含噻唑环的新型二肽基肽酶Ⅳ抑制剂的设计、合成及降血糖活性研究
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摘要
2型糖尿病是一种由于代谢紊乱引起的疾病,已经在全世界范围内成为主要的公众健康问题。世界卫生组织最近的统计表明,全世界每年有近三百万人死于糖尿病。到2025年,全球将会有3.33亿2型糖尿病患者,这将占糖尿病患者总数的90-95%左右。在我国,目前2型糖尿病患者总数超过4000万,引起了医药的领域的极大关注。在寻找新的治疗方案中,许多新的药物靶点被开发,其中以DPP-Ⅳ为靶点的药物研究为热点。
DPP-Ⅳ抑制剂能抑制体内二肽基肽酶Ⅳ的活性,保护肠胰岛素不被降解,改善糖耐量异常及增加胰岛素敏感性。2006年默克公司的抗糖尿病治疗药物西他列汀(sitagliptin,商品名Januvia)作为首个DPP-Ⅳ抑制剂成功上市,随后诺华公司的维格列汀(vildagliptin,商品名Galvus)也于2007年也获得欧盟、美国等国的批准。由BMS公司研制的Saxagliptin,于2009年在美国上市,成为第三个上市的DPP-Ⅳ抑制剂类2型糖尿病治疗药物。临床应用的成功,更加引发了DPP-Ⅳ抑制剂研究的新的热潮。
在2004年,默克公司还发现了一类具有噻唑烷环的DPP-Ⅳ抑制剂。这一类化合物具有结构简单、活性高等特点。他们发现在这一系列化合物中,有两个是治疗2型糖尿病的非常好的潜在药物,它们的结构如下：
本论文的工作就是以上述两个化合物为先导,设计并合成了一些列含有噻唑环的DPP-Ⅳ抑制剂,以期发现新的潜在的治疗2型糖尿病药物。为了探索不同基团对药物活性的影响,我们分别从R端和噻唑环端对这一系列化合物进行了修饰,总共合成了49个目标化合物,其结构经过核磁氢谱、碳谱、质谱、红外表征。
通过小鼠口服糖耐量实验测试了它们的降血糖作用,结果显示其中九个化合物具有很强的降血糖作用,六个(23,31,35,41,43,49)与格列齐特相当,三个(12,16,38)强于格列齐特,显示了在治疗糖尿病方面的前景。仔细分析,可以确立明显的构效关系,结果表明噻唑环上的大体积基团,会导致化合物的活性较差。
Type 2 diabetes mellitus is a metabolic disorder, which is considered as a major public health issue all over the world. Recent WHO calculations indicate that almost 3 million deaths per year attribute to diabetes worldwide. By the year 2025, it is projected that about 333 million people will suffer from the type 2 diabetes mellitus (T2DM) representing approximately 90-95% of the diagnosed cases. There are more than 40 million people suffering from the type 2 diabetes mellitus (T2DM), which causes great concern in the medical areas. In the search for new treatment therapies, a number of new drug targets have been developed, in which the research based on the target of DPP-IV becomes a hot spot.
DPP-IV inhibitors can inhibit the activity of the body dipeptidyl peptidase IV, protect intestinal insulin from degrading, improve glucose tolerance and increase the sensitivities of insulin. In 2006, Merck's anti-diabetes medication Sitagliptin (trade name Januvia) becomes the first successful listing of DPP-IV inhibitors. Then, Vildagliptin (trade name Galvus) developed by Novartis received the European Union, the United States and other countries' approval in 2007. Another DPP-IV inhibitor Saxagliptin (developed by BMP), becomes the third listing of DPP-IV inhibitor for type 2 diabetes in 2009. The success of clinical application, triggers more research of DPP-IV inhibitors.
In 2004, Merck also developed a class of thiazolidine-bearing DPP-IV inhibitors. This series of compounds have simple structure but high activity. Their research found that there are two potential anti-diabetes drugs in this series of compounds. The two compounds are structured as follows:
The work of this thesis is to design and synthesize a series of thiazole-bearing DPP-IV inhibitors with the two compounds above-mentioned as leading compounds, with a view to the discovery of new potential treatment of type 2 diabetes drugs. In order to explore how drug activities vary among different groups, we modified the R-side and the thiazole-side. As a result,49 target compounds were synthesized and their structures were characterized by 1H NMR,13C NMR, ESI-MS and IR.
