LX2761
目录号 : GC36498
LX2761 在体外是一种化学稳定性和有效性的钠依赖性葡萄糖协同转运蛋白1 (SGLT1) 和 SGLT2 抑制剂，对hSGLT1 和 hSGLT2 的 IC50 值分别为 2.2 nM 和 2.7 nM，但在胃肠道 (GI) 表现出特定的 SGLT1 抑制作用。
Cas No.:1610954-97-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LX2761 is chemically stable and potent inhibitor against sodium-dependent glucose cotransporter 1 (SGLT1) and SGLT2 in vitro with IC50s of 2.2 nM and 2.7nM for hSGLT1 and hSGLT2, but displays specific SGLT1 inhibition in the gastrointestinal (GI) tract[1]. IC50: 2.2 nM (hSGLT1), 2.7nM (hSGLT2)[1]
[1]. Goodwin NC, et al. Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restrictedto the Intestinal Lumen, for the Treatment of Diabetes. J Med Chem. 2017 Jan 26;60(2):710-721.
| Cas No. | 1610954-97-6 | SDF | |
| Canonical 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 | ||
| 分子式 | C32H47N3O6S | 分子量 | 601.8 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6617 mL | 8.3084 mL | 16.6168 mL |
| 5 mM | 0.3323 mL | 1.6617 mL | 3.3234 mL |
| 10 mM | 0.1662 mL | 0.8308 mL | 1.6617 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice
J Pharmacol Exp Ther 2017 Jul;362(1):85-97.PMID:28442582DOI:10.1124/jpet.117.240820.
LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad lib-fed mice. Further, treating mice with LX2761 and the dipeptidyl-peptidase 4 inhibitor sitagliptin synergistically increased active GLP-1 levels, suggesting increased LX2761-mediated release of GLP-1 into the portal circulation. LX2761 also lowered postprandial glucose, fasting glucose, and hemoglobin A1C, and increased plasma total GLP-1, during long-term treatment of mice with either early- or late-onset streptozotocin-diabetes; in the late-onset cohort, LX2761 treatment improved survival. Mice and rats treated with LX2761 occasionally had diarrhea; this dose-dependent side effect decreased in severity and frequency over time, and LX2761 doses were identified that decreased postprandial glucose excursions without causing diarrhea. Further, the frequency of LX2761-associated diarrhea was greatly decreased in mice either by gradual dose escalation or by pretreatment with resistant starch 4, which is slowly digested to glucose in the colon, a process that primes the colon for glucose metabolism by selecting for glucose-fermenting bacterial species. These data suggest that clinical trials are warranted to determine if LX2761 doses and dosing strategies exist that provide improved glycemic control combined with adequate gastrointestinal tolerability in people living with diabetes.
Structural mechanism of SGLT1 inhibitors
Nat Commun 2022 Oct 28;13(1):6440.PMID:36307403DOI:10.1038/s41467-022-33421-7.
Sodium glucose co-transporters (SGLT) harness the electrochemical gradient of sodium to drive the uphill transport of glucose across the plasma membrane. Human SGLT1 (hSGLT1) plays a key role in sugar uptake from food and its inhibitors show promise in the treatment of several diseases. However, the inhibition mechanism for hSGLT1 remains elusive. Here, we present the cryo-EM structure of the hSGLT1-MAP17 hetero-dimeric complex in the presence of the high-affinity inhibitor LX2761. LX2761 locks the transporter in an outward-open conformation by wedging inside the substrate-binding site and the extracellular vestibule of hSGLT1. LX2761 blocks the putative water permeation pathway of hSGLT1. The structure also uncovers the conformational changes of hSGLT1 during transitions from outward-open to inward-open states.
Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes
J Med Chem 2017 Jan 26;60(2):710-721.PMID:28045524DOI:10.1021/acs.jmedchem.6b01541.
The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.
SGLT1 and SGLT1 Inhibitors: A Role to Be Assessed in the Current Clinical Practice
Diabetes Ther 2018 Feb;9(1):427-430.PMID:29177922DOI:10.1007/s13300-017-0342-8.
Diabetes is a complex disease of increasingly common occurrence worldwide. Attaining optimal glycemic control is the main challenge to prevent the development of diabetes-related complications and/or to stop their progression. In recent years, the pharmacologic toolkit for the treatment of diabetes has considerably expanded, thus paving the way to more pathophysiology-oriented therapies. For instance, the sodium-glucose cotransporters SGLT2 and SGLT1 have been in the spotlight because of better knowledge of their physiology and therapeutic potential. At present, whereas the SGLT2 inhibitors are widely applied in current clinical practice as an effective and well-tolerated treatment that increases the urinary excretion of glucose, less is known about the use of SGLT1 inhibitors. SGLT1s are of primary importance in the small intestine, an organ that does not express SGLT2, while in the kidney they are expressed in the late renal proximal tubules, where it reabsorbs the glucose escaped from the upstream SGLT2. Hence, SGLT1-mediated glucose reabsorption in the kidney is increased when the tubular glucose load overwhelms the capacity of SGLT2 or when the latter is inhibited. The role of SGLT1 in intestinal and renal glucose transport makes the transporter a potential target for antidiabetic therapy. Here, we briefly report the evidence on LX2761, a new inhibitor against SGLT1 and SGLT2 in vitro, which acts in vivo as a selective inhibitor of SGLT1 in the gastrointestinal tract. LX2761 improves glycemic control without the glycosuria-related side effects of SGLT2 inhibitors, particularly genitourinary tract infections. However, whether it represents a valid therapeutic option for all patients with diabetes or is more appropriate for specific phenotypes, e.g., patients with concomitant diabetes and chronic kidney disease, who may benefit less from the renal mechanism of selective SGLT2 inhibitors, remains to be tested in large randomized controlled trials.