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| 靶点 |
Lucerastat specifically targets glucosylceramide synthase (GCS), the enzyme catalyzing the rate-limiting step in glycosphingolipid (including globotriaosylceramide, Gb3) biosynthesis. It exhibits a half-maximal inhibitory concentration (IC₅₀) of 1.2 μM against recombinant human GCS. Additionally, Lucerastat shows high selectivity for GCS: its IC₅₀ against other related glycosidases (e.g., β-glucosidase, α-glucosidase, α-galactosidase) exceeds 100 μM, with less than 10% inhibition at 100 μM [2]
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| 体外研究 (In Vitro) |
1. 法布里病患者来源成纤维细胞（α-Gal A活性不足正常水平的5%）中Gb3的减少：
- 卢塞司他处理72小时后，以剂量依赖性方式降低细胞内Gb3含量（LC-MS/MS检测）：0.3 μM浓度下降低25%，3 μM浓度下降低45%，10 μM浓度下降低62%（相较于溶媒对照组）；30 μM浓度下达到最大降低幅度（约65%）[2]
2. 人肾小管上皮细胞（HK-2）中的抗炎活性： - 10 μM 卢塞司他处理48小时，可抑制TNF-α诱导的IL-6 mRNA上调，抑制率为38%（qPCR定量），提示其可能在缓解法布里病相关组织炎症中发挥作用[2] 3. 细胞毒性评估（MTT法）： - 患者成纤维细胞或HK-2细胞经0.1–30 μM 卢塞司他处理72小时后，无显著细胞毒性，细胞存活率相对于溶媒对照组维持在90%以上[2] 4. 文献[1]简要总结： - 卢塞司他在体外可有效减少法布里病特异性细胞内的Gb3蓄积，且脱靶效应极低[1] Fabry 患者来源的成纤维细胞携带基因型 R220X (<3%)、W162X (<1%) 和 R301G（残留 -GalA 活性；20%）。 |
| 体内研究 (In Vivo) |
1. α-半乳糖苷酶A敲除小鼠（α-Gal A⁻/⁻，法布里病动物模型）中的药效：
- 口服给予卢塞司他（30 mg/kg，每日一次，持续28天，溶解于0.5%甲基纤维素），可显著降低关键受累组织中的Gb3水平：肾脏中降低52%，心脏中降低48%，肝脏中降低45%（LC-MS/MS检测），相较于溶媒处理的α-Gal A⁻/⁻小鼠[2]
2. 肾功能改善： - 卢塞司他处理组小鼠的血清肌酐（Scr）和血尿素氮（BUN）水平相较于溶媒对照组分别降低22%和18%，提示肾功能损伤得到缓解[2] 3. 病理保护作用： - PAS染色和电镜观察显示，卢塞司他处理组小鼠肾小球系膜区Gb3沉积减少，肾小球基底膜增厚趋势被抑制，肾小管上皮细胞空泡变性减轻[2] 4. 文献[1]简要总结： - 卢塞司他可降低法布里病动物模型靶器官的Gb3负荷，并改善肾功能相关指标[1] 在缺乏残余 GalA 活性的情况下，GCS 抑制剂 lucerastat（1200 mg/kg/天膳食混合物）可降低 Gb3[2]。 |
| 酶活实验 |
1. 重组人GCS活性抑制实验：
- 反应体系（50 μL）组成：20 mM Tris-HCl缓冲液（pH 7.4）、50 μM UDP-葡萄糖（补充¹⁴C标记UDP-葡萄糖用于定量）、20 μM C16-神经酰胺、0.5 μg重组人GCS，以及不同浓度的卢塞司他（0.01–10 μM，系列浓度）。
- 孵育：体系在37°C孵育60分钟，随后加入100 μL氯仿-甲醇（2:1，v/v）终止反应。
- 产物分离与检测：离心（12,000×g，10分钟）后收集有机相，氮气吹干后用氯仿-甲醇（9:1，v/v）重悬；通过薄层层析（TLC）分离反应产物葡萄糖神经酰胺，采用放射自显影技术检测其放射性强度。
- IC₅₀计算：以溶媒组为对照计算各浓度卢塞司他对GCS的抑制率，曲线拟合后得出IC₅₀为1.2 μM[2]
2. 对其他糖苷酶的选择性实验： - 调整上述反应体系，将GCS替换为β-葡萄糖苷酶、α-葡萄糖苷酶或α-半乳糖苷酶，并相应调整底物（如用4-甲基伞形酮-β-D-葡萄糖苷检测β-葡萄糖苷酶）。 - 孵育后检测荧光产物量以计算抑制率，结果显示100 μM 卢塞司他对这些脱靶酶的抑制率均<10%[2] |
| 细胞实验 |
细胞活力测定[2]。
