Prashant P. Deshpande

Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.

Microbial hydroxylation of o-bromophenylacetic acid: synthesis of 4-substituted-2,3-dihydrobenzofurans

Microbial hydroxylation of o-bromophenylacetic acid provided 2-bromo-5-hydroxyphenylacetic acid. This enabled a route to the key intermediate 4-bromo-2,3-dihydrobenzofuran for synthesizing a melatonin receptor agonist and sodium hydrogen exchange compounds. Pd-mediated coupling reactions of 4-bromo-2,3-dihydrobenzofuran provided easy access to the 4-substituted-2,3-dihydrobenzofurans.

Confirmation of the structure of tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone formed by silylation of D-glucono-1,5-lactone.

The structure of tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone made by the silylation of D-glucono-1,5-lactone has been confirmed by single-crystal X-ray analysis.

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

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.