Name: Dapagliflozin (BMS-512148)
Brand: Selleck Chemicals
SKU: S1548
Rating: 5 (44 reviews)

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Batch: Zuiverheid: 99.99%

99.99

Gerelateerde doelwitten	CXCR Hedgehog/Smoothened PKA Adrenergic Receptor AChR 5-HT Receptor Histamine Receptor Dopamine Receptor Ras KRas
Overige SGLT Inhibitoren	Sotagliflozin (LX4211) Phlorizin Phloretin (RJC 02792) Tofogliflozin(CSG 452) Ipragliflozin (ASP1941) KGA-2727 Mizagliflozin (KWA 0711, DSP-3235 free base) Ipragliflozin L-Proline Bexagliflozin (EGT1442) Swertisin

Celkweek, behandeling & werkconcentratie

Cellijnen	Assaytype	Incubatietijd	Activiteitsbeschrijving	PMID
CHO cells	Function assay	2 h	Inhibition of human SGLT2 expressed in CHO cells assessed as [14C]alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting, IC50=0.00049 μM	20434909
CHOK1 cells	Function assay	3 h	Inhibition of human SGLT2 expressed in CHOK1 cells assessed as inhibition of [14C]-AMG uptake after 3 hrs by microbeta scintillation counting analysis, IC50=0.001 μM	24842618
HEK293.ETN cells	Function assay	1.5 h	Inhibition of human SGLT2 transfected in HEK293.ETN cells assessed as AMG uptake after 1.5 hrs by scintillation counting, IC50=0.0067 μM	19896374
COS-7 cells	Function assay	2 h	Inhibition of human SGLT1 transfected in COS-7 cells assessed as AMG uptake after 2 hrs by scintillation counting, IC50=0.89 μM	19896374
CHO	Function assay		Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]AMG accumulation, EC50 = 0.0011 μM.	18260618
CHO	Function assay		Inhibition of rat SGLT2 expressed in CHO cells assessed as inhibition of [14C]AMG accumulation, EC50 = 0.003 μM.	18260618
CHO	Function assay		Inhibition of human SGLT1 expressed in CHO cells assessed as inhibition of [14C]AMG accumulation, EC50 = 1.39 μM.	18260618
HEK293.ETN	Function assay		Inhibition of human SGLT2 expressed in HEK293.ETN cells assessed as methyl-alpha-D-[U-14C]glucopyranoside uptake by scintillation counting, IC50 = 0.0067 μM.	19700318
COS7	Function assay		Inhibition of human SGLT1 expressed in african green monkey COS7 cells assessed as methyl-alpha-D-[U-14C]glucopyranoside uptake by scintillation counting, IC50 = 0.885 μM.	19700318
HEK293	Function assay		Inhibition of human SGLT1 expressed in HEK293 cells assessed as inhibition of [14C]alpha-methylglucopyranoside uptake, IC50 = 0.81 μM.	19785435
CHO	Function assay	2 hrs	Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of sodium-dependent methyl-alpha-D-[U-14C]glucopyranoside uptake after 2 hrs, IC50 = 0.0014 μM.	20149653
CHO	Function assay	2 hrs	Inhibition of human SGLT1 expressed in CHO cells assessed as inhibition of sodium-dependent methyl-alpha-D-[U-14C]glucopyranoside uptake after 2 hrs, IC50 = 1.2 μM.	20149653
CHO	Function assay		Inhibition of human recombinant SGLT2 expressed in CHO cells by liquid scintillation counting, IC50 = 0.00049 μM.	20181486
HEK293	Function assay	1.5 hrs	Inhibition of human SGLT2 expressed in HEK293 cells assessed as inhibition of [14C]alpha-methyl-D-glucopyranoside uptake after 1.5 hrs by liquid scintillation counting, IC50 = 0.0067 μM.	20576578
COS7	Function assay	2 hrs	Inhibition of human SGLT1 expressed in african green monkey COS7 cells assessed as inhibition of [14C]alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting, IC50 = 0.89 μM.	20576578
CHO	Function assay	2 hrs	Inhibition of human SGLT2 expressed in CHO cells assessed as sodium-dependent [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting, EC50 = 0.003 μM.	21128592
CHO	Function assay	2 hrs	Inhibition of human SGLT1 expressed in CHO cells assessed as sodium-dependent [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting, EC50 = 0.4285 μM.	21128592
CHO	Function assay	2 hrs	Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting, IC50 = 0.00049 μM.	21193308
CHO	Function assay	60 mins	Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]-alpha-methyl-D-glucopyranoside transport after 60 mins by scintillation counting, IC50 = 0.004 μM.	21398124
CHO	Function assay	60 mins	Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]-alpha-methyl-D-glucopyranoside transport after 60 mins by scintillation counting in presence of 100% plasma, IC50 = 0.022 μM.	21398124
CHO	Function assay	60 mins	Inhibition of human SGLT1 expressed in CHO cells assessed as inhibition of [14C]-alpha-methyl-D-glucopyranoside transport after 60 mins by scintillation counting, IC50 = 0.37 μM.	21398124
CHO	Function assay	60 mins	Inhibition of SGLT6 expressed in CHO cells assessed as inhibition of [14C]-alpha-methyl-D-glucopyranoside transport after 60 mins by scintillation counting, IC50 = 0.38 μM.	21398124
