Dapagliflozin
(Synonyms: 达格列净; BMS-512148) 目录号 : GC15530
Dapagliflozin 是一种钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂，是一种新型抗糖尿病药物，由于其抑制 SGLT2 介导的肾葡萄糖重吸收的能力而被批准用于治疗 T2DM。
Cas No.:461432-26-8
Sample solution is provided at 25 µL, 10mM.
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| Cell experiment [1]: | |
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Cell lines |
Human hepatocyte-derived liver cells (LO2) and human hepatocellular carcinoma cells (HepG2) |
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Preparation Method |
Cells cultured in DMEM supplemented with 10% FBS at 37 ⊿in a humidified incubator containing 5% CO2, the cells were treated with 0.3 mM PA for 24 h to create the hepatocyte steatosis model in vitro. Then, hepatocytes were exposed to dapagliflozin at a concentration of 20 µM with or without chloroquine for 24 h. |
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Reaction Conditions |
20 µM;24h |
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Applications |
Exposure to 0.3 mM PA for 24 h dramatically increased the intracellular lipid accumulation in LO2 cells and HepG2 cells, whereas cotreatment with dapagliflozin could obviously attenuate the PA-induced lipid accumulation in both of hepatic cell lines. |
| Animal experiment [2]: | |
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Animal models |
Eight-week-old male BKS.Cg-Dock7m+/+Leprdb/Nju (db/db) mice |
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Preparation Method |
Mice were group-housed conventionally and maintained on a 12-h light/dark cycle with free access to food and water. After a one-week adaptation, the diabetic condition was confirmed if the fasting blood glucose was 11.1 mmol/L. The diabetic mice were randomly assigned to two groups with 9 mice per group, and treated by daily intragastric administration of 1 mg/kg dapagliflozin or vehicle (water) for 6 weeks. |
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Dosage form |
1 mg/kg;6 weeks;i.g. |
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Applications |
In db/db mice, treatment with dapagliflozin for 6 weeks had little effects on body weight. The fasting blood glucose level significantly declined after the 6-week treatment of dapagliflozin. |
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References: [1]. Li L, Li Q, et,al.Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway. Front Pharmacol. 2021 May 17;12:589273. doi: 10.3389/fphar.2021.589273. PMID: 34093169; PMCID: PMC8176308. |
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Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is a novel antidiabetic agent that is approved for the treatment of T2DM by based on its ability to inhibit SGLT2-mediated renal glucose reabsorption. In addition to providing effective glycaemic control, dapagliflozin help decrease body weight, reduce rate of cardiovascular death, and possibly slow the progression of diabetic kidney diseases[1-3].
Dapagliflozin(20 µM;24h) promoted ACC1 phosphorylation and ACOX1 protein expression, promoted autophagy and alleviated lipid accumulation in PA-stimulated LO2 cells and HepG2 cells[4]. In diabetic proximal renal tubule cells, Dapaglide(20 µM;48h) net improved HG-induced autophagy flux reduction and inhibited mTOR by increasing AMPK activity, meanwhile dapagliflozin inhibited NF-κB pathway inflammatory changes[9].
In db/db mice, treatment with dapagliflozin(1 mg/kg;6 weeks;i.g.) for 6 weeks had little effects on body weight. The fasting blood glucose level significantly declined after the 6-week treatment of dapagliflozin[5]. Dapagliflozin(30mg/kg/day; p.o.) attenuated SGLT2 expression, which could prevent excessive glucose absorption and increase AMPK phosphorylation in HFD-induced obese mice or OA-stimulated HuS-E/2 cells[6]. Dapagliflozin (1mg/kg; i.v.) given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury[7]. Dapagliflozin (1.5 mg/kg;23days; p.o.) provided glomerular protection in mice with protein-overload proteinuria induced by bovine serum albumin (BSA). Dapagliflozin limited proteinuria, glomerular lesions, and podocyte dysfunction and loss[8].
References:
[1]. Dhillon S. Dapagliflozin: A Review in Type 2 Diabetes. Drugs. 2019 Jul;79(10):1135-1146. doi: 10.1007/s40265-019-01148-3. Erratum in: Drugs. 2019 Dec;79(18):2013. PMID: 31236801; PMCID: PMC6879440.
