The Discovery Of Novel Anti-diabetic Candidate Targeting To Sodium-glucose Co-transporter 2

Type-II diabetes,a kind of disease people always strive to overcome,severely threats the health of human beings.The development of anti-diabetes drugs with both safety and effectiveness are urgently expected.Sodium glucose co-transporter 2(SGLT2),which is mainly expressed in the kidney,plays a vital role in maintaining the stability of blood glucose,and conducts 90%of the reabsorption of glucose in human body.SGLT2 inhibitors can specifically restrain glucose reabsorption in renal tubule,and promote the excretion of glucose through urine,thus attain the effects of lowering glucose level,losing weight and improving the symptom of obesity indirectly.In summary,it is a brand novel strategy to treat type ? diabetes through looking for specific SGLT2 inhibitors to suppress the activity of SGLT2,restraining the reabsorption of glucose in proximal tubule,and lowering the blood glucose level.The chemical research group cooperating with us in this program has obtained small molecule compounds with novel structure by comprehensively analyzing,designing and synthesizing the structure of current SGLT2 inhibitors.On the basis of optimizing and stabilizing isotope labeling method to screen SGLT2 inhibitors,we have obtained compounds with strong inhibition activity through testing the activity of SGLT2 inhibition the designed and synthesized series of compounds on cellular level.Then we have obtained 3 active compounds(with an IC50 value less than 10 nM,and a selectivity value more than 1000 folds)by examining the selectivity on SGLT1,a homological protein.Then we obtained 2 active compounds(LD-20 and LD-23)by exploring the effect on urine glucose excretion of single administration on normal rats and mice.Through pharmacokinetics research and comparison of LD-20 and LD-23,we ensured LD-20 as our novel target candidate drug of SGLT2.LD-20 boasts 1.4 nM of IC50,more than 2000 folds of SGLT1 selectivity on cellular level.The single administration of LD-20 can promote the urine glucose excretion of SD rats both dose-dependently and dramatically,with an onset dose of 0.3 mg/kg;it can also promote the clearance rate of oral glucose on SD rats dose-dependently,with an onset dose of 1 mg/kg;it can promote the urine glucose excretion of C57BL/6J mice,with an onset dose of 0.3 mg/kg.On db/db mice,a spontaneous type ? diabetes mellitus model,the single administration of LD-20 can lower the random blood glucose in 6 h with dose dependency,and the onset dose is 3 mg/kg;the chronic administration for 4 weeks can dramatically lower the random blood glucose level,fasting glucose level and glycosylated hemoglobin level with an onset dose of 0.3 mg/kg.The efficiency of LD-20 obviously precedes that of positive control Tofogliflozin and is close to that of Dapagliflozin;the chronic administration of LD-20 is able to promote the oral glucose tolerance of db/db mice;whether the multiple adminmstration of LD-20 can protect and promote metabolism-related tissues and organs such as liver,heart,pancreas and kidney,still needs further study.In summary,through activity screening in vitro and effect evaluation in vivo,we have obtained candidate drug LD-20 with excellent activity in vitro and good hypoglycemic activity in vivo.Primary pre-clinical research shows that this compound boasts better hypoglycemic effect compared to positive control Tofogliflozin and good oral bioavailability.Meanwhile,mice showed good tolerance to high dose LD-20,suggesting that this candidate drug possesses promising prospect of development.Systematical pre-clinical research of this candidate drug has been launched at present.