Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.