Ge Xu

Design, Synthesis, and Biological Evaluation of Deuterated C-Aryl Glycoside as a Potent and Long-Acting Renal Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes

SGLT2 inhibitors deuterated at sites susceptible to oxidative metabolism were found to have a slightly longer tmax and half-life (t1/2), dose-dependent increase in urinary glucose excretion (UGE) in rats, and slightly superior effects on UGE in dogs while retaining similar in vitro inhibitory activities against hSGLT2. In particular, deuterated compound 41 has the potential to be a robust long-acting antidiabetic agent.

ortho-Substituted C-aryl glucosides as highly potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors

A series of 2-substituted C-aryl glucosides have been synthesized and evaluated for inhibition of hSGLT1 and hSGLT2. Introduction of an appropriate ortho substituent at the proximal phenyl ring adjacent to the glycosidic bond was found to improve SGLT2 inhibitory activity and dramatically increase selectivity for hSGLT2 over hSGLT1. Selected compounds were investigated for in vivo efficacy.