Synthesis and biological evaluation of novel C-indolylxylosides as sodium-dependent glucose co-transporter 2 inhibitors

Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are the current focus on the indication for the management of hyperglycemia in diabetes. Here, a novel series of C-linked indolylxyloside-based inhibitors of SGLT2 has been discovered. Structure–activity relationship studies revealed that substituents at the 7-position of the indole moiety and a p-cyclopropylphenyl group in the distal position were necessary for optimum inhibitory activity. The pharmacokinetic study demonstrates that the most potent compound 1i is metabolically stable with a low clearance in rats. In further efficacy study, 1i is found to significantly lower blood glucose levels of streptozotocin (STZ)-induced diabetic rats.

Graphical abstractA series of C-linked β-d-indolylxylosides were synthesized, and their inhibitory activities against SGLT1 and SGLT2 were measured. The pharmacokinetic and animal studies of the most potent compound were also performed.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of C-indolylxylosides was designed and synthesized. ► All the synthesized derivatives were evaluated for their inhibitory activities against hSGLT1 and hSGLT2. ► The most potent compound was subjected to pharmacokinetic and animal studies.