(2S,3R,4R,5S,6R)-2-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-6-(hydroxymethyl)oxane-3,4,5-triol

• ChemBase编号: 72736
• 分子式: C21H25ClO6
• 平均质量: 408.8726
• 单一同位素质量: 408.1339662
• SMILES: c1(ccc(c(c1)Cc1ccc(cc1)OCC)Cl)[C@@H]1O[C@@H]([C@H]([C@@H]([C@H]1O)O)O)CO
• Canonical SMILES: CCOc1ccc(cc1)Cc1cc(ccc1Cl)[C@@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O
• InChI: InChI=1S/C21H25ClO6/c1-2-27-15-6-3-12(4-7-15)9-14-10-13(5-8-16(14)22)21-20(26)19(25)18(24)17(11-23)28-21/h3-8,10,17-21,23-26H,2,9,11H2,1H3/t17-,18-,19+,20-,21+/m1/s1
• InChIKey: JVHXJTBJCFBINQ-ADAARDCZSA-N

名称和登记号

名称

• IUPAC标准名: (2S,3R,4R,5S,6R)-2-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-6-(hydroxymethyl)oxane-3,4,5-triol
• IUPAC传统名: dapagliflozin
• 别名: (1S)-1,5-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol; BMS 512148; BMS-512148; Dapagliflozin

登记号

• CAS号: 461432-26-8
• PubChem SID: 162037657
• PubChem CID: 9887712
• ATC码: A10BX09
• CHEMBL: 429910
• Chemspider ID: 8063384
• 美国药典/FDA物质标识码: 1ULL0QJ8UC
• 维基百科标题: Dapagliflozin

理论计算性质

• Acid pKa: 12.567883
• 质子受体: 6
• 质子供体: 4
• LogD (pH = 5.5): 2.1109002
• LogD (pH = 7.4): 2.1108973
• Log P: 2.1109004
• 摩尔折射率: 104.9301 cm^3
• 极化性: 41.44848 Å^3
• 极化表面积: 99.38 Å^2
• 可自由旋转的化学键: 6
• 里宾斯基五规则: true

分子性质

理化性质

• 溶解度: DMSO; Methanol
• 外观: White Solid
• 熔点: 65-70°C

安全信息

• 保存条件: -20°C; -20°C Freezer, Under Inert Atmosphere

药理学性质

• 作用靶点: SGLT
• 给药途径: Oral

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S1548

Research Area

• Description: Type-2 diabetes mellitus

Biological Activity

• Description: Dapagliflozin is a potent and selective hSGLT2 inhibitor with EC50 of 1.1 nM.
• Targets: hSGLT2
• IC50: 1.1 nM (EC50) ^[1]
• In Vitro: Dapagliflozin is not sensitive to hSGLT1 with a 1200-fold IC50. ^[1] Dapagliflozin is 32-fold more potent than phlorizin against hSGLT2 but 4-fold less than phlorizin against hSGLT1. Dapagliflozin is highly selective versus GLUT transporters and displays 8–9% inhibition in protein-free buffer at 20 μM and virtually no inhibition in the presence of 4% bovine serum albumin. ^[2] Dapagliflozin has good permeability across Caco-2 cell membranes and is a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin is stable in rat, dog, monkey, and human serum at 10 μM. Dapagliflozin shows no inhibitory responses or induction to human P450 enzymes. The in vitro metabolic pathways Dapagliflozin are glucuronidation, hydroxylation, and O-deethylation. ^[3]
• In Vivo: Dapagliflozin reduces blood glucose levels by 55% after 0.1 mg/kg oral dose in hyperglycemic streptozotocin (STZ) rats, which is in part to the metabolic stability conferred by the C-glucoside linkage. Dapagliflozin displays a favorable absorption, distribution, metabolism, and excretion (ADME) profile and is orally bioavailable. ^[1] Dapagliflozin (1 mg/kg) causes significant dose-dependent glucosuria and increase in urine volume in normal rats over 24 hours post-dose. Dapagliflozin induces increase in urine glucose and urine volume excretion at 6 hours post-dose in Zucker diabetic fatty (ZDF) rats. Dapagliflozin lowers fasting and fed glucose levels in ZDF rats even by 2 weeks of treatment, without any marker of renal or liver toxicity. ^[2] Dapagliflozin significantly reduces the development of hyperglycaemia, with lowered blood glucose. Dapagliflozin could improve the insulin sensitivity, reduce β-cell mass and the development of impaired pancreatic function. ^[4]
• Clinical Trials: Currently under Phase III study in patients with type 2 diabetes.
• Features: More potent stimulator of glucosuria than other SGLT2 inhibitors.

Protocol

• Protocol: Kinase Assay ^[1]
• SGLT Binding Assays: Chinese hamster ovary (CHO) cells stably expressing human SGLT2 (hSGLT2) and human SGLT1 (\hSGLT1) are utilized for the development of transport assays using the selective SGLT substrate α-methyl-D-glucopyranoside (AMG). Dapagliflozin is assayed for the ability to inhibit [^14C]AMG uptake in a protein- free buffer over a 2 hours incubation period. The response curve is fitted to an empirical four-parameter model to determine the inhibitor concentration at half maximal response, reported as EC50. Protein-free buffer is 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.
• Protocol: Animal Study ^[1]
• Animal Models: Normal Sprague Dawley rats or streptozotocin induced male Sprague Dawley rats
• Formulation: 5% mpyrol, 20% PEG400, and 20 mM sodium diphosphate
• Doses: 0.01 –10 mg/kg (1 mL/kg) followed by a 50% glucose solution (2 g/kg)
• Administration: Dosed orally

References

• References: [1] Meng W, et al. J Med Chem, 2008, 51(5), 1145-1149.
• References: [2] Han S, et al. Diabetes, 2008, 57(6), 1723-1729.
• References: [3] Obermeier M, et al. Drug Metab Dispos, 2010, 38(3), 405-414.
• References: [4] Macdonald FR, et al. Diabetes Obes Metab, 2010, 12(11), 1004-1012.

Toronto Research Chemicals - D185370

A sodium-glucose transporter 2 inhibitor.

参考文献

• Meng W, et al. J Med Chem, 2008, 51(5), 1145-1149.
• Han S, et al. Diabetes, 2008, 57(6), 1723-1729.
• Obermeier M, et al. Drug Metab Dispos, 2010, 38(3), 405-414.
• Macdonald FR, et al. Diabetes Obes Metab, 2010, 12(11), 1004-1012.
• Kasichayanula, S. et al.: Diabetes, Obesity and Metabolism 13, 47 (2011)