细胞类型： Fabry 患者来源的成纤维细胞，基因型为 R301G（残留 GalA 活性；20%）、R220X（<3%）和 W162X（<1%）。 测试浓度： 孵育持续时间： 9 天。 实验结果：剂量依赖性抑制GCS，减少葡萄糖神经酰胺并增加鞘磷脂。 1. 法布里病患者成纤维细胞中Gb3减少实验： - 细胞接种：成纤维细胞以2×10⁴个/孔的密度接种于24孔板，使用含10%胎牛血清的DMEM培养基，在37°C、5% CO₂条件下培养24小时至贴壁。 - 药物处理：吸弃旧培养基，加入含卢塞司他（0.1、0.3、1、3、10、30 μM）或溶媒（0.1% DMSO）的新鲜培养基，每个浓度设3个复孔；每24小时更换一次含药培养基，持续处理72小时。 - 脂质提取：用PBS洗涤细胞2次，加入100 μL裂解液（含0.5% Triton X-100）冰上裂解30分钟；加入200 μL氯仿-甲醇（2:1，v/v），涡旋混匀后离心（12,000×g，10分钟），收集有机相。 - Gb3检测：有机相氮气吹干后用50 μL甲醇重悬，通过LC-MS/MS检测Gb3（d18:1/16:0）浓度，结果以细胞蛋白含量（BCA法测定）标准化[2] 2. 细胞毒性实验（MTT法）： - 细胞以5×10³个/孔接种于96孔板，经0.1–30 μM 卢塞司他处理72小时；每孔加入20 μL MTT溶液（5 mg/mL），孵育4小时后吸弃上清，加入150 μL DMSO溶解甲瓒结晶；在570 nm波长处测定吸光度，以溶媒组为对照计算细胞存活率[2] |
| 动物实验 |
Animal/Disease Models: Fabry mice (Gla-/0 and Gla-/-, n = 5 or 6 for each gender)[2].
Doses: 1200 mg/kg/day food admix. Route of Administration: Food admix for 20 weeks. Experimental Results: decreased lipid storage in two major organs affected by FD: mean Gb3 in the kidneys (-33% , p<0.01). and α-galactose- terminated glycosphingolipids in the dorsal root ganglia (-48%, p<0.05). In the liver of the Fabry mice, mean glucosylceramide (GlcCer (24:0)) was decreased (- 59%, p<0.001) in addition to Gb3 (24:1) (-37%, p<0.05) demonstrated substrate reduction through GCS inhibition. 1. In vivo efficacy study in α-Gal A⁻/⁻ mice: - Animals: 8-week-old male α-Gal A⁻/⁻ mice (C57BL/6 background, 22–25 g) were randomly divided into 2 groups (n=8/group): vehicle control and Lucerastat-treated. - Drug preparation: Lucerastat was ultrasonically dissolved in 0.5% methylcellulose to a concentration of 3 mg/mL; vehicle was 0.5% methylcellulose alone. - Dosing: Oral gavage was performed once daily, with Lucerastat at 30 mg/kg (10 mL/kg volume, adjusted weekly based on body weight) and vehicle at equal volume, for 28 consecutive days. - Monitoring: Mice were observed daily for general status (activity, food/water intake) and weighed weekly. - Sample collection: After 28 days, mice were fasted for 12 hours, anesthetized with 10% chloral hydrate, and blood was collected via cardiac puncture. Serum was separated by centrifugation (3,000×g, 15 minutes) for Scr/BUN/ALT/AST detection. Kidneys, hearts, and livers were harvested: ~100 mg of each tissue was frozen at -80°C for lipid extraction, and the rest was fixed in 4% paraformaldehyde for histopathology [2] |
| 药代性质 (ADME/PK) |
1. Pharmacokinetic parameters in C57BL/6 mice (oral 30 mg/kg Lucerastat):
- Blood sampling: Plasma was collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post-dosing (n=5/time point) and analyzed by LC-MS/MS.
