Design,Synthesis And Bioactivity Of SGLT2 Inhibitors

Objective:Type II diabetes mellitus is the chromic disease,characterized by a relative deficiency in insulin secretion and yperglycemia,and induces many microvascular complications.Agents are not effective to control the glycemic level whether for monotherapy or combination therapy.Therefore,more effective and novel drugs are strongly desired.More than 99%of the plasma glucose filtered in the kidney glomerulus is reabsorbed:90%is mediated predominantly by SGLT2 and to lesser extent by SGLT1.Selective inhibition of SGLT2 has been proposed to reduce plasma glucose levels in patients by inhibiting the renal glucose reabsorption process and progressing glucose excretion in urine.We know two main kinds of SGLT2 inhibitors,aryl O-glucosides and aryl C-glucosides.We pay no attention to aryl O-glucosides due to their poor selectivity and metabolic instability.Come over these shortages above,aryl C-glucosides have received great attention,especially Dapagliflozin and Canagliflozin have marketed in Uroppe and USA respectively.We design,synthesis and evaluated three kinds of aryl C-glucosides,modifying the chemical structure of Dapagliflozin,in order to searchsome effective SGLT2 inhibitors.Methods:We found SGLT2 inhibitors have the similar chemical structures:there is the glucose ring on the left connecting with the central ring-aryl ring by the C-aryl glucosides bond,and the benzylic methylene group between the central ring and the last ring-aryl ring on the right.In order to find some effective SGLT2 inhibitor and investigate the structure-activity relationships of the benzylic methylene group between the two benzene rings of Dapagliflozin,we design and synthesis three kinds of SGLT2 inhibitors:mono-methyl-dapagliflozin,gem-dimethyl-dapagliflozin,cyclopropyl-dapagliflozin.These compounds were synthesized and the bioactivity was evaluated through in vivo and in vitro test.We performed retro-synthetic analysis of D6:the target molecule is characterized by two structural features,6-deoxyglucose and C-glycoside.So two key steps,6-deoxylation and C-glycosidation,should be involved in retro-synthetic analysis.Given the cost of manufacture and the problem that dapagliflozin itself is a drug and has already been fully patented,we carried out 6-deoxylation before C-glycosidation and employed the convergent routes to synthesis D6.Results:We synthesized the target compounds through an about 10-step synthetic routes starting from the substituted-5-bromobenzoic acids,and got 13 compounds and characterize them by 1H-NMR,13C-NMR,HR-MS and IR.Evaluation of biological activity demonstrated that all the three the compounds exhibited potent bioactivity and some compounds performed drugability.We synthesized the compound D6 successfully through the designed route by the starting iodide reductive,acidic hydrolysis of methyl glycosides,Swern oxidation,BF3·Et2O-mediated reduction with Et3SiH,cleavage of benzyl groups,intensively screened iodide reductive under hydrogenolysis,acidic hydrolysis of methyl glycosides,cleavage of benzyl groups.We improved the productivity and lower the cost so that we can satisfy the pharmacology needs.Conclusion:We found the SARs of these compounds:mono-methy\SGLT2 inhibitors were stronger than gem-methyl compounds,then cyclopropyl compounds,so modifying the benzylic methylene group between the two aryl rings can keep the activity of SGLT2 inhibitor,and the bigger the group was,the less potent it has.The best substitution was C-Cl in the aryl ring.We explain the SARs of benzylic methylene group firstly and systermatically in the field.We may find better drugability molecule in this study.The synthesis route of D6 was the general method for the various kinds of deoxy-C-glucosides,characterized by low cost,good reproducibility high yield and the independent intellectualpropert rights.We performed this route and provided material security for the preclinical study of D6.We firstly found SrCl₂ as an efficient,green,controllability co-catalyst for acidic hydrolysis of methyl glucosides.The study was widely used in small-scale labrotary experiments and verified in the bigger-scale synthesis.