Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 Diabetes.

Abstract

A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.