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.

中文翻译：

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发现一种新型噻吩并嘧啶化合物作为尿酸转运蛋白 1 和葡萄糖转运蛋白 9 双重抑制剂，具有更高的功效和良好的成药性

痛风和高尿酸血症是以高血清尿酸（SUA）水平为特征的代谢性疾病，严重影响人类健康。 Lesinurad 是一种促尿酸排泄药，由于其疗效有限和潜在的肾毒性，在临床实践中仅限于与黄嘌呤氧化酶抑制剂（XOIs）同时使用。在此，通过支架跳跃和取代基修饰策略对lesinurad进行了广泛的结构修饰，得到了54种含有嘧啶稠合环状结构的新型衍生物。值得注意的是，与 lesinurad 相比，噻吩并嘧啶化合物29的体内SUA 降低活性显着增加了 2 倍，同时对尿酸转运蛋白 1 (URAT1，IC ₅₀ = 2.01 μM) 和葡萄糖转运蛋白 9 (GLUT9， IC ₅₀ = 18.21 μM）。此外，它具有较低的0.5 mg/kg有效剂量，良好的安全性，在1000 mg/kg剂量下没有任何明显的急性毒性，并且具有改善的药代动力学特性。总体而言，我们发现了一种有效的 URAT1/GLUT9 双重抑制剂，可抑制尿酸盐重吸收，并具有良好的药代动力学特征。