Sinbaglustat
(Synonyms: ACT-519276; OGT2378) 目录号 : GC68391Sinbaglustat (OGT2378) 是葡萄糖神经酰胺合成酶 (GCS) 和非溶酶体葡萄糖神经酰胺酶 (GBA2) 的双重抑制剂。Sinbaglustat 是一种可透过血脑屏障的的口服N-烷基亚氨基糖。Sinbaglustat 可用于与溶酶体功能障碍相关的中枢神经退行性疾病的研究。
Cas No.:441061-33-2
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
Sinbaglustat (OGT2378) is a dual inhibitor of glucosylceramide synthase (GCS) and non-lysosomal glucosyl ceramidase (GBA2). Sinbaglustat is an orally available N-alkyl iminosugar that crosses the blood-brain barrier. Sinbaglustat can be used for the research of central neurodegenerative diseases associated with lysosomal dysfunctions[1][2].
Sinbaglustat (OGT2378; 20 μM) reduces the synthesis of glucosylceramide and ganglioside by 93% and >95% in MEB4 melanoma cells compared with untreated MEB4 cells, respectively, without either cytotoxic or antiproliferative effects[1].
GBA2 is an enzyme involved in the catabolism of glycosphingolipids (GSLs). Sinbaglustat is 50-fold more potent in inhibiting GBA2 than GCS[2].
Sinbaglustat (OGT2378; administered p.o., in the powdered chow, at a dose of 2500 mg/kg/day, corresponding to 35-40 mg of Sinbaglustat per mouse per day) is highly effective in impeding melanoma tumor growth in vivo. The effectiveness of p.o. Sinbaglustat in this murine model suggests that inhibition of glycosphingolipid synthesis is a promising approach to inhibit tumor progression[1].
| Animal Model: | Female syngeneic C57BL/6 mice, 6-8 weeks old bearing MEB4 melanoma tumor[1] |
| Dosage: | 35-40 mg per mouse per day |
| Administration: | Administered p.o., in the powdered chow, at a dose of 2500 mg/kg/day |
| Result: | Inhibited MEB4 melanoma tumor growth in a syngeneic, orthotopic murine model. |
[1]. Michael Weiss,et al. Inhibition of melanoma tumor growth by a novel inhibitor of glucosylceramide synthase. Cancer Res.2003 Jul 1;63(13):3654-8.
[2]. Martine Gehin,et al. Assessment of Target Engagement in a First-in-Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders. Clin Transl Sci.2021 Mar;14(2):558-567.
| Cas No. | 441061-33-2 | SDF | Download SDF |
| 别名 | ACT-519276; OGT2378 | ||
| 分子式 | C11H23NO4 | 分子量 | 233.3 |
| 溶解度 | DMSO : 83.33 mg/mL (357.18 mM; Need ultrasonic) | 储存条件 | Store at -20°C, away from moisture and light |
| 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 | 4.2863 mL | 21.4316 mL | 42.8633 mL |
| 5 mM | 0.8573 mL | 4.2863 mL | 8.5727 mL |
| 10 mM | 0.4286 mL | 2.1432 mL | 4.2863 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。
Effect of Renal Function Impairment on the Pharmacokinetics, Safety, and Tolerability of the Iminosugar Sinbaglustat
J Clin Pharmacol 2021 Jul;61(7):932-938.PMID:33368330DOI:10.1002/jcph.1808.
Sinbaglustat (ACT-519276), a brain-penetrating inhibitor of glucosylceramide synthase and nonlysosomal glucosylceramidase, is developed as a new therapy for lysosomal storage disorders. In the first-in-human study, Sinbaglustat was primarily excreted unchanged in urine. This study was conducted to evaluate the effect of mild, moderate, and severe renal function impairment on the safety, tolerability, and pharmacokinetics (PK) of Sinbaglustat. In this single-center, open-label study, 32 subjects (8 per renal function group, assessed by the Cockcroft-Gault formula, and 8 healthy subjects) received a single oral dose of 200 mg Sinbaglustat. Plasma PK parameters of Sinbaglustat were derived by noncompartmental analysis. Standard safety and tolerability evaluations were analyzed descriptively. When compared with healthy subjects, Cmax did not present clinically relevant differences in subjects with impaired renal function, but median tmax was slightly longer in subjects with moderate and severe renal function impairment. Overall, when compared with healthy subjects, exposure to Sinbaglustat based on AUC0-t (geometric mean and 90% confidence interval) increased in subjects with mild, moderate, and severe renal function impairment by 1.2-fold (1.08- to 1.36-fold), 1.8-fold (1.47- to 2.17-fold), and 2.6-fold (2.23- to 3.00-fold), respectively. There were no clinically relevant findings on electrocardiogram, vital signs, and clinical laboratory variables. Headache was reported by 2 of 24 subjects with renal function impairment and by 2 of 8 healthy subjects. In conclusion, 200 mg of Sinbaglustat was well tolerated in all groups. In future studies, a 2- and 3-fold dose reduction is needed for subjects with moderate and severe renal function impairment, respectively.
Assessment of Target Engagement in a First-in-Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders
Clin Transl Sci 2021 Mar;14(2):558-567.PMID:33142037DOI:10.1111/cts.12911.
In this first-in-human study, the tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of Sinbaglustat, a dual inhibitor of glucosylceramide synthase (GCS) and non-lysosomal glucosyl ceramidase (GBA2), were investigated in healthy subjects. The single-ascending dose (SAD) and multiple-ascending dose (MAD) studies were randomized, double-blind, and placebo-controlled. Single doses from 10 to 2,000 mg in men and multiple doses from 30 to 1,000 mg twice daily for 7 days in male and female subjects were investigated. Tolerability, PK, and PD data were collected up to 3 days after (last) treatment administration and analyzed descriptively. Sinbaglustat was well-tolerated in the SAD and MAD studies, however, at the highest dose of the MAD, three of the four female subjects presented a similar pattern of general symptoms. In all cohorts, Sinbaglustat was rapidly absorbed. Thereafter, plasma concentrations decreased biphasically. In the MAD study, steady-state conditions were reached on Day 2 without accumulation. During Sinbaglustat treatment, plasma concentrations of glucosylceramide (GlcCer), lactosylceramide, and globotriaosylceramide decreased in a dose-dependent manner, reflecting GCS inhibition. The more complex the glycosphingolipid, the more time was required to elicit PD changes. After treatment stop, GlcCer levels returned to baseline and increased above baseline at lowest doses, probably due to the higher potency of Sinbaglustat on GBA2 compared to GCS. Overall, Sinbaglustat was welltolerated up to the highest tested doses. The PK profile is compatible with b.i.d. dosing. Sinbaglustat demonstrated target engagement in the periphery for GCS and GBA2.