Discovery of Flexible Naphthyltriazolylmethane-based Thioacetic Acids as Highly Active Uric Acid Transporter 1 (URAT1) Inhibitors for the Treatment of Hyperuricemia of Gout
作者:Xiansheng Zhang、Jingwei Wu、Wei Liu、Yuqiang Liu、Yafei Xie、Qian Shang、Zhixing Zhou、Weiren Xu、Lida Tang、Jianwu Wang、Guilong Zhao
DOI:10.2174/1573406412666160915163002
日期:2017.4.10
Background: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. Objective: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based
背景:痛风是最常见的炎症性关节炎,如果不及时治疗或治疗不足,会由于晶体沉积而导致关节破坏,骨质侵蚀和残疾。尿酸转运蛋白1(URAT1)是降低尿酸盐治疗的有希望的治疗靶标。 目的:这项工作的目的是了解有效的基于lesinurad的命中2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)钠的结构-活性关系(SAR) )-4H-1,2,4-(三唑-3-基)硫代)乙酸酯(1c),并据此发现了更有效的URAT1抑制剂。 方法:系统地研究1c的SAR,并通过稳定表达人胚胎肾293(HEK293)细胞抑制URAT1介导的[8-14C]尿酸摄取,测定合成化合物1a-1t的体外URAT1抑制活性。人类URAT1。 结果:合成了20种化合物1a-1t。进行SAR分析。两种高活性URAT1抑制剂2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1