尿酸盐转运体1抑制剂的设计、合成及活性研究

Design, synthesis and biological evaluation of inhibitors of urate transporter 1 (URAT1)

摘要: 尿酸盐转运体1（urate transporter 1，URAT1）是抗高尿酸血症的有效靶点。基于目前处于临床Ⅱ期的URAT1抑制剂URC-102的结构，设计合成了14个URC-102类似物，其中4个化合物（9b、9c、10e、10g）显示较强的URAT1抑制活性，化合物9b对URAT1的半数抑制浓度IC₅₀达到0.061 μmol·L^-1，显著强于雷西纳德和苯溴马隆。初步的构效关系研究为后续结构优化提供了依据。

Abstract: Urate transporter 1 (URAT1) is a validated target for the treatment of hyperuricemia. Based on the structure of URC-102, which is currently under a phase Ⅱ clinical trial, fourteen novel analogs were designed and synthesized. Among them, four compounds (9b, 9c, 10e and 10g) exhibited substantial inhibitory effect against URAT1. The most active compound 9b showed an IC₅₀ value of 0.061 μmol·L^-1, which is significantly more potent than Lesinurad and Benzbromarone. Preliminary SAR was drawn, providing clues for further structural optimization.