Design, Synthesis And Anti-diabetic Activities Of Thiazole-bearing Compounds As Novel Dipeptidyl Peptidase Ⅳ Inhibitors

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.