Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners

Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole at the distal ring position were identified as potential antidiabetic agents. A selected compound demonstrated reasonable urinary glucose excretion and glucosuria in normal SD rats along with favorable blood glucose-lowering effects in db/db mice. Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine 59, 2-furan 61, and 3-thiophene 71 showed the best in vitro inhibitory activities to date (IC 50 = 3.51–7.03 nM) against SGLT2. A selected compound 61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.