[2]. Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs. 2012 Dec 3;72(17):2289-312. doi: 10.2165/11209910-000000000-00000. PMID: 23170914.
[3]. Plosker GL. Dapagliflozin: a review of its use in patients with type 2 diabetes. Drugs. 2014 Dec;74(18):2191-209. doi: 10.1007/s40265-014-0324-3. PMID: 25389049.
[4]. Li L, Li Q,et,al.Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway. Front Pharmacol. 2021 May 17;12:589273. doi: 10.3389/fphar.2021.589273. PMID: 34093169; PMCID: PMC8176308.
[5]. Wei R, Cui X, et,al. Dapagliflozin promotes beta cell regeneration by inducing pancreatic endocrine cell phenotype conversion in type 2 diabetic mice. Metabolism. 2020 Oct;111:154324. doi: 10.1016/j.metabol.2020.154324. Epub 2020 Jul 23. PMID: 32712220.
[6]. Chiang H, Lee JC, et,al. Delayed intervention with a novel SGLT2 inhibitor NGI001 suppresses diet-induced metabolic dysfunction and non-alcoholic fatty liver disease in mice. Br J Pharmacol. 2020 Jan;177(2):239-253. doi: 10.1111/bph.14859. Epub 2019 Nov 12. PMID: 31497874; PMCID: PMC6989948.
[7]. Lahnwong S, Palee S, et,al. Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury. Cardiovasc Diabetol. 2020 Jun 15;19(1):91. doi: 10.1186/s12933-020-01066-9. PMID: 32539724; PMCID: PMC7296726.
[8]. Cassis P, Locatelli M, et,al. SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy. JCI Insight. 2018 Aug 9;3(15):e98720. doi: 10.1172/jci.insight.98720. PMID: 30089717; PMCID: PMC6129124.
[9]. Xu J, Kitada M, et,al. Dapagliflozin Restores Impaired Autophagy and Suppresses Inflammation in High Glucose-Treated HK-2 Cells. Cells. 2021 Jun 10;10(6):1457. doi: 10.3390/cells10061457. PMID: 34200774; PMCID: PMC8230404.
Dapagliflozin 是一种钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂，是一种新型抗糖尿病药物，由于其抑制 SGLT2 介导的肾葡萄糖重吸收的能力而被批准用于治疗 T2DM。除了提供有效的血糖控制外，达格列净还有助于减轻体重、降低心血管死亡率，并可能减缓糖尿病肾病的进展[1-3]。
达格列净(20 µM;24h ) 促进 ACC1 磷酸化和 ACOX1 蛋白表达，促进自噬并减轻 PA 刺激的 LO2 细胞和 HepG2 细胞中的脂质积累[4]。在糖尿病近端肾小管细胞中，Dapaglide(20 µM;48h)通过增加AMPK活性净改善HG诱导的自噬通量减少和抑制mTOR，同时dapagliflozin抑制NF-κB通路炎症改变[9]。
在 db/db 小鼠中，用达格列净（1 mg/kg；6 周；i.g.）治疗 6 周对体重几乎没有影响。达格列净治疗 6 周后空腹血糖水平显着下降[5]。 Dapagliflozin（30mg/kg/天；口服）减弱了 SGLT2 的表达，这可以防止 HFD 诱导的肥胖小鼠或 OA 刺激的 HuS-E/2 细胞中的葡萄糖过度吸收并增加 AMPK 磷酸化[6]。缺血前给予达格列净（1mg/kg；静脉注射）可通过减少心律失常、缩小梗塞面积、减少心脏细胞凋亡和改善心脏线粒体功能、生物发生和动力学来量化最大水平的心脏保护作用，从而导致心脏 I 期间的 LV 功能改善/R 伤害[7]。 Dapagliflozin（1.5 mg/kg；23 天；口服）在牛血清白蛋白 (BSA) 诱导的蛋白质过载蛋白尿小鼠中提供肾小球保护。达格列净限制蛋白尿、肾小球病变以及足细胞功能障碍和丢失[8]。
| Cas No. | 461432-26-8 | SDF | |
| 别名 | 达格列净; BMS-512148 | ||
| 化学名 | (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol | ||
| Canonical SMILES | CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)C3C(C(C(C(O3)CO)O)O)O)Cl | ||
| 分子式 | C21H25ClO6 | 分子量 | 408.87 |
| 溶解度 | ≥ 15.1mg/mL in DMSO, ≥ 116.6 mg/mL in EtOH | 储存条件 | Store at-20°C,sealed storage, away from moisture |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4458 mL | 12.2288 mL | 24.4577 mL |
| 5 mM | 0.4892 mL | 2.4458 mL | 4.8915 mL |
| 10 mM | 0.2446 mL | 1.2229 mL | 2.4458 mL |
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Dapagliflozin: A Review in Type 2 Diabetes
Dapagliflozin (Forxiga?) is a highly potent, reversible and selective sodium-glucose cotransporter-2 inhibitor indicated worldwide for the treatment of type 2 diabetes (T2D). In the EU, oral dapagliflozin once daily is approved for use as monotherapy (in patients who are intolerant of metformin) and as add-on combination therapy (with other glucose-lowering agents, including insulin) for T2D when diet and exercise alone do not provide adequate glycaemic control. In numerous well-designed clinical studies and their extensions, dapagliflozin as monotherapy and combination therapy with other antihyperglycaemic agents provided effective glycaemic control and reduced bodyweight and blood pressure (BP) across a broad spectrum of patients. Dapagliflozin reduced the rate of cardiovascular (CV) death or hospitalization for heart