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^[1][2][3]. IC50 & Target:IC50: 2.2 nM (hSGLT1), 2.7nM (hSGLT2)^[1] In Vitro: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]. In Vivo:LX2761 (0.009-1.5 mg/kg; p.o.; once daily; for 4 or 5 days) dose-dependently reduces postprandial blood glucose fluctuations in healthy mice fed a high-fat and high-glucose (HGD) diet. When combined with Sitagliptin (HY-13749), it synergistically increases systemic active GLP-1 levels, and this effect is maintained during repeated daily administration^[2].
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].