Discovery and Development of Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Dapagliflozin for the Treatment of Type 2 Diabetes

Abstract

When blood flows through the renal capillaries, glucose is one of the many substances filtered by the kidney. However, glucose is subsequently recovered primarily by the sodium-dependent glucose transporter 2 (SGLT2) as the glomerular filtrate flows down the renal tubules. SGLT2 inhibitors inhibit this transporter leading to the loss of a significant fraction of the filtered glucose. The resulting glucosuria is of sufficient magnitude to reduce diabetes-related hyperglycemia and ameliorate-associated complications of diabetes. A systematic study was conducted to identify superior SGLT2 inhibitors based on a β- 1C-arylglucoside with substituted diarylmethane moieties. Such compounds are potent and selective SGLT2 inhibitors with metabolic stability that promote glucosuria when administered in vivo. Through this investigation, the β- 1C-arylglucoside dapagliflozin was identified as a potent and selective hSGLT2 inhibitor with an EC50 for hSGLT2 of 1.0 nM and 1,200-fold selectivity over hSGLT1. Dapagliflozin produced glucosuria in normal Sprague Dawley rats in a dose-dependent fashion. Moreover, a 0.1 mg/kg oral dose reduced blood glucose levels by as much as 55% in rats that had been made hyperglycemic by streptozotocin, a pancreatic toxin. These findings, combined with a favorable ADME profile and vivo data, led to nomination of dapagliflozin as a drug for the treatment of type 2 diabetes. The structural architecture of β- 1C-arylglucosides and their amphiphilic nature presented significant obstacles to the synthesis of dapagliflozin and similar candidates for toxicological and clinical testing, prompting the development of a new, safe, efficient, and economical process for the synthesis of C-4′ and C-4 substituted β- 1C-arylglucosides. A key element of the process was a remarkable discovery of novel crystalline complexes that enabled isolation and quality control.