Their activities to decrease blood glucose level were determined through rat oral glucose tolerance test (OGTT) and the result showed that nine compounds exhibited potent activities to decrease the blood glucose level, with six (23,31,35,41,43,49) being comparable with Gliclazide, and three(12,16,38) being more potent than Gliclazide. The result indicated that these nine compounds are promising in the treatment of diabetes. Careful examination leads to the establishment of a significantly regular structure-activity relationship (SAR), which indicates that a bulk group of thiazole ring, will lead to less active compounds.
DPP-Ⅳ抑制剂能抑制体内二肽基肽酶Ⅳ的活性,保护肠胰岛素不被降解,改善糖耐量异常及增加胰岛素敏感性。2006年默克公司的抗糖尿病治疗药物西他列汀(sitagliptin,商品名Januvia)作为首个DPP-Ⅳ抑制剂成功上市,随后诺华公司的维格列汀(vildagliptin,商品名Galvus)也于2007年也获得欧盟、美国等国的批准。由BMS公司研制的Saxagliptin,于2009年在美国上市,成为第三个上市的DPP-Ⅳ抑制剂类2型糖尿病治疗药物。临床应用的成功,更加引发了DPP-Ⅳ抑制剂研究的新的热潮。
在2004年,默克公司还发现了一类具有噻唑烷环的DPP-Ⅳ抑制剂。这一类化合物具有结构简单、活性高等特点。他们发现在这一系列化合物中,有两个是治疗2型糖尿病的非常好的潜在药物,它们的结构如下：
本论文的工作就是以上述两个化合物为先导,设计并合成了一些列含有噻唑环的DPP-Ⅳ抑制剂,以期发现新的潜在的治疗2型糖尿病药物。为了探索不同基团对药物活性的影响,我们分别从R端和噻唑环端对这一系列化合物进行了修饰,总共合成了49个目标化合物,其结构经过核磁氢谱、碳谱、质谱、红外表征。
通过小鼠口服糖耐量实验测试了它们的降血糖作用,结果显示其中九个化合物具有很强的降血糖作用,六个(23,31,35,41,43,49)与格列齐特相当,三个(12,16,38)强于格列齐特,显示了在治疗糖尿病方面的前景。仔细分析,可以确立明显的构效关系,结果表明噻唑环上的大体积基团,会导致化合物的活性较差。
Type 2 diabetes mellitus is a metabolic disorder, which is considered as a major public health issue all over the world. Recent WHO calculations indicate that almost 3 million deaths per year attribute to diabetes worldwide. By the year 2025, it is projected that about 333 million people will suffer from the type 2 diabetes mellitus (T2DM) representing approximately 90-95% of the diagnosed cases. There are more than 40 million people suffering from the type 2 diabetes mellitus (T2DM), which causes great concern in the medical areas. In the search for new treatment therapies, a number of new drug targets have been developed, in which the research based on the target of DPP-IV becomes a hot spot.
DPP-IV inhibitors can inhibit the activity of the body dipeptidyl peptidase IV, protect intestinal insulin from degrading, improve glucose tolerance and increase the sensitivities of insulin. In 2006, Merck's anti-diabetes medication Sitagliptin (trade name Januvia) becomes the first successful listing of DPP-IV inhibitors. Then, Vildagliptin (trade name Galvus) developed by Novartis received the European Union, the United States and other countries' approval in 2007. Another DPP-IV inhibitor Saxagliptin (developed by BMP), becomes the third listing of DPP-IV inhibitor for type 2 diabetes in 2009. The success of clinical application, triggers more research of DPP-IV inhibitors.
In 2004, Merck also developed a class of thiazolidine-bearing DPP-IV inhibitors. This series of compounds have simple structure but high activity. Their research found that there are two potential anti-diabetes drugs in this series of compounds. The two compounds are structured as follows:
The work of this thesis is to design and synthesize a series of thiazole-bearing DPP-IV inhibitors with the two compounds above-mentioned as leading compounds, with a view to the discovery of new potential treatment of type 2 diabetes drugs. In order to explore how drug activities vary among different groups, we modified the R-side and the thiazole-side. As a result,49 target compounds were synthesized and their structures were characterized by 1H NMR,13C NMR, ESI-MS and IR.
Their activities to decrease blood glucose level were determined through rat oral glucose tolerance test (OGTT) and the result showed that nine compounds exhibited potent activities to decrease the blood glucose level, with six (23,31,35,41,43,49) being comparable with Gliclazide, and three(12,16,38) being more potent than Gliclazide. The result indicated that these nine compounds are promising in the treatment of diabetes. Careful examination leads to the establishment of a significantly regular structure-activity relationship (SAR), which indicates that a bulk group of thiazole ring, will lead to less active compounds.
引文
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