醛糖还原酶抑制剂的研究进展

糖尿病是由遗传和环境因素相互作用引起胰岛素绝对或相对不足以及靶组织细胞对胰岛素敏感性降低，从而导致蛋白质、脂肪、水和电解质等代谢紊乱的综合征。根据世界卫生组织的报告，目前全球糖尿病人数1．8亿，中国高达6000多万。糖尿病患者长期高血糖状态可导致多种并发症，如糖尿病性白内障、周围神经病变、肾脏病、视网膜病、动脉粥样硬化等（见表1）。糖尿病并发症所致的高致死率和高致残率已成为严重的社会问题。从2001年起，连续5年，世界糖尿病日都将关注的重点放在糖尿病并发症的预防和控制上。研究证实，糖尿病并发症与高糖激活醛糖还原酶介导的多元醇代谢通路有关。醛糖还原酶抑制剂（aldose reductase inhibitor，ARI）可通过抑制多元醇通路有效地防治糖尿病并发症。本文综述了醛糖还原酶抑制剂的研究进展。     

醛糖还原酶抑制剂的研究进展

糖尿病慢性并发症与糖代谢多元醇通路激活有关,醛糖还原酶是此聚醇代谢通路中的限速酶.醛糖还原酶抑制剂能有效抑制此通路,减慢或改善糖尿病并发症,尤其是周围神经病变的进展.     

醛糖还原酶抑制剂筛选模型的研究进展

醛糖还原酶抑制剂是防治糖尿病急慢性并发症的重要药物之一,高通量、高灵敏度的筛选模型对于醛糖还原酶抑制剂的开发至关重要。本文对近年来醛糖还原酶抑制剂筛选模型的途径、类型、方法、优缺点及其应用进行了综述,为今后醛糖还原酶抑制剂的研究提供一定的参考。     

醛糖还原酶抑制剂筛选模型的建立和初步应用

本研究从牛晶状体中提取醛糖还原酶（AR），以DL－甘油醛为底物、还原型辅酶II（NADPH）为辅酶，应用96孔石英板建立醛糖还原酶抑制剂（ARI）微量高效筛选模型。酶促反应体系体积为200μl，其组成成分为：50mmol/L磷酸盐缓冲液（pH6.2)、400mmol/L硫酸锂、5mmol/L 2－硫基乙醇、0．24mmol/L NADPH 1.2mg粗酶、2mmol/L DL-甘油醛，用蒸馏水补足体积。反应温度为37℃，规定反应体系吸光度每分钟下降0．001为一个酶活力单位。以不含底物的样品为空白对照。开展了从微生物代谢产物中筛选ARI的工作，已经累计筛选真菌和稀有放线菌发酵样品约1500个，其中获得阳性样品6个，阳性率约为0．4％。     

微生物来源的醛糖还原酶抑制剂的研究进展

糖尿病并发症与糖代谢多元醇通路激活有关。醛糖还原酶是多元醇代谢通路中的限速酶,醛糖还原酶抑制剂能有效抑制此通路,减慢或改善糖尿病并发症。本文主要概述了微生物来源的醛糖还原酶抑制剂的研究进展。     

醛糖还原酶抑制剂的微量筛选模型的建立

从牛晶状体中提取醛糖还原酶，采用９６孔板建立该酶的体外微量高效筛选模型，筛选过程简便快捷。     

中药来源醛糖还原酶抑制剂的研究进展

醛糖还原酶抑制剂是治疗糖尿病并发症的重要药物之一,可通过抑制体内高血糖状态下被激活的多元醇通路中醛糖还原酶的活性而减少山梨醇的蓄积,预防和延缓糖尿病及其并发症的发生发展。中药来源的醛糖还原酶抑制剂来源更加广泛,显示了良好的应用前景。综述了2010—2020年报道的来源于中药的醛糖还原酶抑制剂及其在改善糖尿病并发症症状等方面取得的研究进展,主要包括生物碱类、黄酮类、酚酸类、皂苷类、多糖类,以及中药提取物,以期为新药研发提供依据。     

新型醛糖还原酶抑制剂的设计合成及活性评价

目的 设计合成一系列靛红衍生物,研究其对醛糖还原酶的抑制活性和选择性。方法 以5-溴靛红为起始原料合成5′-溴螺[[1,3]二氧戊环-2,3′-吲哚啉]-2′-酮的三环骨架,然后经N烷基化反应、Suzuki或Heck偶联、水解合成了目标化合物。测定目标化合物对醛糖还原酶的抑制活性和选择性,通过计算机辅助药物设计软件在分子水平上研究化合物与醛糖还原酶活性位点的相互作用模式。结果 设计合成了14个目标化合物,其结构经¹H-NMR、¹³C-NMR与MS谱确证。化合物6a～6g,8a～8f对醛糖还原酶具有良好的抑制活性和选择性。其中,化合物8d的活性最强,IC₅₀为0.090μmol·L^-1,与阳性对照药依帕司他相当。分子对接结果显示,化合物7、6b、8a和8d能与醛糖还原酶的活性位点较好结合。结论 构效关系和分子对接研究表明三环结构上N-1位的羧酸基团与C-5侧链上的苯乙烯结构是提高醛糖还原酶抑制活性的关键。甲氧基或者酚羟基的引入可显著改善化合物对醛糖还原酶的抑制活性和选择性。     

醛糖还原酶抑制剂的研究进展

醛糖还原酶是多元醇代谢通路的综述了醛糖还原酶抑制剂的研究进展.     

