Exploration of novel C-glucoside formation and application for SGLT2 inhibitors - Discovery of canagliflozin as a SGL T2 inhibitor

Inhibition of sodium glucose co-transporter 2 (SGLT2) in vivo increases urinary glucose excretion (UGE) and controls blood glucose levels in hyperglycemic animals. T-1095 is the first orally active SGLT2 inhibitor, and it was discovered by optimizing the natural glucosyl product phlorizin. We focused on aryl-C-glucosides and optimized the analogs, resulting in the discovery of canagliflozin, which is metabolically more stable than T-1095. Canagliflozin markedly induced UGE compared with that of T-1095 because of its excellent pharmacokinetic properties in vivo and its high potency for inhibiting SGLT2. Canagliflozin was selected as a clinical candidate for treating type 2 diabetes mellitus and was approved in the USA and EU in 2013 and in Japan in 2014. In this study, we describe the synthesis of new C-glucoside analogs using a palladium-catalyzed crosscoupling reaction of glucal boronate and its application as an SGLT2 inhibitor.