failure (HHF), did not adversely affect major adverse CV events (MACE) and possibly reduced progression of renal disease relative to placebo in patients with established atherosclerotic CV disease (CVD) or multiple risk factors for CVD. Dapagliflozin was generally well tolerated, with a low risk of hypoglycaemia; diabetic ketoacidosis (DKA), although rare, and genital infections were more common with dapagliflozin than placebo. Given its antihyperglycaemic, cardioprotective and possibly renoprotective properties and generally favourable tolerability profile, dapagliflozin provides an important option for the management of a broad patient population, regardless of the history of CVD.
Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease
Background: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes.
Methods: Adults with eGFR of 25-75 ml/min per 1.73 m2 and urinary albumin-to-creatinine ratio of 200-5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin's effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m2) at baseline. The primary end point was a composite of time to ≡50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death.
Results: A total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval [95% CI]: -2 to 47%) reduction in the primary composite endpoint, and 29% (-2 to 51%), 17% (-53 to 55%), and 32% (-21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m2 per year in the dapagliflozin and placebo groups, respectively (P=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest.
Conclusions: Among patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.
Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy
Background: Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2.
Methods: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1.
Results: Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNF汐, TLR4). Dapagliflozin decreased blood glucose (874 ㊣ 111 to 556 ㊣ 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment.
Conclusion: Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.
A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy
Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 [94%] confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m2; and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were -3.5 and -4.7 mL/min/1.73m2/year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile.
Dapagliflozin: A Review in Type 1 Diabetes
Oral dapagliflozin (Edistride?, Forxiga?) is approved in the EU at a dosage of 5 mg/day as an adjunct to insulin in adults with type 1 diabetes (T1D) and a body mass index (BMI) of ≡ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. As a highly selective SGLT2 inhibitor, dapagliflozin decreases plasma glucose levels independently of insulin action and enables glycaemic control improvement without increasing the risks associated with intensive insulin therapy. In the phase III DEPICT-1 and -2 trials, dapagliflozin 5 mg/day as an adjunct to insulin improved glycaemic control and reduced total daily insulin dose and bodyweight relative to placebo in adults with inadequately controlled T1D, including in patients with a BMI of ≡ 27 kg/m2, over 24 weeks of treatment. In extensions of these trials, these improvements were maintained up to 52 weeks. Dapagliflozin was generally well tolerated with a manageable safety profile and a hypoglycaemia profile generally similar to placebo. The incidence of diabetic ketoacidosis with dapagliflozin in patients with a BMI ≡ 27 kg/m2 was less than half that of the overall population who received dapagliflozin. Dapagliflozin is the first SGLT2 inhibitor to be approved for use in T1D and, while further clinical experience in T1D is required to more definitively establish its efficacy and safety profile, it provides a promising adjunctive treatment option for adults with T1D and a BMI of ≡ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.