The Synthesis Of Vildagliptin Derivatives And Activity Screening

Glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP) are two important incretin hormones which secreted by gastrointestinal tract, also are the important adjustment factor of Insulin secretion and glycaemic control. Incretin can promote insulin secretion and control postprandial glucose in normal levels. But the dipeptidyl peptidase-4(DPP-4) is exist widely in tissue, it could make the GLP-1and GIP degrade rapidly and then loss biological activity, thus could prevent the secretion of insulin.By inhibiting DPP-4, the inhibitors prolong the action of GLP-1which stimulates the secretion of insulin, and protects0-cells, increases insulin sensitivity and delay gastric emptying. Finally, achieve the purpose of controlling blood sugar.Vildagliptin is a DPP-4inhibitors developed by Novartis for the treatment of type â…¡ diabetes which is launched officially in European Union in2008. It is a competitive, reversible and selective dipeptidyl peptidase-IV inhibitor. So the study of synthesis of vildagliptin is of great significance. In this paper, L-proline and amantadine hydrochloride were used as the starting materials for preparing the key intermediate1-(2-chloroacetyl) pyrrolidine-2-carbonitrile and3-amino-1-adamantanol respectively, Further to prepare the vildagliptin.In the second part, the chemical structure of vildagliptin is modified. vildagliptin was treated with lipoic acid to afford lipoic vildagliptin reported in a patent. Subsequently, the action of the control blood sugar concentration of lipoic vildagliptin is increased by the validation of pharmacology experiments. Using the experience of lipoic vildagliptin, vildagliptin is modified to obtain new chemical structures of which the action of the control blood sugar concentration is effective and the side effects is mild. As a result, the structure of vildagliptin was derived with cinnamon chloride,2-chlorobenzoyl chloride and3,5-dinitrobenzoyl chloride. Simultaneously, In the understanding of structure-activity relationship on vildagliptin, combined with the basic principle of the drug design and the mechanism of DPP-4. We used the4-chloroacetyl amino-N-methyl-3-propyl-lH-pyrazole-5-carboxamide replace the1-(2-chloroacetyl) pyrrolidine-2-carbonitrile. Finally, we gain four new chemical structures. Then the pure of vildagliptin derivatives was determined and the chemical structure was identified.In the third part, we mainly introduced the activity screening of the derivatives. Through the determination of IC50, the efficiency of inhibit DPP-4activity was compare for choosing the derivatives with higher activity.