Showing papers by "William N. Washburn published in 2014"

Identification of a Nonbasic Melanin Hormone Receptor 1 Antagonist as an Antiobesity Clinical Candidate

Abstract: Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).

Chapter Twenty-Three - Case History: ForxigaTM (Dapagliflozin), a Potent Selective SGLT2 Inhibitor for Treatment of Diabetes

Abstract: Sodium–glucose cotransporter 2 inhibitors are a novel class of agents for the treatment of type 2 diabetes mellitus. These agents reduce hyperglycemia via a paradigm-breaking insulin-independent mechanism entailing promotion of glucosuria by inhibiting renal recovery of glucose. This chapter relates the salient events that enabled the evolution from hydrolytically unstable phenolic O-glucosides beginning with natural product phlorizin to glucosidase impervious C-aryl glucosides that culminated with the identification of dapagliflozin. The synthesis and pharmacology of dapagliflozin is briefly summarized. Disclosure of the synthesis and properties of these novel agents prompted the pharmaceutical industry to initiate more than 20 programs seeking C-glucosides that would emulate dapagliflozin.

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.