Zhang Xiansheng, Wu Jingwei, Liu Wei, Liu Yuqiang, Xie Yafei, Shang Qian, Zhou Zhixing, Xu Weiren, Tang Lida, Wang Jianwu, Zhao Guilong
Shandong Lukang Pharmaceutical Co., Ltd., Jining 272021, China.
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
Med Chem. 2017;13(3):260-281. doi: 10.2174/1573406412666160915163002.
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.
The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor.
The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1.
Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 μM and 0.094 μM, respectively, against human URAT1 vs 7.18 μM for lesinurad).
Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane- bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.
痛风是最常见的炎性关节炎，如果不治疗或治疗不充分，由于晶体沉积会导致关节破坏、骨质侵蚀和残疾。尿酸转运蛋白1（URAT1）是降尿酸治疗中很有前景的治疗靶点。
本研究旨在了解基于雷西纳德的有效先导化合物2-((5-溴-4-((4-环丙基萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫代)乙酸钠（1c）的构效关系（SAR），并在此基础上发现一种更有效的URAT1抑制剂。
系统研究1c的构效关系，通过稳定表达人URAT1的人胚肾293（HEK293）细胞对URAT1介导的[8-14C]尿酸摄取的抑制作用，测定合成化合物1a-1t的体外URAT1抑制活性。
合成了20种化合物1a-1t。进行了构效关系分析。鉴定出两种高活性URAT1抑制剂，2-((5-溴-4-((4-正丙基萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫代)乙酸钠（1j）和2-((5-溴-4-((4-溴萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫代)乙酸钠（1m），在体外URAT1抑制试验中，它们的活性分别比母体雷西纳德高78倍和76倍（1j和1m对人URAT1的IC50值分别为0.092μM和0.094μM，而雷西纳德为7.18μM）。
发现了两种高活性URAT1抑制剂。构效关系研究还确定了更具柔性的萘基三唑甲烷作为一种新型分子骨架，这对于URAT1抑制剂的设计将具有重要价值，这一点从观察到许多合成的含萘基三唑甲烷的衍生物（1b-1d、1g、1j和1m）与具有刚性萘基三唑骨架的雷西纳德相比显示出显著提高的UART1抑制活性（亚微摩尔IC50值）可以看出。