CHO	Function assay	2 hrs	Inhibition of human SGLT2 expressed in CHO cells assessed as [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counter, IC50 = 0.00049 μM.	21514014
CHO	Function assay	60 mins	Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of [14C]-Glucose uptake using [14C]-methyl glucopyranoside after 60 mins by microbeta plate counting, IC50 = 0.003 μM.	21565497
CHO	Function assay		Inhibition of human SGLT2 expressed in CHO cells using methyl-alpha-D-glucopyranoside by liquid scintillation counting, IC50 = 0.00135 μM.	21592794
COS7	Function assay	2 hrs	Inhibition of human SGLT2 expressed in african green monkey COS7 cells assessed as inhibition of [14C]-methyl-alpha-D-glucopyranoside uptake after 2 hrs by scintillation counting in presence of 25 % human plasma, IC50 = 0.0032 μM.	21737266
293	Function assay	1.5 hrs	Inhibition of human SGLT1 expressed in human 293 cells assessed as inhibition of [14C]-methyl-alpha-D-glucopyranoside uptake after 1.5 hrs by scintillation counting in presence of 25 % human plasma, IC50 = 3.1 μM.	21737266
CHO	Function assay	2 hrs	Inhibition of human SGLT2 expressed in CHO cells assessed as reduction of [14C]-labeled AMG after 2 hrs by liquid scintillation counting, IC50 = 0.00135 μM.	21868239
CHO	Function assay	2 hrs	Inhibition of human SGLT2 expressed in CHO cells assessed as [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting, IC50 = 0.00049 μM.	21906953
CHO-K1	Function assay		Inhibition of human SGLT2 expressed in CHO-K1 cells by [14C]AMG uptake assay, IC50 = 0.0013 μM.	22652255
CHO-K1	Function assay		Inhibition of human SGLT1 expressed in CHO-K1 cells by [14C]AMG uptake assay, IC50 = 0.8 μM.	22652255
CHO-K1	Function assay	120 mins	Inhibition of human SGLT2 expressed in CHO-K1 cells incubated for 120 mins at 37 degC by [14C]-AMG uptake assay, EC50 = 0.0024 μM.	22818040
CHO-K1	Function assay	120 mins	Inhibition of human SGLT1 expressed in CHO-K1 cells incubated for 120 mins at 37 degC by [14C]-AMG uptake assay, EC50 = 0.593 μM.	22818040
CHO	Function assay	45 mins	Inhibition of human SGLT2 expressed in CHO cells assessed as inhibition of sodium-dependent [14C]methyl-alpha-D-glucopyranoside uptake after 45 mins, IC50 = 0.0013 μM.	22889351
CHO	Function assay	45 mins	Inhibition of human SGLT1 expressed in CHO cells assessed as inhibition of sodium-dependent [14C]methyl-alpha-D-glucopyranoside uptake after 45 mins, IC50 = 0.8 μM.	22889351
CHOK1	Function assay	3 hrs	Inhibition of human SGLT1 expressed in CHOK1 cells assessed as inhibition of [14C]-AMG uptake after 3 hrs by microbeta scintillation counting analysis, IC50 = 0.891 μM.	24842618
CHO	Function assay	2 hrs	Inhibition of human SGLT2 expressed in CHO cells assessed as [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by liquid scintillation counting, IC50 = 0.00049 μM.	24900297
CHO	Function assay	2 hrs	Competitive inhibition of full-length human SGLT2 expressed in CHO cells assessed as inhibition of sodium-dependent [14C]-alpha-methyl-D-glucopyranoside uptake after 2 hrs by scintillation counting, IC50 = 0.005 μM.	25650254
CHO	Function assay	120 mins	Inhibition of human SGLT2 expressed in CHO cells assessed as decrease in uptake of [14C]AMG after 120 mins by TopCount method, IC50 = 0.0015 μM.	28447791
CHO	Function assay	120 mins	Inhibition of human SGLT1 expressed in CHO cells assessed as decrease in uptake of [14C]AMG after 120 mins by TopCount method, IC50 = 0.629 μM.	28447791
CHO	Function assay	1 hr	Inhibition of human SGLT2 expressed in CHO cells assessed as reduction in [14C]AMG uptake after 1 hr by microbeta counting method, EC50 = 0.002 μM.	29216560
CHO	Function assay	1 hr	Inhibition of human SGLT1 expressed in CHO cells assessed as reduction in [14C]AMG uptake after 1 hr by microbeta counting method, EC50 = 0.86 μM.	29216560
CHO	Function assay	1 hr	Inhibition of full-length human SGLT2 expressed in CHO cells assessed as decrease in [14C]-methyl alpha-D-glucopyranoside uptake after 1 hr by liquid scintillation counting method, IC50 = 0.00105 μM.	29764742
HEK293	Function assay	10 mins	Inhibition of human SGLT2 expressed in HEK293 cells assessed as decrease in [14C]-AMG uptake preincubated for 10 mins followed by [14C]-AMG addition and measured after 2 hrs by liquid scintillation counting method, IC50 = 0.0014 μM.	29954682
HEK293	Function assay	10 mins	Inhibition of human SGLT1 expressed in HEK293 cells assessed as decrease in [14C]-AMG uptake preincubated for 10 mins followed by [14C]-AMG addition and measured after 2 hrs by liquid scintillation counting method, IC50 = 1.83 μM.	29954682
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Chemische informatie, Opslag en Stabiliteit

