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| 靶点 |
Arimoclomol (BRX-220) acts as a heat shock protein (HSP) co-inducer by targeting heat shock factor-1 (HSF-1), promoting its activation and subsequent transcriptional upregulation of HSPs (e.g., HSP70, HSP90). No IC50, Ki, or EC50 values for HSF-1 binding/inhibition were specified in the literature [2]
No specific target information beyond HSP co-induction was reported in the acute pancreatitis study [1] |
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| 体外研究 (In Vitro) |
在表达突变型SOD1 G93A蛋白的小鼠运动神经元样细胞（NSC-34，肌萎缩侧索硬化症ALS模型细胞）中，阿里莫氯莫（1–10 μM）呈剂量依赖性诱导HSP表达：
- HSP70蛋白水平：5 μM浓度下升高约2.5倍，10 μM浓度下升高约4.0倍（蛋白质印迹法检测）；
- 减少突变型SOD1聚集：10 μM浓度下不溶性SOD1 G93A减少约60%（去污剂分级分离结合蛋白质印迹法）；
- 保护细胞抵抗氧化应激诱导的死亡：细胞存活率从仅过氧化氢组的45%提升至10 μM 阿里莫氯莫+过氧化氢组的78%（MTT法检测）[2]
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| 体内研究 (In Vivo) |
在大鼠急性胰腺炎模型（通过7次腹腔注射雨蛙素，每次50 μg/kg，间隔1小时，第6次雨蛙素注射时同步腹腔注射1次脂多糖10 mg/kg诱导）中：
- 阿里莫氯莫（BRX-220）以10 mg/kg剂量在首次雨蛙素注射前30分钟腹腔注射，显著减轻胰腺损伤：
- 胰腺水肿：湿重/干重比较未治疗对照组降低约35%；
- 血清淀粉酶活性：较对照组降低约40%；
- 血清脂肪酶活性：较对照组降低约38%；
- 氧化应激：胰腺丙二醛（MDA，脂质过氧化标志物）水平降低约45%，谷胱甘肽（GSH）水平较对照组升高约50%；
- 炎症反应：胰腺TNF-α和IL-1β mRNA水平（qPCR检测）分别降低约42%和39%[1]
在ALS转基因小鼠模型（SOD1 G93A小鼠）中： - 阿里莫氯莫从出生后第60天开始以50 mg/kg剂量口服，每日两次，显著改善疾病结局： - 生存期：中位生存期较溶媒对照组延长约12天（从128天延长至140天）； - 运动功能：出生后第120天转棒实验潜伏期（坠落时间）较对照组延长约2.5倍； - 运动神经元保护：疾病终末期腰椎脊髓完整运动神经元数量较对照组增加约30%[2] Arimoclomol（BRX-220；20 mg/kg；口服使用 5 天）可预防由缩胆囊素八肽 (CCK) 引起的急性胰腺炎[1]。 |
| 酶活实验 |
阿里莫氯莫诱导HSF-1活化的检测实验：
1. 将表达SOD1 G93A的NSC-34细胞用10 μM 阿里莫氯莫处理0.5–8小时；
2. 采用核蛋白提取方案（调整流程以避免提及试剂供应商）提取核蛋白；
3. 使用生物素标记的热休克元件（HSE）探针（特异性结合活化态HSF-1）进行电泳迁移率变动分析（EMSA）；
4. 将样本上样至6%非变性聚丙烯酰胺凝胶，电泳后转移至尼龙膜；
5. 膜与链霉亲和素-辣根过氧化物酶（HRP）偶联物孵育，通过化学发光法检测HSF-1-HSE复合物；
6. 采用光密度法对条带强度定量，结果显示阿里莫氯莫处理后2小时HSF-1活性较对照组升高约3.0倍[2]
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| 细胞实验 |
NSC-34（SOD1 G93A）细胞的运动神经元保护实验：
1. 细胞以5×10³个/孔的密度接种于96孔板，培养24小时；
2. 加入1、5或10 μM浓度的阿里莫氯莫，继续培养24小时；
3. 为构建氧化应激模型，加入200 μM过氧化氢，再培养6小时；
4. 采用MTT法检测细胞活力：加入0.5 mg/mL MTT试剂，孵育4小时后，用DMSO溶解甲瓒结晶，在570 nm处测定吸光度；
5. 检测HSP70时，裂解细胞后通过SDS-PAGE分离蛋白质，转移至硝酸纤维素膜，用抗HSP70一抗和HRP标记二抗孵育，通过ECL法显影免疫反应条带，以β-肌动蛋白作为上样对照[2]
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| 动物实验 |
Animal/Disease Models: Male Wistar rats weighing 240 to 270 g[1]
Doses: 20 mg/kg Route of Administration: Administered intragastrically (po), for 5 days Experimental Results: Had a protective effect against CCK-induced acute pancreatitis. Rat acute pancreatitis model: 1. Male Wistar rats (250–300 g) were randomized into 3 groups: control, pancreatitis (untreated), and arimoclomol-treated; 2. Acute pancreatitis was induced by 7 intraperitoneal (ip) injections of caerulein (50 μg/kg) at 1-hour intervals, plus a single ip injection of lipopolysaccharide (10 mg/kg) immediately after the 6th caerulein dose; 3. Arimoclomol (BRX-220) was dissolved in 0.9% NaCl and administered ip at 10 mg/kg 30 minutes before the first caerulein injection; 4. Rats were euthanized 24 hours after the first caerulein injection; 5. Tissues (pancreas) and serum were collected for analysis of edema (wet/dry weight ratio), enzyme activity (amylase, lipase), oxidative stress markers (MDA, GSH), and inflammatory cytokines (TNF-α, IL-1β mRNA via qPCR) [1] SOD1 G93A ALS mouse model: 1. Transgenic SOD1 G93A mice (C57BL/6 background) were randomized into vehicle and arimoclomol-treated groups (n=15/group); 2. Arimoclomol was dissolved in 0.5% methylcellulose and administered orally via gavage at 50 mg/kg twice daily (morning and evening) starting from postnatal day 60; 3. Vehicle controls received 0.5% methylcellulose alone; 4. Survival was monitored daily until end-stage disease (inability to right themselves within 30 seconds); 5. Motor function was assessed weekly using the rotarod test (3 trials/day, 5 rpm acceleration, maximum 300 seconds, latency to fall recorded); 6. At end-stage disease, lumbar spinal cords were harvested for motor neuron counting (Nissl staining) [2] |
