促尿酸排泄药物研究进展.doc

促尿酸排泄药物研究进展 尧贵林1,2 ，2，陆涛*1 （1. 中国药科大学学院药物化学室江苏 南京2198；2. 湘北威尔曼制药股份北京新天宇科技开发有限公司北京100083Lesinurad；Verinurad；UR-1102；拉布立酶；聚乙二醇重组尿酸酶 Progress on the uricosuric drugs YAO Guilin1,2, WANG Haiyong2, LU Tao*1 (1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; 2. Beijing Xintianyu Technology Development Co., Ltd., Xiangbei Welman Pharmaceuticals, Beijing 100083, China) Abstract: High plasma uric acid can lead to gout, as well as a variety of cardiovascular diseases (CVD). Promoting uric acid excretion is an important approach for the treatment of gout and hyperuricemia, which mainly includes two kinds of mechanism: ?inhibiting renal tubular uric acid transporter to reduce the absorption of uric acid and using uricase to catalyze the oxidation of uric acid to a good water-soluble product (allantoin) to increase the excretion. Organic anion transporter, urate anion transporter 1?and some other renal tubular uric acid transporters are introduced in this article. Uricosuric drugs like lesinurad、verinurad and UR-1102 are target on renal tubular uric acid transporter, while rasburicase and pegloticase can oxidize uric acid. Key words: uricosuric; renal tubular uric acid transporter; uricase; lesinurad; verinurad; UR-1102; rasburicase; pegloticase 由于人体缺乏编码尿酸酶的基因，尿酸成为人体嘌呤代谢的终产物，主要是以原型通过肾脏排泄，其过程包括肾小球滤过、肾小管和集合管重吸收、分泌及分泌后重吸收。人体肾脏近端小管上皮细胞表达了多种尿酸转运蛋白，重吸收大部分被滤过的尿酸，导致最终进入尿液的尿酸仅占10%，血清尿酸水平升高，当超过0.42 mmol/L即被称为高尿酸血症。尿酸浓度过高导致尿酸单钠盐结晶沉积在关节和某些组织，引发痛风。研究[-]表明，尿酸水平变化还与多种人类疾病相关，包括高血压、心血管疾病、肾病、多发性硬化症、帕金森症、阿尔茨海默症和视神经炎等。近几十年来痛风的发病率和患病率在不断增高，降低尿酸水平药物的研究也越来越受到人们重视。 目前降低尿酸水平的策略主要包括：别嘌醇和非布索坦等黄嘌呤氧化还原酶抑制剂减少尿酸的生成；丙磺舒、苯溴马隆和Lesinurad等抑制肾小管尿酸转运体，减少尿酸重吸收以促进尿酸排泄；Rasburicase等尿酸酶将尿酸氧化分解成溶解性更好的尿囊素以提高排泄量；还有进入临床试验的既能减少尿酸生成又能促进尿酸排泄的双重作用机制药物（如KUX-1151和RLBN-1001）。高尿酸血症的临床治疗首选别嘌醇类药物，但有些患者对其高敏感，对于此类患者促尿酸排泄药物是更好的选择。已经上市或仍处于临床研究的促尿酸排泄药有多种，其作用机制主要包括抑制肾小管尿酸转运体，减少对尿酸的重吸收；促进尿酸氧化分解成尿囊素，提高排泄量。本文主要介绍了有机阴离子转运体、尿酸盐阴离子转运体1等肾小管尿酸转运体及作用于这些转运体的药物研究进展，同时介绍了Rasburicase等通过促进尿酸氧化分解以提高排泄量的尿