LX2761
LX2761 is an orally active, dual SGLT1/SGLT2 inhibitor with IC50 values of 2.2 nM and 2.7 nM against human SGLT1 and SGLT2, respectively. LX2761 locks human SGLT1 in an outward-open conformation and blocks its putative water permeation pathway. After oral administration, LX2761 is confined exclusively to the intestinal lumen, delays intestinal glucose absorption, regulates intestinal glucose metabolism, increases cecal glucose levels, reduces cecal pH, improves glycemic control and elevates plasma total GLP-1 levels. However, LX2761 induces diarrhea in a dose-dependent manner. LX2761 can be used in diabetes-related research.
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- CAS. Nr.: 1610954-97-6
- Formel: C32H47N3O6S
- Molecular Weight:601.80
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
- Reinheit & Dokumentation
- Verweise
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Help & FAQs
Biologische Aktivität
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hSGLT1 2.2 nM (IC50) |
hSGLT2 2.7 nM (IC50) |
mSGLT1 3.7 nM (IC50) |
rSGLT1 5.7 nM (IC50) |
mSGLT2 1.0 nM (IC50) |
rSGLT2 1.1 nM (IC50) |
SGLT1 5.1 nM (IC50, dog) |
SGLT1 1.4 nM (IC50, monkey) |
SGLT2 1.8 nM (IC50, dog) |
SGLT2 1.1 nM (IC50, monkey) |
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Cell Line
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Type | Value | Description | References |
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| HEK293 | IC50 |
2.2 nM
Compound: 21
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Inhibition of human HA-tagged SGLT1 expressed in HEK293 cells assessed as decrease in [14C]-AMG uptake measured after 1 to 2 hrs by scintillation counting method
Inhibition of human HA-tagged SGLT1 expressed in HEK293 cells assessed as decrease in [14C]-AMG uptake measured after 1 to 2 hrs by scintillation counting method
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[PMID: 28045524] |
| HEK293 | IC50 |
2.7 nM
Compound: 21
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Inhibition of human HA-tagged SGLT2 expressed in HEK293 cells assessed as decrease in [14C]-AMG uptake measured after 1 to 2 hrs by scintillation counting method
Inhibition of human HA-tagged SGLT2 expressed in HEK293 cells assessed as decrease in [14C]-AMG uptake measured after 1 to 2 hrs by scintillation counting method
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[PMID: 28045524] |
LX2761 (1.0-5.7 nM) potently inhibits SGLT1 and SGLT2 across multiple mammalian species, with IC50 values ranging from 1.0 nM to 5.7 nM in HEK293 cells expressing the respective transporters[2].
LX2761 (1-400 μM; 1 h) binds with high affinity to the hSGLT1-MAP17 complex, locking it in an outward-open conformation and blocking the transporter's water permeation pathway[3].
LX2761 (0.01-1000 nM; 1 h) potently inhibits 1-NBD-glucose uptake by non-tagged wild-type hSGLT1 in AD293 cells with an IC50 of 2.03 nM[3].
LX2761 (0.01-1000 nM; 1 h) potently inhibits 1-NBD-glucose uptake by the hSGLT1_GFP-MAP17_nb complex in AD293 cells with an IC50 of 2.30 nM[3].
LX2761 (0.01-1000 nM; 1 h) has reduced potency for inhibition of 1-NBD-glucose uptake in AD293 cells due to the L274A mutation in hSGLT1[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
LX2761 (0.0225-0.25 mg/kg; p.o.; once daily; for 5 consecutive days) dose-dependently reduces postprandial blood glucose fluctuations and increases tGLP-1 levels in healthy rats fed a high-fat and high-glucose (HGD) diet; the 0.0625 mg/kg dose produces a significant hypoglycemic effect without inducing diarrhea[2].
LX2761 (3 mg/kg; p.o.; once daily; for 49 consecutive days) improves glycemic control, significantly increases the survival rate of mice with advanced Streptozotocin (HY-13753)-induced diabetes, while reducing fasting blood glucose, improving A1C and decreasing postprandial blood glucose fluctuations[2].
A stepwise oral dose escalation regimen of LX2761 (0.5-0.7 mg/kg; p.o.; daily; for 7 consecutive days, with dose escalation gradually implemented between days 45 and 59) significantly reduces the incidence of diarrhea in mice fed a HGD diet, compared to acute administration at the same final dose[2].
Diarrhea induced by LX2761 (0.2-1.5 mg/kg; p.o.; daily; for 4 consecutive days) in HGD mice is antagonized by resistant starch, without impairing the glucose-lowering efficacy of LX2761[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6-Tyrc-Brd (male, adult, streptozotocin-induced early-onset diabetes)[2]
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Dosage:1.5 mg/kg; 3 mg/kg
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Administration:p.o.; daily; 39 days
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Result:Significantly and dose-dependently decreased OGTT glucose excursions on days 21 and 39.
Significantly decreased fasting blood glucose levels after 32 days of treatment.
Slowed the rise in A1C levels relative to vehicle after 32 days of treatment.
Significantly increased cecal glucose levels and decreased cecal pH at necropsy.
Did not alter plasma tGLP-1 levels post-glucose challenge.
Did not significantly affect food consumption and body weight.
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Animal Model:C57BL/6-Tyrc-Brd (male, adult, streptozotocin-induced advanced-onset diabetes)[2]
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Dosage:1.5 mg/kg; 3 mg/kg
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Administration:p.o.; daily; 49 days
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Result:Significantly improved mouse survival relative to vehicle at 3 mg/kg.
Significantly decreased baseline blood glucose and OGTT glucose excursions on day 20 at both doses.
Significantly improved A1C values on day 30 at 3 mg/kg.
Significantly decreased fasting blood glucose and OGTT glucose excursions on day 49 at both doses.
Significantly increased plasma tGLP-1 levels, cecal glucose levels, and decreased cecal pH relative to vehicle at 3 mg/kg on day 49.
Caused rarely observed diarrhea limited to the first few days of treatment.
Chemical Information
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CAS. Nr. 1610954-97-6
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Molecular Weight 601.80
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Formel C32H47N3O6S
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SMILES
CC1=CC=C([C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](SC)O2)C=C1CC3=CC=C(CCCC(NC(C(NCCN(C)C)=O)(C)C)=O)C=C3
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
[1]. Spatola L, et al. SGLT1 and SGLT1 Inhibitors: A Role to Be Assessed in the Current Clinical Practice. Diabetes Ther. 2018;9(1):427-430. [Content Brief]
[2]. Powell DR, et al. LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice. J Pharmacol Exp Ther. 2017;362(1):85-97. [Content Brief]
[3]. Niu Y, et al. Structural mechanism of SGLT1 inhibitors. Nat Commun. 2022;13(1):6440. Published 2022 Oct 28. [Content Brief]
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
LX2761 Related Classifications
HY-101122 Related Classifications
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