Moleculair gewicht	408.87	Formule	C₂₁H₂₅ClO₆	Opslag (Vanaf de ontvangstdatum)	3 years -20°C powder (seal)
CAS-nr.	461432-26-8	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	BMS-512148			Smiles	CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)C3C(C(C(C(O3)CO)O)O)O)Cl

Oplosbaarheid

In vitro
Batch:

DMSO : 100 mg/mL (244.57 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 100 mg/mL

Water : Insoluble

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Massa	Concentratie	Volume	Moleculair gewicht
=	×	×

Verdunningscalculator Moleculair gewicht calculator

In vivo Batch:
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.
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.
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.
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.
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.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Gevalideerd door Selleck labs. Mocht u aanpassingen aan deze formulering nodig hebben, neem dan contact op met ons verkoopteam voor aangepaste tests.	4.100mg/ml (10.03mM)	Taking the 1 mL working solution as an example, add 50 μL 82 mg/ml clarified DMSO stock solution to 400 μL PEG300, mix evenly to clarify it; add 50 μL Tween80 to the above system, mix evenly to clarify it; then continue to add 500 μL ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

In vivo Formuleringscalculator (Heldere oplossing)

Stap 1: Voer de onderstaande informatie in (Aanbevolen: Een extra dier voor het geval van verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in het gedeelte Oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-mastervloeistof: mg geneesmiddel vooraf opgelost in μL DMSO ( Concentratie mastervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de partij geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toeμL PEG300, mengen en helder maken, voeg vervolgens toeμL Tween 80, mengen en helder maken, voeg vervolgens toe μL ddH₂O, mengen en helder maken.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toe μL Maïsolie, mengen en helder maken.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysische methoden zoals vortexen, echografie of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme

