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EC50: 1.1±0.06 nM for hSGLT2
Selective inhibition of SGLT2 has been proposed to aid in the normalization of plasma glucose levels in patients with diabetes by preventing the renal glucose reabsorption process and promoting glucose excretion in urine. Dapagliflozin is a potent, selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) inhibitor.
In vitro: EC50 values of 1.1 nM for hSGLT2 and 1.4 μM for hSGLT1 determined for Dapagliflozin corresponded to 1200-fold selectivity for SGLT2 as compared with phlorizin’s 10-fold selectivity. Dapagliflozin inhibitory potencies against rat SGLT (rSGLT)2 and hSGLT2 were comparable, but the selectivity of Dapagliflozin for rSGLT2 versus rSGLT1 decreased to 200-fold [1].
In vivo: In vivo, dapagliflozin acutely induced renal glucose excretion in diabetic and normal rats, improved glucose tolerance in normal rats, as well as reduced hyperglycemia in Zucker diabetic fatty rats after single oral doses ranging between 0.1 and 1.0 mg/kg [2].
Clinical trial: Dapagliflozin dosing at 1, 2.5 and 5 mg/day is effective in reducing glycaemic levels and body weight in treatment-naive patients with type 2 diabetes. Dapagliflozin was well tolerated [3].
References:[1] Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008 Mar 13;51(5):1145-9. [2] Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, Wetterau JR, Washburn WN, Whaley JM. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008 Jun;57(6):1723-9.[3] Bailey CJ, Iqbal N, T'joen C, List JF. Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab. 2012 Oct;14(10):951-9.
Cell lines
Chinese hamster ovary cells stably expressing human SGLT2 and SGLT1
Reaction Conditions
1.1 nM (EC50)
Applications
Dapagliflozin inhibited accumulation of radiolabeled α-methyl-D-glucopyranoside, with EC50 values of 1.1 nM for human SGLT2 (hSGLT2) and 1.4 μM for hSGLT1.
Animal models
Sprague-Dawley rats
Dosage form
0.1, 1.0, and 10 mg/kg
Administered orally
In normal rats, a single oral dose of 0.1, 1.0, and 10 mg/kg of dapagliflozin induced respective losses of 550, 1100, and 1900 mg of glucose per 200 g of body weight over 24 h. In streptozotocin-induced diabetic rats, a single oral dose of 0.1 mg/kg of dapagliflozin resulted in a 55% reduction in blood glucose level. The above correlation of SGLT2 inhibition, glucosuria, and blood glucose-lowering effects suggest that selective SGLT2 inhibition by dapagliflozin holds promise as a viable approach to treat type 2 diabetes.
Note
The technical data provided above is for reference only.
References:
1. Meng W, Ellsworth BA, Nirschl AA, et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. Journal of Medicinal Chemistry, 2008, 51(5): 1145-1149.
