Urate transporter URAT1 inhibitors: a patent review (2012 - 2015)

Introduction: Human urate transporter 1 (URAT1, encoded by SLC22A12) has been identified as a key urate transporter expressed at the apical membrane of renal proximal tubule cells for regulating urate homeostasis. Therefore, URAT1 is an attractive target for the development of new uricosurics against hyperuricemia. Discovery of novel inhibitors targeting URAT1 has become a research hotspot in recent years.

Areas covered: In this paper, we reviewed the patent applications and related research published during the years 2012–2015, covering the development of URAT1 inhibitors.

Expert opinion: There are some promising and inspiring patent applications in this area. Several compounds have superior inhibitory activity of URAT1 with the availability of urate-lowering treatment. For new drug development and commercialization, further studies are needed to evaluate the efficacy and safety.     

治疗痛风和高尿酸血症药物的研究进展

随着痛风和高尿酸血症发病率的逐年攀升,临床常用治疗药物（别嘌醇、苯溴马隆、非布司他等）市场销售额也逐年递增,但这些药物均存在明显的副作用,国内外药企已将研发重点放在更安全、更高效的新型降尿酸药物尿酸盐重吸收转运子1（URAT1）抑制剂领域,已上市的雷西那德在近几年备受关注,而在研新药SHR4640、SIM1909-13已处于临床试验阶段,同时用中医药治疗高尿酸血症和痛风也是未来的研究方向。对治疗痛风及高尿酸血症的药物研究进展进行综述,以期为临床用药和新药研发提供参考。     

高尿酸合并高血压患者URAT1 6092(T/C)基因多态性对氯沙坦降尿酸疗效的影响

目的:探讨尿酸盐阴离子转运体(Urate Transporter 1,URAT1) SNP6092(T/C)基因多态性对高尿酸血症合并原发性高血压患者服用氯沙坦降尿酸疗效的影响.方法:应用PCR-RFLP方法对101名高尿酸血症合并原发性高血压患者和117名健康对照者进行基因分型,并且所有患者均每天口服氯沙坦药物100 mg,连服2周.测定用药前后的血压、血尿酸(Ur)、尿素氮(BUN)、肌酐(Cr)、胆固醇(CHOL),高密度脂蛋白胆固醇(HDL-c),低密度脂蛋白胆固醇(LDL-c)和甘油三酯(TG).结果:服用氯沙坦后,突变基因型患者(TC/CC)的Ur和Cr的降低水平均明显低于TT基因型患者(P＜0.05),并且TC和CC型患者的Ur降低幅度(1.34％±2.12％,-0.2％±3.8％)也明显低于TT基因型患者(22.58％±14.46％) (P ＜0.05).结论:URAT1基因6092T/C遗传变异影响氯沙坦的降尿酸疗效,并且可能是氯沙坦降尿酸潜在的遗传靶点.     

栀子苷对氧嗪酸钾盐致小鼠高尿酸血症的作用及其机制研究

目的探讨栀子苷对氧嗪酸钾盐致小鼠高尿酸血症的作用及其机制。方法连续7d灌胃给予氧嗪酸钾盐诱导小鼠高尿酸血症,对比各组血清尿酸水平和24h尿酸排泄量,检测肝脏黄嘌呤氧化酶（XOD）的活性和肾脏尿酸转运体（mURAT1、mGLUT9、mOAT1）的mRNA和蛋白表达水平。结果栀子苷可显著降低高尿酸血症小鼠血清尿酸水平并升高24h尿酸排泄量,同时可抑制肝脏XOD活性,调节肾脏尿酸转运体的表达。结论栀子苷对氧嗪酸钾盐致小鼠高尿酸血症具有明显的改善作用,其作用机制可能是通过抑制XOD活性和调节尿酸转运体的表达水平实现。     

抗高尿酸血症药物研究进展

痛风是一种代谢性疾病,危害严重,近年来患病率呈上升趋势。尿酸排泄减少或生成增多所致的高尿酸血症是痛风的主要病因,而高尿酸又与多种疾病密切相关。降低血尿酸水平是治疗痛风,预防痛风复发的重要措施。目前,抗高尿酸血症药物主要有3类,分别是黄嘌呤氧化酶抑制剂、尿酸盐阴离子转运蛋白1(URAT1)抑制剂和尿酸氧化酶类似物。对现有抗高尿酸血症药物的现状以及研究进展进行总结,希望对其研发提供参考。     