醛糖还原酶抑制剂的研究进展

醛糖还原酶是多元醇代谢通路的关键酶,对糖尿病并发症的产生有重要的影响。本文从作用机制、构效关系等方面综述了醛糖还原酶抑制剂的研究进展。     

New aldose reductase inhibitors as potential agents for the prevention of long-term diabetic complications

The results of recent clinical trials emphasise the importance of an improved glycaemic control in diabetic patients in order to prevent or at least to delay long-term complications. The difficulty in obtaining normalisation of blood glucose values has underlined the importance of the search for new and effective aldose reductase inhibitors (ARIs) to control the consequences of elevated glucose levels, therefore delaying the onset and retarding the progression of diabetic complications such as neuropathy, nephropathy, retinopathy and cataract. Although the physiological role of aldose reductase (ALR2) has not been clearly elucidated yet, it has been shown that this enzyme, the first of the polyol pathway, is responsible for the production of sorbitol from glucose. There are several pieces of evidence which link this process to the occurrence of diabetic complications. Orally active aldose reductase inhibitors can be grouped into two chemical classes: cyclic imide and carboxylic acid derivatives. This review describes the recent insights into these two classes of inhibitors, and the further development of ARIs provided with antidiabetic and antihyperlipidaemic properties. The most recent developments in understanding of the structure, catalytic mechanism and biochemical behaviour of ALR2 are also reported.     

Recent advances in aldose reductase inhibitors: potential agents for the treatment of diabetic complications

The development of long-term diabetic complications in diabetes patients is considered to be closely related to hyperglycaemia. Aldose reductase was first found to be implicated in the aetiology of secondary complications of diabetes. A variety of structurally diverse compounds have been observed to inhibit aldose reductase and effective, orally-active inhibitors of the enzyme have been investigated for almost 30 years. Although several of these compounds have progressed to the clinical level, only a few are currently on the market. Furthermore, the number of patents related to aldose reductase inhibitors has declined during recent years, whereas the number for other compounds, such as the inhibitors of the formation of advanced glycated end products and antioxidants, has increased. In this review, recent patents relevant to aldose reductase inhibitors are presented, following a short summary of early works. Lastly, rational approaches to the discovery of aldose reductase inhibitors are briefly reviewed.     

Ranirestat as a therapeutic aldose reductase inhibitor for diabetic complications

Background: There are currently very few drugs available to directly treat diabetic complications. Those that are indicated clinically provide symptomatic relief and do not address the underlying biochemical problems. The involvement of the sorbitol pathway in complications has provided mechanistic insights into the biochemistry of complications and the key enzyme, aldose reductase, has become an attractive pharmacologic target. Objective: Among the aldose reductase inhibitors, the most promising is ranirestat. This review outlines the studies with ranirestat and compares its efficacy with other similar inhibitors. Methods: A survey of in vitro and in vivo studies was conducted, and with publicly available data from clinical trials, ranirestat efficacy was compared with other similar agents. Results/conclusion: Ranirestat is safe, exhibits some efficacy and is perhaps the only agent advanced enough in clinical trials to warrant further consideration for diabetic complications.     

Aldose reductase inhibitors: 2013-present

Introduction: Aldose reductase (ALR2) is both the key enzyme of the polyol pathway, whose activation under hyperglycemic conditions leads to the development of chronic diabetic complications, and the crucial promoter of inflammatory and cytotoxic conditions, even under a normoglycemic status. Accordingly, it represents an excellent drug target and a huge effort is being done to disclose novel compounds able to inhibit it.

Areas covered: This literature survey summarizes patents and patent applications published over the last 5 years and filed for natural, semi-synthetic and synthetic ALR2 inhibitors. Compounds described have been discussed and analyzed from both chemical and functional angles.

Expert opinion: Several ALR2 inhibitors with a promising pre-clinical ability to address diabetic complications and inflammatory diseases are being developed during the observed timeframe. Natural compounds and plant extracts are the prevalent ones, thus confirming the use of phytopharmaceuticals as an increasingly pursued therapeutic trend also in the ALR2 inhibitors field. Intriguing hints may be taken from synthetic derivatives, the most significant ones being represented by the differential inhibitors ARDIs. Differently from classical ARIs, these compounds should fire up the therapeutic efficacy of the class while minimizing its side effects, thus overcoming the existing limits of this kind of inhibitors.     

