Dapagliflozin (BMS-512148) is a novel selective inhibitor of sodium-glucose co-transporter type 2. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of glucuretic, antihyperglycemic drugs that target the process of renal glucose reabsorption and induce glucuresis independently of insulin secretion or action. Dapagliflozin (BMS-512148) inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine. In initial clinical trials, Dapagliflozin 10 mg reduced HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40) compared to placebo. Phase II and III clinical trials have demonstrated that dapagliflozin is a safe and effective method for treating type 2 diabetes. Dapagliflozin (BMS-512148) produces a sustained, dose-dependent reduction in plasma glucose levels while simultaneously improving insulin secretion and sensitivity. Therapy with dapagliflozin also results in a mild osmotic-diuretic effect that may account for decreases in total body weight (~2-3 kg) and blood pressure (systolic 2-5 mm Hg, diastolic 1.5-3 mm Hg), and increases in hematocrit (1-2%).
|Cell lines||CHO cells|
|Preparation method||SGLT Binding Assays.
Chinese hamster ovary (CHO) cells stably expressing human SGLT2 (hSGLT2) and human SGLT1 (hSGLT1) (Genbank accession numbers M95549 and M24847, respectively) were utilized for the development of transport assays using the selective SGLT substrate -methyl-D-glucopyranoside (AMG). Inhibitors were assayed for the ability to inhibit [14C]AMG uptake in a protein-free buffer over a 2 h incubation period. The response curve was fitted to an empirical four-parameter model to determine the inhibitor concentration at half maximal response, reported as EC50. Protein-free buffer was used to simulate the low-protein conditions of the glomerular filtrate, which bathes the SGLT targets on the lumenal surface of the proximal tubule in the kidney.
|Incubation time||2 h|
|Animal models||Normal Sprague Dawley rats|
|Formulation||5% mpyrol, 20% PEG 400, and 20 mM sodium diphosphate|
|Dosages||single dose of 0.01-10 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO 80 mg/mL|
|Storage||-20°C, dry, sealed|
 Whaley JM, et al. Diabetes Metab Syndr Obes. Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus.
|Related SGLT Products|
Enavogliflozin (DPW-16001), an antidiabetic compound, is a first class selective sodium-glucose cotransporter-2 (SGLT-2) inhibitor with oral activity.
|Remogliflozin etabonate (GSK189075)
Remogliflozin etabonate (GSK189075) is an orally active, selective and low-affinity inhibitor of sodium glucose cotransporter (SGLT2) with Ki of 1950 nM, 2140 nM, 43100 nM, 8570 nM for hSGLT2, rSGLT2, hSGLT1, rSGLT1, respectively. Remogliflozin etabonate exhibits antidiabetic efficacy in rodent models.
Bexagliflozin (EGT1442, EGT-0001442, THR-1442) is a potent and selective SGLT2 inhibitor with an IC50 of 2 nM.
KGA-2727 is a potent, selective, high-affinity inhibitor of sodium glucose cotransporter 1 (SGLT1) with Ki of 97.4 nM and 43.5 nM for human SGLT1 and rat SGLT1, respectively. The selectivity ratios (Ki for SGLT2/Ki for SGLT1) of KGA-2727 are 140 (human) and 390 (rat). KGA-2727 exhibits antidiabetic efficacy in rodent models.
|Ertugliflozin L-pyroglutamic acid
Ertugliflozin L-pyroglutamic acid (PF-04971729 L-pyroglutamic acid) is a potent, selective and orally active inhibitor of the sodium-dependent glucose cotransporter 2 (SGLT2), with an IC50 of 0.877 nM for h-SGLT2.
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