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| Targets |
Luseogliflozin targets the sodium-dependent glucose cotransporter 2 (SGLT2), a protein primarily expressed in the proximal tubule of the kidney. SGLT2 is responsible for the reabsorption of the majority of filtered glucose from the glomerular filtrate back into the bloodstream. By inhibiting SGLT2, Luseogliflozin reduces glucose reabsorption, leading to increased urinary glucose excretion (glucosuria) and a consequent decrease in blood glucose levels. This mechanism is insulin-independent, making it effective even in patients with insulin resistance or impaired insulin secretion. Luseogliflozin is a competitive inhibitor of human SGLT2, with a Ki of 1.10 nM and an IC50 of 2.26 nM. It demonstrates high selectivity for SGLT2 over SGLT1 (approximately 1,765-fold), which is clinically relevant because SGLT1 is also expressed in the gastrointestinal tract, and its inhibition can cause gastrointestinal side effects. The compound's selectivity and potency make it an effective and well-tolerated antidiabetic agent. In addition to its effects on glucose, SGLT2 inhibition also promotes β-cell proliferation and improves glycemic control. Luseogliflozin's target, SGLT2, is a well-validated therapeutic target for type 2 diabetes, and its inhibition provides a safe and effective approach to lowering blood glucose.
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| ln Vitro |
Luseogliflozin (TS-071, 3p), a strong inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2), with an IC50 of 2.26 nM and a selectivity that is roughly 1765 times more than that of SGLT1 (IC50, 3990 nM). It may be used as a treatment for type 2 diabetes [1].
Luseogliflozin demonstrates potent in vitro activity as an inhibitor of SGLT2. It competitively inhibits human SGLT2-mediated glucose uptake with a Ki of 1.10 nM and an IC50 of 2.26 nM. This high potency indicates that Luseogliflozin binds with high affinity to SGLT2 and effectively blocks its function. The compound demonstrates approximately 1,765-fold selectivity over SGLT1 (IC50 = 3,990 nM). This selectivity is critical for minimizing off-target effects, particularly in the gastrointestinal tract where SGLT1 is expressed. The inhibition of SGLT1 can lead to glucose malabsorption and diarrhea, so the high selectivity of Luseogliflozin for SGLT2 is a significant advantage. In vitro studies using cells expressing human SGLT2 have confirmed the compound's potent and selective inhibitory activity. These findings establish Luseogliflozin as a highly potent and selective SGLT2 inhibitor with a favorable in vitro profile for the treatment of type 2 diabetes. |
| ln Vivo |
In rats and dogs, luteogliflozin (1 mg/kg, po) demonstrates good PK properties, excellent urine glucose excretion properties, and hypoglycemic effects [1].
Luseogliflozin demonstrates significant in vivo activity, primarily by lowering blood glucose levels through increased urinary glucose excretion. In vivo, oral administration at 1 mg/kg produces marked blood glucose–lowering effects and robust urinary glucose excretion in both rat and dog models. This demonstrates its efficacy in different species and supports its potential for human use. In addition to its glucose-lowering effects, Luseogliflozin (10 mg/kg, oral, 7 days) improves hyperglycemia and promotes β-cell proliferation in mice. This suggests that Luseogliflozin may have beneficial effects on pancreatic β-cell function beyond simply lowering blood glucose. The compound's favorable pharmacokinetic profile, including oral bioavailability, supports its utility in metabolic disease studies. Luseogliflozin is approved in Japan for the treatment of type 2 diabetes, confirming its clinical efficacy and safety. These in vivo results demonstrate that Luseogliflozin is a potent and effective SGLT2 inhibitor with significant therapeutic potential for the management of type 2 diabetes. |
| Enzyme Assay |
The in vitro enzyme/receptor binding (non-cellular) assay for Luseogliflozin typically involves assessing its inhibitory activity against SGLT2 and SGLT1 using a cell-free system or cells expressing the transporters. In a typical assay, cells expressing human SGLT2 or SGLT1 are incubated with a radiolabeled or fluorescently labeled glucose analog (e.g., [14C]-α-methyl-glucopyranoside, AMG) and varying concentrations of Luseogliflozin. The uptake of the labeled substrate into the cells is measured, and the inhibition of uptake by Luseogliflozin is used to calculate the IC50 and Ki values. For Luseogliflozin, this method has been used to determine its Ki of 1.10 nM and IC50 of 2.26 nM for SGLT2, and its IC50 of 3,990 nM for SGLT1, demonstrating its high potency and selectivity. These assays are crucial for characterizing the compound's inhibitory activity and selectivity at the molecular level.
