI:10.1021/acs.jmedchem.4c00136
摘要
Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 μM) and glucose transporter 9 (GLUT9, IC50 = 18.21 μM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.
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