ABSTRACT
OBJECTIVE: To study the generality of the structure-activity relationships (SARs) of 3-deoxylation and 6-deoxylation of the sugar moiety in SGLT2 inhibitors. METHODS: Based on the earlier study, 3-deoxycanagliflozin (compound 5), 6-deoxyipra-gliflozin (compound 6), 6-deoxyempagliflozin (compound 7) and 3-deoxyempagliflozin(compound 8) were synthesized and evaluated by in vitro hSGLT2 and hSGLT1 inhibitory assay. RESULTS: The deoxylated SGLT2 inhibitors were synthesized from their corresponding aryl halides 9a-9c and 3-/6-deoxylated perbenzylated gluconolactones 11a-11b. In vitro hSGLT2 and hSGLT1 inhibitory assay showed that compounds 5 and 8 almost lost SGLT2 inhibitory activity, while compounds 6 and 7 exhibited similar activities to their corresponding parent compounds. CONCLUSION: It seems a general rule that 6-deoxylation of the sugar moiety in SGLT2 inhibitors has no effect on the SGLT2 inhibitory activity, whereas the effect of 3-deoxylation on SGLT2 inhibitory activity depends on the structures of the specific SGLT2 inhibitors, which does not show a universal rule.