摘要
C-Aryl 5a-carba-尾-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound <strong class="boldFont">5hstrong> with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (<strong class="boldFont">1strong>) and sergliflozin (<strong class="boldFont">2strong>), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that <strong class="boldFont">5hstrong> might be a promising drug candidate for the treatment of type 2 diabetes.