痛风康宁片对高尿酸血症的预防作用及机制研究

目的 采用多种实验模型评价痛风康宁片（TKT）对高尿酸血症的预防作用并研究其作用机制。方法 采用ig酵母膏联合ip氧嗪酸钾法制备大鼠高尿酸血症模型,酵母膏（20 g·kg^-1）连续ig 7 d,且于ig酵母膏第5天开始给药,设置对照组、模型组和 TKT 低、中、高（0.58、1.15、2.30 g·kg^-1）组和苯溴马隆 27 mg·kg^-1组,对照及模型组给予等容量 0.5%CMC-Na,每天 ig给药 1次,给药第 3天（即 ig酵母膏第 7天）,ip注射氧嗪酸钾 200 mg·kg^-1造模。检测注射氧嗪酸钾后 2、4 h的血清尿酸浓度、尿量、尿液中尿酸排出量及肾脏中尿酸盐转运体 1（URAT1）、有机阴离子转运体 1（OAT1）、OAT3抗体表达,评价TKT对大鼠高尿酸血症的预防作用;采用次黄嘌呤诱导小鼠高尿酸血症模型,设置对照组、模型组和TKT低、中、高剂量（0.83、1.66、3.33 g·kg^-1）组及苯溴马隆 39 mg·kg^-1组,每天 ig给药 1次,连续给药 5 d,对照及模型组给予等容量0.5% CMC-Na,检测血尿酸、尿酸酶及黄嘌呤氧化酶（XOD）含量,评价TKT对小鼠高尿酸血症的预防作用;采用大鼠水负荷模型,设置对照组和TKT低、中、高（0.58、1.15、2.30 g·kg^-1）组及氢氯噻嗪27 mg·kg^-1组,每天ig给药1次,连续给药 3 d,对照组给予等容量 0.5% CMC-Na,通过检测给药后 1、2、3、4、5 h 的尿量及给药后 5 h 内总尿量,评价TKT 对大鼠的利尿作用。结果 与模型组比较,TKT（0.58、1.15、2.30 g·kg^-1）能明显降低大鼠血清尿酸浓度（P＜0.05、0.01）,明显增加尿酸排出量（P＜0.05、0.01）,明显增加肾脏OAT1的表达（P＜0.05、0.01）,1.15、2.30 g·kg^-1能明显减少肾脏 URAT1 的表达 （P＜0.05、 0.01）; TKT （1.66、 3.33 g·kg^-1） 能明显降低小鼠血清尿酸浓度 （P＜0.05、 0.01）,TKT（0.83、1.66、3.33 g·kg^-1）能明显增加尿酸酶含量（P＜0.05、0.01）;TKT（0.58、1.15、2.30 g·kg^-1）能明显增加给药后不同时间点的尿量（P＜0.05、0.01）,明显增加给药后5 h总尿量（P＜0.05、0.01）。结论 TKT通过促进尿酸分泌、抑制尿酸重吸收及利尿作用,使血清尿酸浓度明显降低、尿尿酸排出量明显增加,显示对实验性高尿酸血症有明显的预防作用。     

高尿酸血症的发病机制与药物治疗研究进展

高尿酸血症是由于嘌呤代谢紊乱使尿酸生成增多和（或）排泄减少所致的代谢性疾病。高尿酸血症不仅是引起痛风的重要生化基础,而且与高血压、高脂血症、动脉粥样硬化、肥胖、胰岛素抵抗的发生密切相关。因此,针对其发病机制和药物治疗的研究已成为关注热点。本文阐述了高尿酸血症的发病机制,并从抑制尿酸合成与促进尿酸排泄两个方面介绍了相关药物治疗的研究进展。     

