The Study Of Screening Drugs And Efficacy Evaluation For SGLT-1/2 Inhibitor

Sodium-dependent glucose transporters 1/2?SGLT-1/2?inhibitor is a kind of novel oral hypoglycemic drug with non-insulin-dependent.Currently,there is only one drug approved for the development as a SGLT-1/2 dual-target inhibitor drug.However,SGLT-2 single-target inhibitor hypoglycemic drugs have completed multiple clinical studies and accumulated a large number of clinical efficacy and safety data.SGLT-2 inhibitor drugs can not only effectively reduce Hb A1c,but also reduce body weight and blood pressure with low risk of hypoglycemia.In addition,there are related studies showing that it can reduce the risk of cardiovascular events and end-stage renal disease.In this project,SGLT-1/2 dual-target inhibitors were used as drug targets.Through pre-clinical in vitro and in vivo evaluation experiments,compounds with good efficacy for type 2 diabetes were screened to meet the clinical needs.Firstly,through the in vitro activity screening experiments related to SGLT-1/2 targets,Compound 05,a candidate compound with better in vitro activity which meets the screening criteria at the same time,was selected from 25 new compounds.The SGLT-1 target IC₅₀ of this compound is 53.7n M,and the SGLT-2 target IC₅₀ is 1.4n M,which is similar to the positive drug.In order to research the preclinical pharmacokinetics of Compound 05,we carried out pharmacokinetic study on SD rats,C57BL/6 mice and beagle dogs,and the stability test in liver microsomes in vitro.The results show that Compound 05 is well absorbed in animals and has high bioavailability.Stability is moderately superior in dog and human liver microsome systems,but in rat,mouse,and monkey liver microsome systems is relatively poor.Finally,in order to further investigated the hypoglycemic activity of the Compound 05through a series of in vivo pharmacodynamic verification study.The results show that for normal animals,Compound 05 has a significant effect of reducing postprandial blood glucose and urinary glucose excretion,and the effective dose in mice is 3 mg/kg.For the diabetic model animals,after single and long-term administration with Compound 05 has obvious diabetes treatment effect on type 2 diabetic db/db mice.When the dose is 2mg/kg,it shows a significant effect of reducing blood sugar and Hb A1C.The hypoglycemic effect is similar to LX4211.In summary,Compound 05,a candidate compound,shows excellent pharmacodynamic activity in preclinical pharmacodynamic studies and is expected to develop into a new SGLT1/2inhibitor drug for the treatment of type 2 diabetes.