Synthesis And Pharmacodynamics Study Of A Dual SGLT-1/SGLT-2 Inhibitor

Diabetes is a very common chronic metabolic disease that has become a very prominent public health problem worldwide.Sodium-glucose co-transfer protein-1/sodium-glucose co-transfer protein-2（SGLT-1/SGLT-2）are two important glucose transporter proteins.SGLT-1 mainly mediates glucose uptake in the intestine,while SGLT-2 mainly mediates glucose reabsorption in the kidney.Therefore,by simultaneously inhibiting SGLT-1 and SGLT-2,it is possible to achieve a better hypoglycemic effect.In this thesis,A series of compounds based on Sotagliflozin as the lead compound have been synthesized and evaluated,of which a dual SGLT-1/SGLT-2 inhibitor,compound HEC82375,have been successfully screened with high in vitro and in vivo inhibitory activity.Compound HEC82375 is a dual SGLT-1/SGLT-2 inhibitor compound(SGLT-1:IC₅₀=5.21 n M;SGLT-2:IC₅₀=2.22 n M).OGTT and urinary glucose excretion data from SD rats showed that the hypoglycemic rate of compound HEC82375 at the dose of 1 mg/kg and the effect of promoting urinary glucose excretion were better than sotagliflozin at the dose of 3 mg/kg.In db/db diabetic mice,compound HEC82375 at the dose of 0.3 mg/kg to reduce random blood glucose in mice was close to Sogliflozin at the dose of 1 mg/kg.At different doses of 1.0 mg/kg,3.0 mg/kg and 10mg/kg,the blood glucose decline rate of compound HEC82375 on a sugar load(AUC_{0¹20 min})in C57BL/6 mice was 30.94%,47.07%,and 59.31%,respectively.The results of the OGTT test in normal SD rats showed that the blood glucose lowering rate(AUC_{0⁶0 min})was 35.63%,45.17%,and 60.32%,respectively.Additionally,urinary glucose excretion was significantly increased in a dose-dependent manner.Compound HEC82375 increased t GLP-1 secretion of rats in a dose-dependent manner.In the db/db diabetic mice,the efficacy of compound HEC82375 in reducing random blood glucose at the dose of 0.3 mg/kg was similar to that of Sotagliflozin at the dose of 1 mg/kg.The results of a single pharmacodynamic experiment in ZDF rats showed that compound HEC82375 reduced random blood glucose even at the dose of 0.1 mg/kg.The long-term efficacy tests of ZDF rats showed that compound HEC82375could reduce fasting blood glucose,random blood glucose and Hb A1c in a dose-dependent manner at doses of 0.1 mg/kg,0.3 mg/kg and 1.0 mg/kg.Pharmacokinetic data showed that the oral bioavailability of compound HEC82375 was 100.2%.In order to more conveniently provide a large number of samples for the subsequent development of compound HEC82375,a pratical synthesis method of compound HEC82375 suitable for amplification has been subsequently designed and amplified based on this method.