Canagliflozin (JNJ-28431754)

CatalogusnummerS2760 Batch:S276003

Afdrukken

Technische gegevens

Formule

C24H25FO5S
Moleculair gewicht 444.52 CAS-nr. 842133-18-0
Oplosbaarheid (25°C)* In vitro DMSO 88 mg/mL (197.96 mM)
Water Insoluble
Ethanol Insoluble
In vivo (Voeg oplosmiddelen afzonderlijk en in volgorde toe aan het product.)
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml betekent licht oplosbaar of onoplosbaar.
* Houd er rekening mee dat Selleck de oplosbaarheid van alle verbindingen intern test en de werkelijke oplosbaarheid enigszins kan afwijken van gepubliceerde waarden. Dit is normaal en is te wijten aan lichte batch-tot-batch variaties.
* Verzending op kamertemperatuur (Stabiliteitstests tonen aan dat dit product zonder koelmaatregelen kan worden verzonden.)

Voorbereiden van stamoplossingen

Biologische activiteit

Beschrijving Canagliflozin (TA 7284, JNJ 28431754) is een zeer potente en selectieve SGLT2-remmer voor hSGLT2 met een IC50 van 2,2 nM in een celvrije test, en vertoont een 413-voudige selectiviteit ten opzichte van hSGLT1.
Doelen
mSGLT2
(Cell-free assay)		 rSGLT2
(Cell-free assay)		 hSGLT2
(Cell-free assay)
2 nM 3.7 nM 4.4 nM
In vitro Canagliflozin (JNJ 28431754) is a novel C-glucoside with thiophene ring. It inhibits Na+-dependent 14C-AMG uptake in a concentration-dependent fashion. This compound inhibits 14C-AMG uptake in CHO-hSGLT1 and mSGLT1 cells with IC50 of 0.7 μM and >1 μM, respectively. It 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.
In vivo Canagliflozin (JNJ 28431754) shows pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice. Oral administration at 30 mg/kg of this compound 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 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 is likely to continuously suppress reabsorption of glucose. The extensive UGE would reflect excellent pharmacokinetic properties 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 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, it only slightly affects blood glucose levels in normoglycemic mice. Therefore, Canagliflozin would control hyperglycemia in the therapy of T2DM with low risk of hypoglycemia.

Protocol (uit referentie)

Celassay:[1]
  • Cellijnen

    L6 cell lines

  • Concentraties

    0-10 μM

  • Incubatietijd

    24 hours

  • Methode

    The effect of Canagliflozin (JNJ 28431754) on glucose transporter 1 (GLUT1) activity was tested using cells from the rat skeletal muscle cell line, L6. 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 this compound (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.
Dierstudie:[2]
  • Dierlijke modellen

    KK (HF-KK) mice

  • Doseringen

    10 mg/kg

  • Toediening

    Oral administration

Referenties

  • https://pubmed.ncbi.nlm.nih.gov/22355316/
  • https://pubmed.ncbi.nlm.nih.gov/20690635/

Klantproductvalidatie

Canagliflozin dose-dependently increases pAMPK and pACC in PC3 cells after 30 min

Gegevens van [ , , Mol Metab, 2016, 5(10):1048-56 ]

Serum lipid and fasting blood glucose levels in Cana- and control-groups after 5 weeks of canagliflozin/vehicle oral administration. Significant reduction in total cholesterol, triglyceride, LDL-cholesterol and fasting blood glucose levels was observed in Cana-group at the end of experimental procedure compared to baseline. Fasting glucose was the only significantly increased parameter observed in the control group at the end of intervention. Data are shown as mean ± SD (***P ≤ 0.001, **P ≤ 0.01)

Gegevens van [ , , Cardiovasc Diabetol, 2018, 17(1):106 ]

Pretreatment of SGLT inhibitors significantly attenuates sodium nitroprusside (SNP)-induced vascular relaxation in pulmonary arteries. A: dose-response curves of SNP-induced relaxation in the presence or absence of phlorizin in pulmonary arteries (vehicle: 0.05% methanol, phlorizin: 100 µmol/l). Data are means ± SE; n = 4 mice/group. *P < 0.05 vs. vehicle. B: dose-response curves of SNP-induced relaxation in the presence or absence of canagliflozin in pulmonary arteries (vehicle: 0.1% DMSO, canagliflozin: 10 µmol/l). Data are means ± SE; n = 3 mice/group. *P < 0.05 vs. vehicle. C: dose-response curves of SNP-induced relaxation in the presence or absence of phlorizin in coronary arteries. Data are means ± SE; n = 5 mice/group. D: dose-response curves of SNP-induced relaxation in the presence or absence of canagliflozin in coronary arteries. Data are means ± SE; n = 3 mice/group.

Gegevens van [ , , Am J Physiol Lung Cell Mol Physiol, 2015, 309(9):L1027-36. ]

Dixon plots for canagliflozin inhibition of the enzyme/substrate pairs: (A) UGT1A1/β-EST; (B) HLM/β-EST; (C) UGT1A9+BSA/4MU; (D) UGT1A9+BSA/PRO; and (E) HLM+BSA/PRO. Concentrations of canagliflozin and substrates are corrected for binding to the respective enzyme sources and BSA (0.5% w/v). Points are experimentally derived values (mean of duplicate estimates; < 5% variance), whereas lines are from fitting with eq. 1 (UGT1A9) or eq. 4 (UGT1A1).

Gegevens van [ , , Drug Metab Dispos, 2015, 43(10):1468-76. ]

Selleck's Canagliflozin (JNJ-28431754) Is geciteerd door 35 Publicaties

The sodium-glucose cotransporter-2 inhibitor canagliflozin alleviates endothelial dysfunction in a rat bypass model [ Biochem Pharmacol, 2026, 244:117601] PubMed: 41349911
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 reverses doxorubicin-induced cardiotoxicity via restoration of autophagic homeostasis [ Toxicol Appl Pharmacol, 2024, 495:117183] PubMed: 39631538
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

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NIET VOOR HUMANE, VETERINAIRE DIAGNOSTISCHE OF THERAPEUTISCHE DOELEINDEN.