Design, Synthesis And Antidiabetic Activities Of A Novel Dipeptidyl Peptidase Ⅳ Inhibitors

Diabetes as a common comprehensive chronic disease can be divided in insulin-dependent diabetes mellitus (Type 1) and non-insulin-dependent diabetes mellitus (Type 2).Type 2 diabetes is a disease as a result of metabolic disorder caused by the islet cell function defect, occurring with the insulin resistance of peripheral tissue (such as muscle and fat), reduction of insulin secretion induced glucose in vivo and the increasing of liver gluconeogenesis. Type 2 diabetes has become a major worldwide public health problem. By the year 2025, it is projected that about 333 million patients will suffer from the type 2 diabetes mellitus representing approximately 90-95% of the diagnosed cases. Therefore, the study of this kind of medicine has become a very popular research. In order to search for new treatment methods, a lot of new drug targets have been developed, in which the research based on the target of DPP-Ⅳbecomes a hot spot.DPP-IV inhibitors can inhibit the activity of the body dipeptidyl peptidase IV, protect intestinal insulin from degrading, increase the activity of the glucagon-like peptide 1, 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 (developed by Novartis) and Saxagliptin (developed by BMS) are appearing on the market.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 some potential anti-diabetes drugs in this series of compounds. The one compound of them structured as follows:The work of this thesis is to design and synthesize a series of thiazole-bearing DPP-IV inhibitors with the compound above-mentioned as leading compound, 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,36 target compounds were synthesized and their structures were characterized by 1H NMR, 13C NMR, ESl-MS and IR.Their activities to decrease blood glucose level were determined through rat oral glucose tolerance test (OGTT) and the result showed that four compounds (6,8,21,26) exhibited potent activities to decrease the blood glucose level, with two(8 and26) being more potent than Sitagliptin. The result indicated that these four compounds are promising in the treatment of diabetes.