Design, Synthesis And Activity Study Of New Hypoglycemic Drugs Based On Glycine Receptors

Diabetes that preceded only by cardiovascular disease and neoplastic diseases is the third biggest leading cause of death,and it has been a serious killer to human health.It is lack of effective clinical treatment due to the complexity of pathological mechanism.The isletβcells of type 2 diabetes mellitus(T2DM)patients can not secrete adequate insulin in response to varying degrees of insulin resistance caused by over-nutrition,inactivity or obesity,which lending to high blood glucose levels.Consistently high blood glucose levels can lead to serious diseases affecting the heart and blood vessels,eyes,kidneys,and nerves.Cardiovascular disease is the most common cause of death and disability among patients with T2DM.In addition,the amount of isletβcell decrese because of apoptosis with the development of T2DM.More and more research showed that the chang of some amino acid、small molecules and their metabolites in human blood serum were directly or indirectly related to the prevention and development of T2DM.The study on these small molecules and their mechanism may bring new breakthrough in the treatment of T2DM.The previous study in our team showed that glycine provided cytoprotection on impaired isletβcell via glycine reccptor(GlyR);It is also confirmed that glycine had the effect of synergistic reaction with metformin hydrochloride.In addition,glycine can increase the amount of insulin secreted from impaired isletβcell.Base on the effect of cytoprotection and hypoglycemic of glycine receptor agonists,we carried out the drug design as follows:1.A series of twin drugs were synthesized with the amide linked between glycine receptor agonists and metformin.We expected a better effect of cytoprotection,hypoglycemic,pharmacokinetic and less side effect.2.A series of novel drugs are synthesized with glycine receptor agonists and the pharmacophore component.20 target compounds have been designed and synthesized and their structures were confirmed by ~1H-NMR and MS.The pharmacological experiment result showed that some target compounds provided excellent hypoglycemic effect,which shed new light on the prevention and treatment of hypoglycemic drug in T2DM.