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 resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO 80 mg/mL
Ethanol 80 mg/mL
Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes.
Clar C, et al. BMJ Open. 2012 Oct 18;2(5). PMID: 23087012.
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.
Whaley JM, et al. Diabetes Metab Syndr Obes. 2012;5:135-48. PMID: 22923998.
Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus.
Shah NK, et al. Pharmacotherapy. 2012 Jan;32(1):80-94. PMID: 22392830.
Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Meng W, et al. J Med Chem. 2008 Mar 13;51(5):1145-9. PMID: 18260618.
|Related SGLT Products|
Canagliflozin hemihydrate (JNJ-28431754; TA 7284) is a highly potent and selective SGLT2 inhibitor for hSGLT2 with IC50 of 2.2 nM.
|Dapagliflozin ((2S)-1,2-propanediol, hydrate)
Dapagliflozin(BMS512148) is a selective, orally active inhibitor of the renal sodium-glucose co-transporter type 2 (SGLT2) is in development for the treatment of type 2 diabetes mellitus (T2DM).
LX-4211 is an oral dual SGLT1/SGLT2 inhibitor with IC50 of 36 nM and 1.8 nM, respectively.
Phloretin is a dihydrochalcone found in apple tree leaves, which shows beneficial effects on diabetes.
Empagliflozin (BI-10773) is a potent and selective SGLT-2 inhibitor with IC50 of 3.1 nM, exhibits >300-fold selectivity over SGLT-1, 4, 5 and 6.
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