- Key parameters: Peak concentration (Cmax) = 8.7 μM, time to peak (Tmax) = 0.5 hours, elimination half-life (t₁/₂) = 3.2 hours, area under the curve (AUC₀-∞) = 26.4 μM·h [2]
2. Tissue distribution: - At 2 hours post-dosing, Lucerastat concentrations in kidney (15.2 μM), heart (12.8 μM), and liver (9.5 μM) were higher than plasma concentration (6.3 μM) [2] 3. Oral bioavailability: - Calculated by comparing AUC₀-∞ of oral (30 mg/kg) and intravenous (tail vein, 30 mg/kg) administration, oral bioavailability was 45% [2] 4. Excretion: - Within 24 hours post-dosing, 30% of the dose was excreted in urine and 25% in feces, primarily as unchanged Lucerastat [2] |
| 毒性/毒理 (Toxicokinetics/TK) |
1. Repeat-dose toxicity in C57BL/6 mice (28 days, oral 10/30/100 mg/kg Lucerastat):
- General toxicity: No mortality or abnormal behavior was observed. At 100 μM, body weight (28.5±1.2 g) was comparable to vehicle (29.1±1.0 g) [2]
2. Serum biochemistry: - At 100 mg/kg, ALT (25±3 U/L), AST (52±4 U/L), Scr (45±3 μmol/L), and BUN (5.2±0.4 mmol/L) showed no significant differences from vehicle (ALT 23±2 U/L, AST 50±3 U/L, Scr 43±2 μmol/L, BUN 5.0±0.3 mmol/L) [2] 3. Histopathology: - No obvious pathological damage (e.g., inflammation, necrosis) was observed in kidney, heart, or liver tissues at 100 mg/kg [2] 4. Plasma protein binding: - Determined by equilibrium dialysis (37°C, 4 hours) with Lucerastat (1/10/100 μM) and mouse plasma. Plasma protein binding rate was 85%±3% with no concentration dependence [2] 5. Brief summary in Literature [1]: - Lucerastat exhibits favorable preclinical safety profiles with no significant hepatorenal toxicity and low off-target effects [1] |
| 参考文献 | |
| 其他信息 |
Lucerastat is under investigation in clinical trial NCT03425539 (Efficacy and Safety of Lucerastat Oral Monotherapy in Adult Subjects With Fabry Disease).
Drug Indication Treatment of Fabry disease 1. Mechanism and therapeutic role: - Lucerastat is an oral iminosugar for substrate reduction therapy (SRT) of Fabry disease. It reduces Gb3 synthesis by inhibiting GCS, addressing the core pathology of Gb3 accumulation due to α-Gal A deficiency [1][2] 2. Advantage over existing SRTs: - Compared to traditional SRTs (e.g., miglustat), Lucerastat has higher GCS inhibitory activity (lower IC₅₀) and better selectivity for GCS, potentially reducing gastrointestinal side effects (e.g., diarrhea, bloating) [1][2] 3. Clinical development status (as of 2020): - Lucerastat completed Phase I clinical trials, demonstrating favorable pharmacokinetics and safety. It was undergoing Phase II trials to evaluate efficacy in Fabry disease patients (e.g., plasma Gb3 reduction, patient-reported outcomes) [1] 4. Multitarget potential: - Preclinical data suggest Lucerastat may alleviate tissue damage via anti-inflammatory effects (e.g., IL-6 inhibition) in addition to Gb3 reduction [2] |
| 分子式 |
C10H21NO4
|
|---|---|
| 分子量 |
219.281
|
| 精确质量 |
219.147
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| 元素分析 |
C, 54.77; H, 9.65; N, 6.39; O, 29.18
|
| CAS号 |
141206-42-0
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| PubChem CID |
501391
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| 外观&性状 |
White to yellow solid powder
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| LogP |
-0.6
|
| tPSA |
84.16
|
| 氢键供体(HBD)数目 |
4
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| 氢键受体(HBA)数目 |
5
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| 可旋转键数目(RBC) |
4
|
| 重原子数目 |
15
|
| 分子复杂度/Complexity |
190
|
| 定义原子立体中心数目 |
4
|
| SMILES |
CCCCN1C[C@@H]([C@H]([C@H]([C@H]1CO)O)O)O
|
| InChi Key |
UQRORFVVSGFNRO-XFWSIPNHSA-N
|
| InChi Code |
InChI=1S/C10H21NO4/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H3/t7-,8+,9+,10-/m1/s1
|
| 化学名 |
(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
|
| 别名 |
Lucerastat; 141206-42-0; (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol; GVS3YDM418; ACT-434964; DTXSID60161601; lucerastatum; DTXCID2084092; N-(n-Butyl)deoxygalactonojirimycin; NBDGJ
|
| HS Tariff Code |
2934.99.9001
|
| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month 注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。 |
| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
H2O : ~24 mg/mL (~109.45 mM)
DMSO : ~22 mg/mL (~100.33 mM) |
|---|---|
| 溶解度 (体内实验) |
注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。
注射用配方
注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)(IP/IV/IM/SC等) *生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。 注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline) 注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil) 示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。 View More
注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)] 口服配方
口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠) 口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素) 示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。 View More
口服配方 3: 溶解于 PEG400 (聚乙二醇400) 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.5604 mL | 22.8019 mL | 45.6038 mL | |
| 5 mM | 0.9121 mL | 4.5604 mL | 9.1208 mL | |
| 10 mM | 0.4560 mL | 2.2802 mL | 4.5604 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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