LX-4211 is an oral, potent dual SGLT2/1 inhibitor, with IC50 values of 36nM and 1.8nM for SGLT1 and SGLT2, respectively[1][2]. LX-4211 enhances urinary glucose excretion by inhibiting SGLT2 and reduces gastrointestinal glucose absorption by inhibiting SGLT1, thereby effectively lowering blood glucose levels[3][4]. LX-4211 is commonly used in diabetes-related research[5][6].
In vitro, treatment of porcine coronary artery cultured endothelial cells (ECs) with LX-4211 (10nM) for 30 minutes before the subsequent incubation in normo glucose or high glucose (HG: 25mmol/L) for 24 hours reduced glucose uptake stimulated by HG, and decreased ECs senescence markers and oxidative stress, upregulated eNOS expression and NO formation, and reduced the expression of VCAM-1, tissue factor, and the local angiotensin system[7].
In vivo, Oral treatment of nonobese diabetes-prone mice with cyclophosphamide-induced T1D with LX-4211(orally;2/30mg/kg/day)for 22 days significantly decreased blood glucose levels and A1c levels without increasing the rate of hypoglycemia measurements[8]. Oral administration of LX-4211 (60mg/kg)in mice reduces intestinal glucose absorption by inhibiting SGLT1, increases the release of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), while reducing the release of glucose-dependent insulinotropic polypeptide (GIP) and fluctuations in blood glucose levels during the 6 hours after a glucose-containing meal[4].
References:
[1] Zambrowicz, B., Freiman, J., Brown, P. M., Frazier, K. S., Turnage, A., Bronner, J., Ruff, D., Shadoan, M., Banks, P., Mseeh, F., Rawlins, D. B., Goodwin, N. C., Mabon, R., Harrison, B. A., Wilson, A., Sands, A., & Powell, D. R. (2012). LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clinical pharmacology and therapeutics, 92(2), 158–169.
[2] Goodwin, N. C., Ding, Z. M., Harrison, B. A., Strobel, E. D., Harris, A. L., Smith, M., Thompson, A. Y., Xiong, W., Mseeh, F., Bruce, D. J., Diaz, D., Gopinathan, S., Li, L., O'Neill, E., Thiel, M., Wilson, A. G., Carson, K. G., Powell, D. R., & Rawlins, D. B. (2017). Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes. Journal of medicinal chemistry, 60(2), 710–721.
[3] Goodwin, N. C., Mabon, R., Harrison, B. A., Shadoan, M. K., Almstead, Z. Y., Xie, Y., Healy, J., Buhring, L. M., DaCosta, C. M., Bardenhagen, J., Mseeh, F., Liu, Q., Nouraldeen, A., Wilson, A. G., Kimball, S. D., Powell, D. R., & Rawlins, D. B. (2009). Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. Journal of medicinal chemistry, 52(20), 6201–6204.
[4] Powell, D. R., Smith, M., Greer, J., Harris, A., Zhao, S., DaCosta, C., Mseeh, F., Shadoan, M. K., Sands, A., Zambrowicz, B., & Ding, Z. M. (2013). LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. The Journal of pharmacology and experimental therapeutics, 345(2), 250–259.
[5] Herat, L. Y., Matthews, J. R., Hibbs, M., Rakoczy, E. P., Schlaich, M. P., & Matthews, V. B. (2023). SGLT1/2 inhibition improves glycemic control and multi-organ protection in type 1 diabetes. iScience, 26(8), 107260.
[6] Bhatt, D. L., Szarek, M., Steg, P. G., Cannon, C. P., Leiter, L. A., McGuire, D. K., Lewis, J. B., Riddle, M. C., Voors, A. A., Metra, M., Lund, L. H., Komajda, M., Testani, J. M., Wilcox, C. S., Ponikowski, P., Lopes, R. D., Verma, S., Lapuerta, P., Pitt, B., & SOLOIST-WHF Trial Investigators (2021). Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. The New England journal of medicine, 384(2), 117–128.
[7] Khemais-Benkhiat, S., Belcastro, E., Idris-Khodja, N., Park, S. H., Amoura, L., Abbas, M., Auger, C., Kessler, L., Mayoux, E., Toti, F., & Schini-Kerth, V. B. (2020). Angiotensin II-induced redox-sensitive SGLT1 and 2 expression promotes high glucose-induced endothelial cell senescence. Journal of cellular and molecular medicine, 24(3), 2109–2122.
[8] Powell, D. R., Doree, D., Jeter-Jones, S., Ding, Z. M., Zambrowicz, B., & Sands, A. (2015). Sotagliflozin improves glycemic control in nonobese diabetes-prone mice with type 1 diabetes. Diabetes, metabolic syndrome and obesity : targets and therapy, 8, 121–127.
LX-4211是一种口服的强效双重SGLT2/1抑制剂，对SGLT1和SGLT2的IC50值分别为36nM和1.8nM[1][2]。LX-4211通过抑制SGLT2增强尿糖排泄，并通过抑制SGLT1减少胃肠道葡萄糖吸收，从而有效地降低血糖水平[3][4]。LX-4211通常用于糖尿病相关研究[5][6]。
在体外实验中，用10nM LX-4211 处理猪冠状动脉培养的内皮细胞（ECs）30分钟后，再在正常葡萄糖或高葡萄糖（HG：25mmol/L）条件下继续孵育24小时，可以减少由高葡萄糖刺激引起的葡萄糖摄取，并降低内皮细胞衰老标志物和氧化应激水平，上调eNOS的表达和NO的形成，并减少VCAM-1、组织因子和局部血管紧张素系统的表达[7]。
在体内，用LX-4211（口服；2/30mg/kg/day）治疗环磷酰胺诱导的非肥胖糖尿病易感小鼠22天，显著降低了血糖水平和糖化血红蛋白（A1c）水平，而没有增加低血糖测量的比率[8]。在小鼠中，口服LX-4211（60mg/kg）可在含糖餐后6小时内通过抑制SGLT1减少肠道葡萄糖吸收，增加胰高血糖素样肽-1（GLP-1）和肽YY（PYY）的释放，并减少葡萄糖依赖性促胰岛素多肽（GIP）的释放以及血糖水平的波动[4]。