Design, Synthesis And Antidiabetic Activities Of Novel Sodium-glucose Co-transporter 2(SGLT2) Inhibitors

Diabetes mellitus is a serious and highly prevalent disease characterized by hyperglycemia, which leads to a number of complications including heart disease, retinopathy, nephropathy and neuropathy. Diabetes mellitus has become a significant social and economic problem. The use of current agents for diabetes mellitus is often limited by their potential to induce significant adverse effects. In addition, glycemic control can be difficult to attain, even with a combination of multiple oral agents, and with insulin added. Thus, the quest to develop therapeutic agents with novel mechanisms of action without side effects has been an urgent demand. The kidney has a key role in regulating glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood, which is a crucial evolutionary adaptation to maintaining glucose homeostasis and to retaining calories. Inhibiting this glucose reabsorption, thereby allowing its excretion in the urine (glycosuria), is therefore emerging as a potential new approach to the treatment of diabetes. Glycosuria, however, has historically been perceived as a sign of metabolic decompensation and of adverse clinical sequelae. Therefore, utilizing this manifestation as a therapeutic strategy for diabetes represents a paradigm shift. Sodium-dependent glucose co-transporters (SGLTs) are responsible for renal glucose reabsorption, with SGLT2 performing 90% of the glucose in the urine back to the bloodstream and the remaider by SGLT1. So SGLT2 has become an attractive target for a new class of antidiabetic drugs.Docking is a powerful computer-aided drug design approach, which is now widely applied in the drug screening and design. The crystal structure of SGLT2 has not been reported yet, so the three-dimensional structure model of SGLT2 was built by a homology method and then refined using a molecular dynamics method. Finally the antidiabetic activity of new designed compounds was predicted using molecular docking software (Schrodinger 9.0 and GROMACS 4.0).The reported SGLT2 inhibitors so far mainly consisted of O-glucosides and C-glucosides. All the O-glucosides did not undergo further development later because of their poor metabolic stabilities, lack of efficacies and side-effect profiles; however, C-glucosides overcame these defects. Our strategy was to substitute one of the benzene rings in the lead compound dapagliflozin with other aromatic heterocycles and saturated carbon rings. Thus, three rings, thiadiazole, tetrazole and trans-cyclohexane, were chosen to be incorporated into the newly designed inhibitors. Binding mode was demonstrated using the docking procedure.The convergent routes were employed to synthesize the target compounds. The desired thiadiazole, tetrazole and trans-cyclohexane rings were constructed via multi-step synthesis, which were subsequently coupled to the following glycoside moieties, 2,3,4,6-tetra-O-acetylglucopyranosyl bromide,2,3,4,6-tetra-O-acetylgalactopyranosyl bromide and persilylated gluconolactone. The adducts thus obtained were then elaborated to the target compounds through a sequence of reactions. Thirty-two new target compounds have been synthesized. All the compounds were characterized by 1H NMR,13C NMR, IR and HRMS, and the results were in agreement with the proposed structures.All the synthesized 32 compounds were evaluated in vivo with mice oral glucose tolerance test (OGTT), and compoundsâ…¢-1a,â…¢-1b,â…¢-1f,â…¢-11,â…£-11c,â…£-11e and â…¤-11c were found to exhibit significant hypoglycemic activity, which would direct the design of SGLT2 inhibitors in the future.