Hyperuricemia is a kind of metabolic disease resulted from imbalance between urate production and excretion. Xanthine oxidase (XOD) or renal urate transporter 1 (URAT1) inhibitors have been applied for hyperuricemia treatment in clinic, but available drugs could not simultaneously target XOD and URAT1 and had various adverse effects. (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime (BDEO), as a deoxybenzoins oxime analog, was obtained from a cluster of deoxybenzoins derivatives synthesized by our research group with potent anti-hyperuricemic activity, which was expected to be dual inhibitor of XOD and URAT1. This study aimed to investigate effects of BDEO on XOD and URAT1 in vitro, as well as the possible mechanism by which BDEO attenuated hyperuricemia in vivo. In vitro, BDEO obviously inhibited XOD activity with an IC50 value of 3.33μM, moreover, in Human embryonic kidney (HEK)293 cells expressing URAT1, BDEO and benzbromarone blocked uptake of uric acid with a Ki value of 0.145μM. On the other hand, mice were orally administrated by oxonate for seven consecutive days to induce hyperuricemia, BDEO at various doses were administered intragastrically to hyperuricemic and normal mice daily. BDEO dose-dependently decreased serum urate level and uric acid excretion in 24h in hyperuricemic mice. More importantly, BDEO significantly suppressed hepatic XOD activity and down-regulated renal URAT1 protein level in hyperuricemic mice. Notably, BDEO exhibited no effects on all these detected biochemical indicators in normal mice, predicting its safety. Taken together, the data suggested that BDEO may serve as a dual XOD and URAT1 inhibitor for treatment of hyperuricemia.

中文翻译：

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（E）-2-（4-溴苯基）-1-（2,4-二羟基苯基）乙酮肟是一种潜在的治疗高尿酸血症的治疗剂，通过其对 XOD 和 URAT1 的双重抑制作用


高尿酸血症是由于尿酸盐产生和排泄失衡引起的一种代谢性疾病。黄嘌呤氧化酶 （XOD） 或肾尿酸转运蛋白 1 （URAT1） 抑制剂已在临床上用于高尿酸血症治疗，但现有药物不能同时靶向 XOD 和 URAT1，并具有各种不良反应。（E）-2-（4-溴苯基）-1-（2,4-二羟基苯基）乙酮肟 （BDEO） 作为脱氧苯甲酸酯肟类似物，由我们研究小组合成的具有强效抗高尿酸血症活性的脱氧苯甲酸衍生物簇获得，有望成为 XOD 和 URAT1 的双重抑制剂。本研究旨在探讨 BDEO 在体外对 XOD 和 URAT1 的影响，以及 BDEO 在体内减轻高尿酸血症的可能机制。在体外，BDEO 明显抑制 XOD 活性，IC50 值为 3.33 μM，此外，在表达 URAT1 的人胚胎肾 （HEK） 293 细胞中，BDEO 和苯溴马隆阻断了尿酸的摄取，Ki 值为 0.145 μM。另一方面，小鼠连续 7 天口服氧酸盐诱导高尿酸血症，每天对高尿酸血症和正常小鼠灌胃内给予不同剂量的 BDEO。BDEO 剂量依赖性地降低高尿酸血症小鼠 24 小时内血清尿酸盐水平和尿酸排泄。更重要的是，BDEO 显著抑制高尿酸血症小鼠肝脏 XOD 活性和下调肾脏 URAT1 蛋白水平。值得注意的是，BDEO 对正常小鼠中检测到的所有这些生化指标都没有影响，预测了其安全性。综上所述，数据表明 BDEO 可能作为治疗高尿酸血症的双重 XOD 和 URAT1 抑制剂。