基于URAT1蛋白表达研究小檗碱对高尿酸血症小鼠炎症反应及氧化应激的影响

目的 探索小檗碱对高尿酸血症小鼠炎症因子水平和氧化应激损伤的影响机制。方法 选取雄性SPF级昆明小鼠48只,分为对照组、模型组、苯溴马隆(20 mg/kg)组和小檗碱低、中、高剂量(50、100、200 mg/kg)组,每组8只。除对照组ig等量蒸馏水外,其余各组采用ig氧嗪酸钾和次黄嘌呤药物建立高尿酸血症小鼠模型,造模后苯溴马隆组ip给予20 mg/kg苯溴马隆,小檗碱低、中、高剂量组分别ig 50、100、200 mg/kg小檗碱,各组均连续给药1周。检测小鼠血清指标尿酸、肌酐(Cr)水平;ELISA法测定C反应蛋白(CRP)水平、超氧化物歧化酶(SOD)的活性及丙二醛(MDA)的含量;苏木素-伊红染色观察小鼠肾脏病理组织变化情况;Western blotting法检测肾脏尿酸转运蛋白URAT1在小鼠体内的表达水平。结果 与对照组相比,模型组小鼠血清尿酸、Cr、CRP水平、MDA含量和URAT1蛋白表达均显著升高,SOD含量明显减少(P<0.01)。与模型组相比,苯溴马隆组和小檗碱50、100、200 mg/kg组小鼠血清尿酸、Cr、CRP水平、MDA含量和URAT1蛋白表达显著降低,SOD含量明显增加(P<0.05、0.01)。小鼠肾脏HE染色结果提示,与模型组相比,小檗碱50、100、200 mg/kg组肾脏病理性改变的程度均有所缓解。而小檗碱100、200 mg/kg组与苯溴马隆组比较无明显差异。结论 小檗碱能降低高尿酸血症小鼠体内炎症水平,提高抗氧化能力。同时减轻高尿酸血症小鼠血清尿酸水平,其机制与抑制URAT1表达相关。     

萆薢降酸方对高尿酸血症小鼠模型的药效作用及其对肾脏尿酸盐转运体表达的影响

目的 研究萆薢降酸方提取物对高尿酸血症小鼠的抗高尿酸血症药效作用及其对肾脏蛋白的转运机制。方法 采用氧嗪酸钾致高尿酸血症小鼠模型,观察萆薢降酸方提取物对高尿酸血症小鼠的影响。以220、440、880mg/kg的剂量,连续10 d,以别嘌醇(5mg/kg)为阳性对照。采用比色法测定血清、尿酸、肌酐水平。同时用Western blot法分析肾脏尿酸盐转运蛋白1(URAT1)和阴离子转运蛋白1(OAT1)的蛋白质水平。结果 与模型组比较,高剂量萆薢降酸方可抑制血清中黄嘌呤氧化酶(XOD)活性(18.12±1.33u/L)和肝脏活性蛋白(70.15±5.20u/g)(P<0.05),降低血清尿酸(2.04±0.64mg/L)(P<0.05)和血清肌酐(0.35±0.18mol/L)尿素氮(8.83±0.71mmol/L)(P<0.05);升高尿酸(38.34±8.23mg/L)和尿肌酐(34.38±1.98mmol/L)水平,URAT1表达水平下调,OAT1表达水平上调(P<0.05)。结论 萆薢降酸方可能通过上调OAT1蛋白表达促进尿酸排泄、下调URAT1蛋白表达抑制尿酸重吸收的双重调节功能来促进尿酸在肾脏中的排泄。     

lesinurad的合成工艺研究

目的寻找一条合成尿酸转运体1(URAT1)抑制剂lesinurad的实用的合成路线。方法利用1-溴萘和环丙基溴化镁作为起始原料,经过10步反应合成了目标化合物lesinurad,并着重研究了由中间体4-环丙基-1-萘基异硫氰酸酯(4)合成中间体3-氨基-4-(4-环丙基萘-1-基)-1H-1,2,4-三唑-5(4H)-硫酮(7)的方法。结果合成了目标化合物,并利用IR、MS和1H-NMR确证了结构,此路线所得产品收率为18.2%,质量分数为99.17%。同时得到了一条由化合物4合成化合物7的新路线,大幅度提高了合成化合物7的收率。结论得到了一条合成lesinurad的实用路线,并获得了一种产率更高的合成重要中间体7的新方法。     

Novel drug discovery strategies for gout

Introduction: The increasing prevalence of gout has been accompanied by a growing number of patients intolerant to or with disease refractory to available urate-lowering therapies. These difficult-to-treat patients currently represent about 3 – 5% of people with gout in Europe and the United States, which highlights the need for emerging treatments to effectively lower urate levels.

Areas covered: In this review, the authors describe the putative pharmacological targets to lower urate levels. Furthermore, the authors discuss various strategies used to discover novel molecules or to improve available drugs used to treat gout.

