Preparation Of Sodium-glucose Co-transporter-2Inhibitors And Study On Their Type II Antidiabetic Activities

Diabetes can be divided into type I diabetes and type II diabetes, theformer is due to pancreatic β-cells can not produce enough insulin(absolute lack of insulin), and the later is due to lack of insulin secretionor insulin resistance (the relative lack of insulin). There are about90-95%of type II diabetes in diabetic patients.Sodium-glucose co-transporters (SGLT) are a family of glucosetransporter which are found in the intestinal mucosa of the small intestine(SGLT1) and the proximal tubule of the nephron (SGLT2and SGLT1).They contribute to renal glucose reabsorption. The sodium-glucoseco-transporter-2(SGLT2) is a low-affinity transport system that isspecifically expressed in the kidney and play a very important role inrenal glucose reabsorption in the proximal tubule. Selective inhibitors ofSGLT2is an innovative therapeutic strategy for the treatment of type IIdiabetes patients by enhancing glucose loss through the urine.Now the leader in the field of SGLT2inhibitors is Dapagliflozin(BMS-512148), which is developed by Bristol-Myers Squibb and AstraZeneca, and it is in Phase III clinical study. This article is based onDapagliflozin as the lead, through the modification and improvement ofits chemical structure, we synthesize the analogue of Dapagliflozin. Weexpect to get a better activity, selectivity and metabolic stability ofcompounds, for the development of the new foundation as SGLT2inhibitors.We first synthesized Dapagliflozin, and studied its structure-activityrelationship. We found that it had less steric hindrance between A ringand B ring. Based on the molecular structure of simulation, if we addsome groups or side chains to B ring, the steric hindrance between A ringand B ring will be increased, and maybe it will form more stablemolecular conformation, so it is possible to make the compounds moreselectively bind the proteins, thereby enhancing SGLT2/SGLT1selectivity. In addition, the structural modification of B ring may increasethe metabolic stability of the compounds. Therefore, this paper mainlycarried out the modification and transformation of its B ring. Wesynthesized six compounds, whose structures were confirmed byHPLC-MS and H1-NMR. After experimental testing and comparison, theinitial in vitro screening tests of antidiabetic effects shown that thesecompounds had better in vitro human SGLT2inhibition activity thanDapagliflozin. The human SGLT2inhibition activity of compound C isabout100times of Dapagliflozin. In terms of human SGLT2/SGLT1 selectivity, compound A and compound E are equal to or slightly higherthan Dapagliflozin, while compound D, B and F, are respectively2times,3times and6times comparing with Dapagliflozin. Moreover, compoundC whose selectivity of human SGLT2and SGLT1is about660times ofDapagliflozin, so compound C deserves further study. Basically, thesedata achieves the initial design purpose, which lay the foundation for theexploration of new selective SGLT2inhibitors.