Extraction and identification of three major aldose reductase inhibitors from Artemisia montana

Aldose reductase inhibitors (ARIs) provide an important therapeutic and preventive opportunity against hyperglycemia associated diabetic complications. The methanolic extracts of 12 species from the genus Artemisia exhibited significant in vitro rat lens AR (RLAR) inhibitory activities with IC₅₀ values ranging from 0.51 to 13.45 μg/mL (quercetin, 0.64 μg/mL). Since the whole plant of Artemisia montana showed the highest RLAR inhibitory activity, bioassay-guided fractionation was performed to obtain ethyl acetate and n-butanol fractions. Repeated column chromatography of two active fractions, yielded fifteen compounds, including four chlorogenic acids (3,5-di-O-caffeoylquinic acid, chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid), six flavonoids (apigenin, luteolin, quercetin, isoquercitrin, hyperoside, luteolin 7-rutinoside), and five coumarins (umbelliferone, scoparone, scopoletin, esculetin, and scopolin); their structures were confirmed by spectroscopic methods. 3,5-Di-O-caffeoylquinic acid and chlorogenic acid, as well as test flavonoids, displayed the most potent RLAR inhibitory activities with IC₅₀ values ranging from 0.19 to 5.37 μM. Furthermore, the HPLC profiles of the ethyl acetate and n-butanol fractions indicated that 3,5-di-O-caffeoylquinic acid, chlorogenic acid, and hyperoside, as major compounds, might play crucial roles in RLAR inhibition. The results suggest that A. montana and three key AR inhibitors therein would clearly be potential candidates as therapeutic or preventive agents for diabetic complications.     

糖尿病致病基因醛糖还原酶基因及其抑制剂筛选模型的构建及功能研究

目的基因工程方法建立人醛糖还原酶基因(AR)的蛋白分子模型,并将该模型应用于中草药AR抑制剂的初步筛选。方法将含基因AR及融合基因AR∷GFP的重组质粒pcDNA3.1/myc-His-AR及pcDNA3.1/myc-His-AG瞬时转染HEK293细胞,分别命名为HAR、HAG细胞株。通过荧光显微镜观察AR∷GFP的绿色荧光直接判断转染效果及估计基因AR的表达;Western blot、紫外分光光度法检测AR蛋白表达及AR酶活性。应用此HAR模型对黄芩苷等5种中草药进行初步筛选,并与经典AR抑制剂Sorbinil、Zopolrestat的抑制效果比较。结果GFP绿色荧光表达丰富,表明质粒转染效率较高;Western blot和紫外分光光度法显示:转染后HEK293细胞中AR蛋白表达量高,AR酶活性强(空白对照的2.5倍)。AR抑制剂筛选实验揭示,黄芩苷、虎杖苷、蕨麻多糖JM等中草药表现出与Sorbinil相近的AR抑制活性。结论AR的蛋白分子模型成功建立,此模型可得到较大量高活性AR酶蛋白,并可应用于AR抑制剂的初步稳定筛选;黄芩苷、虎杖苷、蕨麻多糖JM等中草药显示出潜在的AR抑制活性。     

人参皂苷对醛糖还原酶的抑制作用

目的糖尿病并发症与糖代谢的多元醇通路有关,而醛糖还原酶(aldose reductase,AR)是该通路的关键限速酶。本研究拟分析不同类型人参皂苷对AR的抑制作用,探讨其在糖尿病并发症治疗中的潜在应用价值。方法采用分光光度法测定不同类型人参皂苷对AR的抑制作用,并依据动力学曲线计算其半数抑制浓度((IC50));通过双倒数作图法确定人参皂苷对AR抑制作用的类型。结果人参皂苷Rb1、Rd、Rg1和Rg2对AR具有抑制作用,而人参皂苷Rb2、Rb3、Rc和Re的抑制作用不明显。进一步分析表明,人参皂苷Rd、Rg1和Rg2对AR的抑制作用强于"依帕司他",而Rb1的抑制作用较弱;另外,人参皂苷的浓度与其对AR的抑制作用正相关,且抑制类型均为反竞争性抑制。结论人参皂苷Rg2、Rg1、Rd对该AR具有较强的抑制作用,在糖尿病并发症治疗方面具有潜在的应用价值。     

Development of aldose reductase inhibitors for the treatment of inflammatory disorders

Introduction: Accumulating evidence attributes a significant role to aldose reductase (ALR2) in the pathogenesis of several inflammatory pathologies. Aldose reductase inhibitors (ARIs) were found to attenuate reactive oxygen species (ROS) production both in vitro and in vivo. Thus, they disrupt signaling cascades that lead to the production of cytokines/chemokines, which induce and exacerbate inflammation. As a result, ARIs might hold a significant therapeutic potential as alternate anti-inflammatory drugs.

Areas covered: The authors present a comprehensive review of the current data that support the central role of ALR2 in several inflammatory pathologies (i.e., diabetes, cancer, sepsis, asthma and ocular inflammation). Further, the authors describe the potential underlying molecular mechanisms and provide a commentary on the status of ARIs in this field.

Expert opinion: It is important that future efforts focus on delineating all the steps of the molecular mechanism that implicates ALR2 in inflammatory pathologies. At the same time, utilizing the previous efforts in the field of ARIs, several candidates that have been proven safe in the clinic may be evaluated for their clinical significance as anti-inflammatory medication. Finally, structurally novel ARIs, designed to target specifically the proinflammatory subpocket of ALR2, should be pursued.