Expert opinion: Major advances in our understanding of urate renal transport from in vitro, animal and genetic studies could lead to the development of novel uricosuric drugs. Targeting one or several urate transporters such as urate transporter 1, organic anion transporter 4 and 10 and glucose transporter 9 is promising. Moreover, design of small molecules capable of blocking the site activity of enzymes other than xanthine oxidase and involved in the purine pathway could generate novel hypouricemic drugs. Finally, polyethylene glycol (PEGylation) can significantly extend the biological half-life of drugs and reduce antigenicity and immunogenicity of proteins. The technology has been successfully applied to an uricase (pegloticase), but the drug was immunogenic in some patients. Strategies to decrease the immunogenicity of a PEG–uricase are important for developing next-generation uricase.     

RDEA3170的合成工艺研究

目的 寻找一条合成尿酸转运体1(URAT1)抑制剂RDEA3170的实用的合成路线。方法 利用3-溴-4-氯吡啶和1,4-二溴萘作为起始原料来合成RDEA3170,并着重研究1,4-二溴萘合成4-溴-1-萘腈(3)、化合物3 合成(4-氰基萘-1-基)硼酸(4)和Suzuki偶合3步关键反应的反应条件。结果 经6步反应合成了RDEA3170,并利用MS和¹H-NMR确证了结构,此路线总收率为16%;同时得到了上述3个关键步骤的最优化的反应条件。结论 得到了一条合成RDEA3170的实用路线。     

Investigational drugs for hyperuricemia

Introduction: The unmet need and the growing prevalence of hyperuricemia and its complications worldwide have pushed investigators to identify new agents to manage hyperuricemia.

Areas covered: This review discusses the drugs in preclinical and early clinical trials for hyperuricemia, their mechanisms of action and available results. This article reviews a total of 10 novel agents: i) drugs in Phase II/III trials – arhalofenate (MBX201), AC201, RDEA group of drugs (including lesinurad), tranilast, ulodesine (BCX4208); and ii) drugs in Phase I trials, including levotofisopam, UR1102, KX1151, LC350189 and Marine Active.

Expert opinion: The goal of emerging therapies is to address the unsatisfactory control of serum uric acid in patients with symptomatic hyperuricemia such as those with gout, to provide better tolerability compared to traditional agents and minimize the risk of adverse events, especially in patients with comorbidities and the elderly. Some drugs like arhalofenate, ulodesine (BCX-4208) and lesinurad are in or have completed Phase II and Phase III trials. The growing knowledge about the urate transporters in the kidney have advanced our knowledge of pathophysiology of hyperuricemia and have led to the development of several new potential treatment options. Availability of new drugs will lead to better management and address the unmet need in patients with symptomatic hyperuricemia in the coming years.     

小鼠高尿酸血症模型的研究

目的　建立小鼠高尿酸血症模型。方法　小鼠腹腔注射尿酸 ,1h后取血测定血清尿酸水平。结果　小鼠腹腔注射尿酸 12 5、2 5 0、5 0 0、10 0 0mg·kg-1,血清尿酸水平明显升高。尿酸 2 5 0mg·kg-1ip ,10min后小鼠血尿酸达高峰 ,高尿酸血症维持 4h以上。结论　小鼠腹腔注射尿酸可以形成高尿酸血症动物模型 ,以 2 5 0mg·kg-1剂量较好     

高尿酸血症研究进展

尿酸是人类嘌呤代谢的终产物 ,主要经过肾脏排泄。近年来高尿酸血症和痛风的发病率逐渐上升 ,长期高尿酸血症易诱发痛风 ,还容易累及肾脏和心血管系统。本文就高尿酸血症与X综合征、嘌呤代谢与尿酸的消除、高尿酸血症的遗传学研究、以及高尿酸血症的发生机制等方面进行了综述     

