Design And Synthesis Of Novel Small Molecule Glucokinase Activators

In recent years, the incidence of diabetes increased rapidly, people's health has been seriously threatened. With the development of research, glucokinase has been an important target of treating type-2 diabetes. Based on this target, the research of small molecule glucokinase activators are very active.The main work of the thesis is design and synthesis of noval small molecule glu-cokinase activators, and this paper can be devided into three chapters.In the first chapter, we systematically summarized mostly glucokinase activators, which had been reported by some well-known companies and research institutions, and found the main design idea:First, a central structure was established, this center could be single atoms, such as carbon, nitrogen, etc., or it might be benzene ring or other aromatic rings. According to the combination principles, other necessary active groups were brought in. In consideration of the space structure of glucokinase and the binding sites between glucokinase and small molecule activators, most of the molecules need three branchs. One of the three branchs was heterocyclic amide, as hydrogen bond's donator and receptor, it combined with glucokinase activators. That's the main part of active structure. The other two branches were alkyl or aryl groups, as hydrophobic groups they embed into the hydrophobic cavity of glucokinase.In the second chapter, we designed and synthesised small molecule glucokinase activators with pyridine-2(1H)-one ring. The pyridine-2(1H)-one ring's 1,3,5-site can be replaced,1-site and 5-site were the structure of hydrophobic groups,3-site was the structure of heterocyclic amides. At last we got 40 new compounds, including 6 5-phenyl substitude pyridine-2(1H)-one compounds.19 nitrogen substitude compounds. 8 oxygen replace by-products and 7 variable compounds of heterocyclic part.In the last chapter, Shanghai Pharmaceutical Research Institute's test results showed that eight of these compounds could active glucokinase. After that, we primary analysed the structure-activity relationship of these compounds. it have an important meaning for the further design of small molecule glucokinase activator with pyridine-2(1H)-one ring.