Design,Synthesis And Biological Evaluation Of Novel Sodium Glucose Co-transporter 2(SGLT2)Inhibitors

Diabetes mellitus(DM)is becoming a common and frequently occurring disease,trending to be a serious threat to human health.Type 2 diabetes mellitus(T2DM),a chronic metabolic disorder of glucose homeostasis characterized by hyperglycemia,which results mainly from the impaired insulin secretion and/or insulin resistance(the relative lack of insulin),accounts for nearly 90%of all cases of diabetes.Hyperglycemia without adequate treatment can cause a number of severe complications,including retinopathy,nephropathy,stroke and neuropathy,as well as macrovascular changes.Several therapeutic agents are available for monotherapy or for combination therapy with different mechanisms to treat diabetics,such as sulphonylureas,thiazolidinediones,biguanides,alpha-glucosidase inhibitors,DPP-4 inhibitor,GLP-1 agonist and insulin.Although there are many anti-diabetic drugs,the hyperglycemia still can not be controlled in many cases.In addition,These agents described above are known to cause undesirable side effects.Thus,there is a strong medical need for novel potent hypoglycemic agents with novel mechanisms of action and a good safety and efficacy to treat patients with uncontrolled T2DM.Recently,inhibitors of sodium glucose co-transporter 2(SGLT2)have received considerable attention due to their distinct mechanism of action that reduces blood glucose levels independently of insulin secretion.The kidney plays an important role in regulating glucose levels.greater than 99%of the plasma glucose is filtered through the renal glomerulus and then reabsorbed into the blood in the proximal tubules of the nephron.sodium dependent glucose co-transporters(SGLTs)are membrane proteins and mediators of reabsorption of filtered glucose in the kidney.There are two major types of glucose co-transporters in SGLTs,namely SGLT1 and SGLT2.SGLT2,a high-capacity,low-affinity transporter,is located mainly on the luminal surface of the epithelial cells lining SI segment of the proximal convoluted tubule in the kidney,which is responsible for approximately 90%of renal glucose reabsorption against a concentration gradient.Suppressing glucose reabsorption through inhibition of human SGLT2 would promote urinary glucose excretion,thereby reducing plasma glucose levels.The sodium glucose co-transporter 2(SGLT2)was considered as an important target.This report describes the design and synthesis of a series of novel SGLT2 inhibitors(al-a7)as well as their dehydrate dihydrofuran derivatives(bl-b7),which were prepared by Mitsunobu reaction.The cell-based SGLT2 inhibition assay was then performed to evaluate the inhibitory effects of all synthesized compounds on hSGLT2 activities,and used dapagliflozin as positive reference.Compound a6 and a7 were found to be the most potent compounds with IC50 values of 0.63 and 0.81 nM,respectively.However,all the dehydrate derivatives lose the SGLT2 inhibitory activity,with inhibition percentage no more than 66.5%at the concentration of 0.5μM,which might because of the configuration inversion at C-2 of glucose or the loss of structural flexibility.In conclusion,the present study improves understanding of the SAR of SGLT2 inhibitors,and provided more information that could be applied to design new molecules.