尿毒清颗粒联合非布司他治疗高尿酸血症的临床研究

目的探讨尿毒清颗粒联合非布司他治疗高尿酸血症的临床疗效。方法选取2014年3月—2016年3月在驻马店市中心医院治疗的高尿酸血症患者140例,随机分为对照组(70例)和治疗组(70例)。对照组患者口服非布司他片,40 mg/次,1次/d;治疗组在对照组基础上口服尿毒清颗粒,5 g/次,4次/d。两组患者均经过12周治疗。观察两组患者临床疗效,比较治疗前后两组患者血清黄嘌呤氧化酶(XOD)、尿酸(BUA)、血肌酐(Scr)、尿素氮(BUN)、血清炎性因子水平以及血清NO和ET-1水平。结果对照组临床总有效率为87.14%,显著低于治疗组的97.14%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者血清XOD、BUA、Scr、BUN水平均明显降低(P0.05);且治疗组比对照组降低的更明显(P0.05)。治疗后,两组患者血清白细胞介素-1β(IL-1β)、髓过氧化物酶(MPO)、可溶性细胞间黏附分子-1(s ICAM-1)、肿瘤坏死因子-α(TNF-α)水平均明显降低(P0.05);且治疗组患者血清炎性因子水平明显低于对照组(P0.05)。治疗后,两组患者血清NO水平显著升高,内皮素-1(ET-1)水平显著降低,同组比较差异具有统计学意义(P0.05);且治疗组患者NO和ET-1水平明显优于对照组(P0.05)。结论尿毒清颗粒联合非布司他治疗高尿酸血症可有效降低机体炎症反应,改善血管内皮功能,具有一定的临床推广应用价值。     

氯沙坦治疗原发性高血压并高尿酸血症

目的:观察氯沙坦治疗原发性高血压并高尿酸血症的降压和降尿酸作用.方法:68例原发性高血压并高尿酸血症患者,随机分为治疗组与对照组,观察给药前后血压和血尿酸变化.结果:两组均降压效果明显,治疗组能明显降低血尿酸,两组差异具有显著性.结论:氯沙坦降压同时可降尿酸.     

Transport of Nicotinate and Structurally Related Compounds by Human SMCT1 (SLC5A8) and Its Relevance to Drug Transport in the Mammalian Intestinal Tract

Purpose To examine the involvement of human SMCT1, a Na⁺-coupled transporter for short-chain fatty acids, in the transport of nicotinate/structural analogs and monocarboxylate drugs, and to analyze its expression in mouse intestinal tract. Materials and Methods We expressed human SMCT1 in X. laevis oocytes and monitored its function by [¹⁴C]nicotinate uptake and substrate-induced inward currents. SMCT1 expression in mouse intestinal tract was examined by immunofluorescence. Results [¹⁴C]Nicotinate uptake was several-fold higher in SMCT1-expressing oocytes than in water-injected oocytes. The uptake was inhibited by short-chain/medium-chain fatty acids and various structural analogs of nicotinate. Exposure of SMCT1-expressing oocytes to nicotinate induced Na⁺-dependent inward currents. Measurements of nicotinate flux and associated charge transfer into oocytes suggest a Na⁺:nicotinate stoichiometry of 2:1. Monocarboxylate drugs benzoate, salicylate, and 5-aminosalicylate are also transported by human SMCT1. The transporter is expressed in the small intestine as well as colon, and the expression is restricted to the lumen-facing apical membrane of intestinal and colonic epithelial cells. Conclusions Human SMCT1 transports not only nicotinate and its structural analogs but also various monocarboxylate drugs. The transporter is expressed on the luminal membrane of the epithelial cells lining the intestinal tract. SMCT1 may participate in the intestinal absorption of monocarboxylate drugs.     

高血压合并高尿酸血症与冠心病关系的研究

目的 观察评价高血压(EH)合并高尿酸血症(HUA)与冠心病(CAD)关系.方法 选取2016年3月至12月本院门诊及住院EH病人117例,随机对照试验(Randomized Controlled Trial,RCT)分为3组:单纯EH病人39例设为对照组,EH伴HUA病人39例设为观察A组,EH伴CAD病人39例设为观察B组;并总结3组之间的关系.结果 观察组TC、GLU、UA、Cr等指标均显著高于对照组(均P＜0.05);观察B组血尿酸浓度、HUA并发率均显著高于对照组(均P＜0.05);随冠状动脉病变血管支数的增加,血尿酸浓度与HUA患病率均明显升高,呈线性趋势(均P＜0.05).结论 EH合并HUA与CAD之间存在着必然的内在联系,HUA可能与EH和CAD的发生发展有一定的相关性,对其预后也产生一定影响,因此,显著控制患者血压、血清尿酸值,才能够有效防治和延缓CAD的发生.