Canagliflozin

Catalog No.S2760

Canagliflozin is a highly potent and selective SGLT2 inhibitor for hSGLT2 with IC50 of 2.2 nM, exhibits 413-fold selectivity over hSGLT1.

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Canagliflozin Chemical Structure

Canagliflozin Chemical Structure
Molecular Weight: 444.52

Validation & Quality Control

Quality Control & MSDS

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Canagliflozin is available in the following compound libraries:

Product Information

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Product Description

Biological Activity

Description Canagliflozin is a highly potent and selective SGLT2 inhibitor for hSGLT2 with IC50 of 2.2 nM, exhibits 413-fold selectivity over hSGLT1.
Targets mSGLT2 [1] rSGLT2 [1] hSGLT2 [1]
IC50 2 nM 3.7 nM 4.4 nM
In vitro Canagliflozin is a novel C-glucoside with thiophene ring. Canagliflozin inhibits Na+-dependent 14C-AMG uptake in a concentration-dependent fashion. Canagliflozin inhibits 14C-AMG uptake in CHO-hSGLT1 and mSGLT1 cells with IC50 of 0.7 μM and >1 μM, respectively. Canagliflozin inhibits the facilitative (non-Na+-linked) GLUT-mediated 2H-2-DG uptake in L6 myoblasts by less than 50%. In sham-injected oocytes, Canagliflozin (10 μM) or phlorizin (3 mM) alone in the presence of 50 μM DNJ does not affect currents. In SGLT3-injected oocytes, DMSO and Canagliflozin 10 μM inhibits DNJ-induced currents by 15.6% and 23.4%, respectively.[1]
In vivo Canagliflozin shows pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice. Oral administration at 30 mg/kg of Canagliflozin to male SD rats induces glucose excretion over 24 hours by 3,696 mg per 200 g body weight. Pharmacokinetic studies reveals a much higher exposure of Canagliflozin following oral administration. Following intravenous and oral doses of 3 and 10 mg/kg, respectively, to male SD rats, AUC0−inf, po, t1/2 and oral bioavailability are determined to be 35,980 ng·h/mL, 5.2 hours, and 85%, respectively. Thus, inhibition of SGLT2 in renal tubules after oral dosing of Canagliflozin is likely to continuously suppress reabsorption of glucose. The extensive UGE would reflect excellent pharmacokinetic properties of Canagliflozin in vivo as well as high potency of SGLT2 inhibition. Since most of the filtered glucose is reabsorbed by SGLT2 in the renal tubules, the novel compound would be useful for an anti-diabetic agent. Single oral administration of Canagliflozin at 3 mg/kg remarkably reduced blood glucose levels without influencing food intake in hyperglycemic high-fat diet fed KK (HF-KK) mice. There is a 48% reduction in blood glucose level versus vehicle at 6 hours. In contrast, Canagliflozin only slightly affects blood glucose levels in normoglycemic mice. Therefore, Canagliflozin would control hyperglycemia in the therapy of T2DM with low risk of hypoglycemia. [2]
Features

Protocol(Only for Reference)

Cell Assay: [1]

Cell lines L6 cell lines
Concentrations 0-10 μM
Incubation Time 24 hours
Method Cells from the rat skeletal muscle cell line, L6, is used to test the effect of Canagliflozin on glucose transporter 1 (GLUT1) activity. Cells are maintained in Dulbecco's modified Eagle's medium containing 5.6 mM glucose supplemented with 10% fetal bovine serum, are seeded in 24-well plates at a density of 3 × 105 cells/well and cultured for 24 hours in an atmosphere of 5% CO2 at 37 °C. Cells are rinsed twice with Kreb's ringer phosphate HEPES buffer (pH 7.4, 150 mM NaCl, 5 mM KCl, 1.25 mM MgSO4, 1.25 mM CaCl2, 2.9 mM Na2HPO4, 10 mM HEPES) and are pre-incubated with the solutions of Canagliflozin (250 μL, 10 μM) for 5 minutes at room temperature. The transport reaction is initiated by adding 50 μL of 4.5 mM 2-DG (a substrate for GLUTs)/3H-2-DG (0.625 μCi) followed by incubation for 15 minutes at room temperature. The 2-DG uptake is halted by aspiration of the incubation mixture. Cells are immediately washed 3 times with ice-cold PBS. Samples are extracted with 0.3 N NaOH, and radioactivity is determined by liquid scintillation.

Animal Study: [2]

Animal Models KK (HF-KK) mice
Formulation 0.2% CMC/0.2% Tween 80
Dosages 10 mg/kg
Administration Oral administration
Solubility 0.5% CMC/0.25% Tween 80, , 18 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA

SpeciesWeight (kg)Body Surface Area (m2)Km factor
Baboon120.620
Dog100.520
Monkey30.2412
Rabbit1.80.1512
Guinea pig0.40.058
Rat0.150.0256
Hamster0.080.025
Mouse0.020.0073
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

Value based on data from FDA Draft Guidelines: Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. (2002) Estimating the safe starting dose in clinical trials for therapeutics in adult healthy volunteers, U.S. Food and Drug Administration, Rockville, Maryland, USA.

For example, to convert the dose of resveratrol used in a mouse (22.4 mg/kg) to a dose based on surface area for 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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Liang Y, et al. PLoS One. 2012, 7(2), e30555.

[2] Nomura S, et al. J Med Chem. 2010, 53(17), 6355-6360.

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02220218 Not yet recruiting Healthy Janssen Research & Development, LLC August 2014 Phase 1
NCT02009488 Not yet recruiting Diabetes Mellitus, Type 2 Janssen Research & Development, LLC August 2014 Phase 1
NCT02139943 Recruiting Diabetes Mellitus, Type 1 Janssen Research & Development, LLC May 2014 Phase 2
NCT02000700 Recruiting Diabetes Mellitus, Type 2 Janssen Research & Development, LLC March 2014 Phase 1
NCT02077803 Completed Healthy Janssen Research & Development, LLC March 2014 Phase 1

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Chemical Information

Download Canagliflozin SDF
Molecular Weight (MW) 444.52
Formula

C24H25FO5S

CAS No. 842133-18-0
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 88 mg/mL (197 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% CMC/0.25% Tween 80, 18 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol

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