Kenmerken	More potent stimulator of glucosuria than other SGLT2 inhibitors.
Targets/IC₅₀/Ki	hSGLT2 (CHO cells) 1.1 nM(EC50)
In vitro	Dapagliflozin is niet gevoelig voor hSGLT1 met een 1200-voudige IC50. Deze verbinding is 32-voudig potenter dan florizine tegen hSGLT2, maar 4-voudig minder potent dan florizine tegen hSGLT1. Het is zeer selectief ten opzichte van GLUT-transporters en vertoont 8-9% remming in proteïnevrije buffer bij 20 μM en vrijwel geen remming in aanwezigheid van 4% runderserumalbumine. Deze chemische stof heeft een goede permeabiliteit over Caco-2 celmembranen en is een substraat voor P-glycoproteïne (P-gp), maar geen significante P-gp-remmer. Het is stabiel in ratten-, honden-, apen- en menselijk serum bij 10 μM. Het vertoont geen remmende reacties of inductie van humane P450-enzymen. De in vitro metabole routes van deze verbinding zijn glucuronidatie, hydroxylatie en O-de-ethylatie.
Kinase Assay	SGLT Bindingsassays
Kinase Assay	Chinese hamsterovarium (CHO) cellen die stabiel humaan SGLT2 (hSGLT2) en humaan SGLT1 (hSGLT1) tot expressie brengen, worden gebruikt voor de ontwikkeling van transportassays met behulp van het selectieve SGLT-substraat α-methyl-D-glucopyranoside (AMG). Dapagliflozin wordt getest op het vermogen om de opname van [¹⁴C]AMG in een proteïnevrije buffer over een incubatieperiode van 2 uur te remmen. De responscurve wordt aangepast aan een empirisch vierparametermodel om de remmerconcentratie bij halfmaximale respons te bepalen, gerapporteerd als EC50. Proteïnevrije buffer wordt gebruikt om de eiwitarme omstandigheden van het glomerulaire filtraat te simuleren, dat de SGLT-doelen op het lumenale oppervlak van de proximale tubulus in de nier baadt.
In vivo	Dapagliflozin verlaagt de bloedglucosespiegels met 55% na een orale dosis van 0,1 mg/kg bij hyperglycemische streptozotocine (STZ) ratten, wat deels te danken is aan de metabolische stabiliteit die wordt geboden door de C-glucosidebinding. Deze verbinding vertoont een gunstig absorptie-, distributie-, metabolisme- en excretieprofiel (ADME) en is oraal biologisch beschikbaar. Deze chemische stof (1 mg/kg) veroorzaakt een significante dosisafhankelijke glucosurie en een toename van het urinevolume bij normale ratten gedurende 24 uur na toediening. Het induceert een toename van de urineglucose en de urinevolume-excretie 6 uur na toediening bij Zucker diabetische vet (ZDF) ratten. Dit middel verlaagt de nuchtere en postprandiale glucosespiegels bij ZDF-ratten, zelfs na 2 weken behandeling, zonder enig teken van nier- of levertoxiciteit. Het vermindert significant de ontwikkeling van hyperglycemie, met verlaagde bloedglucose. Deze verbinding zou de insulinegevoeligheid kunnen verbeteren, de β-celmassa kunnen verminderen en de ontwikkeling van een verminderde pancreasfunctie kunnen vertragen.
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/18260618/ [2] https://pubmed.ncbi.nlm.nih.gov/18356408/ [3] https://pubmed.ncbi.nlm.nih.gov/19996149/ [4] https://pubmed.ncbi.nlm.nih.gov/20880347/ [5] https://pubmed.ncbi.nlm.nih.gov/34836340/

Toepassingen

Methoden	Biomarkers	PMID
Western blot	p-elf2α / t-elf2α / tubulin-α HIF-1α / PHD2 / tubulin DDR1 HIF-1α / p-AMPK / AMPK / p-ERK / ERK / β-actin Bax / Bcl2 / PARP / β-actin	31285506
Growth inhibition assay	Tumor volume	28763435
IHC	HE staining / SGLT2 mice kidney sections TUNEL-positive cells HIF1 TUNEL-positive cells	28763435
Immunofluorescence	podocytes PECAM-1 / α-SMA EdU F-actin Metabolic switch in diabetic kidneys	30089717

Informatie klinische proef

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
NCT06012266	Not yet recruiting	Heart Failure	Centre Hospitalier Universitaire Vaudois\|Great Ormond Street Hospital for Children NHS Foundation Trust\|University College London	August 2024	Phase 2
NCT06336330	Recruiting	Heart Diseases\|Cardiovascular Diseases\|Heart Failure	AstraZeneca	April 25 2024	--
NCT04887935	Not yet recruiting	Prostate Cancer\|Cancer of Prostate	Washington University School of Medicine\|The Foundation for Barnes-Jewish Hospital	April 30 2024	Phase 1
NCT06398977	Recruiting	Peritoneal Dialysis Complication\|Renal Function Aggravated\|Sodium-glucose Co-transporter-2 Inhibitors	Sichuan Academy of Medical Sciences	March 11 2024	Not Applicable

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C5=C4/X	C5:	LOG(C5):
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C7=C6/X	C7:	LOG(C7):
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Dapagliflozin (BMS-512148) SGLT2-remmer

Chemische structuur

Moleculair gewicht: 408.87