Remogliflozin Etabonate, in a Novel Category of Selective Low-Affinity Sodium Glucose Cotransporter (SGLT2) Inhibitors, Exhibits Antidiabetic Efficacy in Rodent Models

Abstract

The low-affinity sodium glucose cotransporter (SGLT2) plays an important role in renal glucose reabsorption and is a remarkable transporter as a molecular target for the treatment of diabetes. We have discovered remogliflozin etabonate, which is a novel category of selective SGLT2 inhibitors. Remogliflozin etabonate is a prodrug based on benzylpyrazole glucoside and is metabolized to its active form, remogliflozin, in the body. We identified remogliflozin to be a potent and highly selective SGLT2 inhibitor by examining COS-7 cells transiently expressing either high-affinity sodium glucose cotransporter (SGLT1) or SGLT2. Orally administered remogliflozin etabonate increased urinary glucose excretion in a dose-dependent manner in both mice and rats. By increasing urinary glucose excretion, remogliflozin etabonate inhibited the increase in plasma glucose after glucose loading without stimulating insulin secretion in normal rats. Remogliflozin etabonate also showed antihyperglycemic effects in both streptozotocin-induced diabetic rats in oral glucose tolerance and in db/db mice in the fed condition. Chronic treatment with remogliflozin etabonate reduced the levels of fasting plasma glucose and glycated hemoglobin, and it ameliorated glucosuria in db/db mice. In high-fat diet-fed Goto-Kakizaki rats, remogliflozin etabonate improved hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and insulin resistance. This study demonstrates that treatment with remogliflozin etabonate exhibits antidiabetic efficacy in several rodent models and suggests that remogliflozin etabonate may be a new and useful drug for the treatment of diabetes.

SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models

“…These increases were much more apparent within the first 6 h rather than 6 h to 24 h postdose administration and were accompanied by an obvious decrease in blood glucose levels, demonstrating the ability of acute oral administration of SHR3824 to reduce blood glucose levels by enhancing urinary glucose excretion in diabetic rats and mice. BMS512148 showed pharmacological effects that were similar to SHR3824, consistent with previous reports using other SGLT2 inhibitors in glucose intolerant rodents, including rats fed a high-fat diet and Zucker fatty rats and mice [13,28] .…”

Familial Renal Glucosuria and SGLT2

“…In a variety of animal models, they have been shown to induce glucosuria, lower blood glucose without altering insulin levels, improve insulin sensitivity, and reduce hepatic glucose output (65)(66)(67)(68)(69). Some are now under evaluation in clinical trials, and published data are available for dapagliflozin, which is 1200-fold more selective for SGLT2 than SGLT1.…”

Carbohydrate Derivatives and Glycomimetic Compounds in Established and Investigational Therapies of Type 2 Diabetes Mellitus

“…Among pyrazole derivatives remogliflozin (Entry 5) showed a reassuring 365-fold selectivity for SGLT2 versus SGLT1 in vitro (Fujimori et al, 2008), and reached clinical developments (Isaji, 2007). In addition, an analogue of remogliflozin (Entry 6) presumably entered clinical trials as BI 44847 (Washburn, 2009b).…”

“…Remogliflozin etabonate R = COOEt (prodrug form) Remogliflozin R = H (active form) 12.4** (Fujimori et al, 2008) BI 44847 (Washburn, 2009b) 7. …”