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| Cell Assay |
The in vitro cellular assay for Luseogliflozin typically involves evaluating its effects on glucose uptake in cells expressing SGLT2. In a typical assay, cells (e.g., Chinese hamster ovary cells) are engineered to express human SGLT2. These cells are then incubated with a radiolabeled or fluorescently labeled glucose analog (e.g., [14C]-AMG) in the presence of varying concentrations of Luseogliflozin. The uptake of the labeled substrate into the cells is measured, and the inhibition of uptake by Luseogliflozin is used to calculate the IC50. The results show that Luseogliflozin potently inhibits SGLT2-mediated glucose uptake. This cellular assay provides functional evidence for the compound's activity as an SGLT2 inhibitor in a relevant biological context.
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| Animal Protocol |
The in vivo animal experimental protocol for Luseogliflozin typically involves the use of rat, dog, or mouse models to assess its effects on blood glucose and urinary glucose excretion. In a typical study, animals are administered Luseogliflozin orally at various doses (e.g., 1 mg/kg). Blood and urine samples are collected at various time points to measure glucose levels. The compound's ability to lower blood glucose and increase urinary glucose excretion is then assessed. For studying its effects on β-cell proliferation, mice are treated with Luseogliflozin (10 mg/kg, oral, 7 days), and pancreatic tissue is collected for histological analysis. These in vivo models are essential for demonstrating the compound's efficacy and for understanding its mechanism of action in a whole-organism context.
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| ADME/Pharmacokinetics |
Luseogliflozin is characterized as being orally active, with favorable pharmacokinetic properties that support its once-daily dosing. In vivo, oral administration at 1 mg/kg produces marked blood glucose–lowering effects and robust urinary glucose excretion in both rat and dog models. This indicates that the compound is well-absorbed and has sufficient systemic exposure to exert its pharmacological effects. Specific PK parameters such as half-life, clearance, and volume of distribution are not detailed in the provided references. However, the compound's approval for clinical use in Japan confirms that it has a favorable PK profile in humans. Luseogliflozin has a molecular weight of 434.55. Further details on its PK properties can be found in the clinical literature.
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| Toxicity/Toxicokinetics |
Specific toxicity (toxicology) data for Luseogliflozin are not detailed in the provided references. However, as an approved drug for the treatment of type 2 diabetes in Japan, its safety profile has been extensively evaluated in clinical trials. The compound is generally well-tolerated, with the most common side effects being related to its mechanism of action, such as urinary tract infections and genital infections due to increased glucose in the urine. Comprehensive toxicological assessments, including acute and chronic toxicity studies, genotoxicity, and carcinogenicity, have been conducted to support its clinical development.
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| References | |
| Additional Infomation |
Luseogliflozin is a diarylmethane drug. Luseogliflozin has been used in clinical trials investigating its use for the treatment of type 2 diabetes.
Luseogliflozin is also known as TS-071 and is co-marketed as Lusefi®. It is a potent, selective, and orally active inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). Luseogliflozin competitively inhibits human SGLT2 with a Ki of 1.10 nM and an IC50 of 2.26 nM, and demonstrates ~1,765-fold selectivity over SGLT1. It reduces the reabsorption of renal filtered glucose and decreases the renal glucose threshold to increase urinary glucose excretion. Luseogliflozin is approved in Japan for the treatment of type 2 diabetes. In vivo, it produces marked blood glucose–lowering effects and promotes β-cell proliferation in mice. Its favorable pharmacokinetic profile supports its utility in metabolic disease studies. |
| Molecular Formula |
C23H30O6S
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|---|---|
| Molecular Weight |
434.547
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| Exact Mass |
434.176
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| CAS # |
898537-18-3
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| Related CAS # |
Luseogliflozin hydrate;1152425-66-5
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| PubChem CID |
11988953
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
624.5±55.0 °C at 760 mmHg
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| Melting Point |
155.0-157.0℃
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| Flash Point |
331.5±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.616
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| LogP |
4.43
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
30
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| Complexity |
514
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CCOC1=CC=C(C=C1)CC2=CC(=C(C=C2C)OC)[C@H]3[C@@H]([C@H]([C@@H]([C@H](S3)CO)O)O)O
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| InChi Key |
WHSOLWOTCHFFBK-ZQGJOIPISA-N
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| InChi Code |
InChI=1S/C23H30O6S/c1-4-29-16-7-5-14(6-8-16)10-15-11-17(18(28-3)9-13(15)2)23-22(27)21(26)20(25)19(12-24)30-23/h5-9,11,19-27H,4,10,12H2,1-3H3/t19-,20-,21+,22-,23+/m1/s1
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| Chemical Name |
(2S,3R,4R,5S,6R)-2-[5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl]-6-(hydroxymethyl)thiane-3,4,5-triol
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| Synonyms |
TS71 TS-071 TS 71 TS071 TS-71
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3012 mL | 11.5062 mL | 23.0123 mL | |
| 5 mM | 0.4602 mL | 2.3012 mL | 4.6025 mL | |
| 10 mM | 0.2301 mL | 1.1506 mL | 2.3012 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Investigation on Renal Protective Effect by Luseogliflozin
CTID: jRCTs071180077
Phase: Status: Complete
Date: 2019-03-26
Products are for research use only; We do not sell to patients
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