Canagliflozin (JNJ 28431754)

Catalog No.S2760 Batch:S276001

Technical Data

Formula	C₂₄H₂₅FO₅S
Molecular Weight	444.52	CAS No.	842133-18-0
Solubility (25°C)*	In vitro	DMSO	89 mg/mL (200.21 mM)
		Ethanol	89 mg/mL (200.21 mM)
		Water	Insoluble
* <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. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

Canagliflozin (TA 7284, JNJ 28431754) is a highly potent and selective SGLT2 inhibitor for hSGLT2 with IC50 of 2.2 nM in a cell-free assay, exhibits 413-fold selectivity over hSGLT1.

Targets

mSGLT2 ^[1] (Cell-free assay)	rSGLT2 ^[1] (Cell-free assay)	hSGLT2 ^[1] (Cell-free assay)
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, AUC_0−inf, po, t_1/2 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]

Protocol (from 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 Dosages 10 mg/kg Administration Oral administration

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
Dosages
10 mg/kg
Administration
Oral administration

References

Customer Product Validation

: Data from [Data independently produced by , , Mol Metab, 2016, 5(10):1048-56]

: Data from [Data independently produced by , , Cardiovasc Diabetol, 2018, 17(1):106]

: Data from [Data independently produced by , , Am J Physiol Lung Cell Mol Physiol, 2015, 309(9):L1027-36. ]

: Data from [Data independently produced by , , Drug Metab Dispos, 2015, 43(10):1468-76.]

Selleck's Canagliflozin (JNJ 28431754) has been cited by 33 publications

Nuclear translocation of metabolic enzyme PKM2 participates in high glucose-promoted HCC metastasis by strengthening immunosuppressive environment [ Redox Biol, 2024, 71:103103]	PubMed: 38471282
Canagliflozin primes antitumor immunity by triggering PD-L1 degradation in endocytic recycling [ J Clin Invest, 2023, 133(1)e154754]	PubMed: 36594471
Canagliflozin ameliorates hypobaric hypoxia-induced pulmonary arterial hypertension by inhibiting pulmonary arterial smooth muscle cell proliferation [ Clin Exp Hypertens, 2023, 10.1080/10641963.2023.2278205]	PubMed: 37970663
The impact of SGLT2 inhibitors on αKlotho in renal MDCK and HK-2 cells [ Front Endocrinol (Lausanne), 2023, 14:1069715]	PubMed: 36967770
Study on the pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in obesity-related atrial fibrillation based on network pharmacology and experimental verification [ Ann Transl Med, 2023, 11(8):300]	PubMed: 37181345
Systematic identification of biomarker-driven drug combinations to overcome resistance [ Nat Chem Biol, 2022, 10.1038/s41589-022-00996-7]	PubMed: 35332332
SGLT2 inhibitor activates the STING/IRF3/IFN-β pathway and induces immune infiltration in osteosarcoma [ Cell Death Dis, 2022, 13(6):523]	PubMed: 35662245
Multi-site desmoplastic small round cell tumors are genetically related and immune-cold [ Cell Mol Life Sci, 2022, 79(5):273]	PubMed: 35503137
Anti-inflammatory effect of SGLT-2 inhibitors viauric acidand insulin [ Cellular and Molecular Life Sciences, 2022, 273]	PubMed: None
m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis [ Front Immunol, 2022, 13:1094556]	PubMed: 36685533

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