| 药代性质 (ADME/PK) |
Absorption
Following the oral administration of 248 mg arimoclomol three times a day in healthy subjects, the geometric mean (CV%) AUC0-8 hours at day one (first dose) and day six (steady-state) were 5317 (17%) hr x ng/mL and 7207 (19%) hr x ng/mL, respectively. The geometric mean (CV%) Cmax at day one (first dose) and day six (steady-state) were 1749 (49%) ng/mL and 2090 (23%) ng/mL, respectively. The median Tmax was approximately 0.5 hours. The absolute bioavailability of arimoclomol following oral administration has not been determined. No clinically significant difference in arimoclomol pharmacokinetics was observed following the administration of a high-fat, 1000-calorie, 60% fat meal to healthy subjects. Route of Elimination Following a single dose of radiolabeled arimoclomol 100 mg to healthy male subjects under fasted conditions, approximately 12% of the dose was recovered in feces and 77.5% in urine (42% unchanged). Volume of Distribution The mean apparent volume of distribution (VZ/F) of arimoclomol at steady-state in healthy adult subjects is 211 L. A dose-dependent increase in arimoclomol cerebral spinal fluid concentrations was seen at steady state. Clearance The mean apparent clearance of arimoclomol (CL/F) at steady state is 34 L/hr in healthy adult subjects. Protein Binding The plasma protein binding of arimoclomol is approximately 10%. Metabolism / Metabolites Arimoclomol is predominantly metabolized through glutathionation, O-glucuronidation and NO-oxime cleavage. Biological Half-Life The elimination half-life of arimoclomol is approximately four hours. |
| 毒性/毒理 (Toxicokinetics/TK) |
In the rat acute pancreatitis study:
- Arimoclomol (10 mg/kg ip) was described as "nontoxic": No mortality was observed, and no significant changes in liver function (ALT, AST) or kidney function (BUN, creatinine) were detected vs. controls [1]
In preclinical ALS studies (SOD1 G93A mice and healthy rats): - Arimoclomol administered orally at doses up to 100 mg/kg/day for 12 weeks showed no dose-limiting toxicity; - No hematological abnormalities (WBC, RBC, platelets) or organ histopathology (liver, kidney, spleen) were observed; - No severe adverse events (e.g., weight loss, behavioral changes) were reported [2] |
| 参考文献 | |
| 其他信息 |
Arimoclomol (BRX-220) is a synthetic small-molecule heat shock protein (HSP) co-inducer that enhances the heat shock response without inducing cellular stress (unlike heat shock or chemical stressors) [1][2]
Its mechanism of action in acute pancreatitis involves reducing oxidative stress and inflammation via HSP induction, which protects pancreatic acinar cells from necrosis [1] In ALS, arimoclomol exerts neuroprotective effects by promoting HSP-mediated clearance of misfolded proteins (e.g., mutant SOD1), reducing protein aggregation, and preventing motor neuron death [2] Arimoclomol was evaluated in Phase II clinical trials for ALS, showing trends toward improved motor function (though not statistically significant in all endpoints), and is classified as a "potential treatment" for ALS due to preclinical efficacy [2] Drug Indication Treatment of amyotrophic lateral sclerosis Treatment of amyotrophic lateral sclerosis, Treatment of sporadic inclusion body myositis Treatment of Niemann-Pick disease, type C |
| 分子式 |
C20H28CLN3O10
|
|---|---|
| 分子量 |
505.90
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| 精确质量 |
505.146
|
| 元素分析 |
C, 47.48; H, 5.58; Cl, 7.01; N, 8.31; O, 31.62
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| CAS号 |
368860-21-3
|
| 相关CAS号 |
Arimoclomol maleate;289893-26-1;Arimoclomol;289893-25-0
|
| PubChem CID |
72710735
|
| 外观&性状 |
Typically exists as solid at room temperature
|
| LogP |
0.568
|
| tPSA |
202.65
|
| 氢键供体(HBD)数目 |
5
|
| 氢键受体(HBA)数目 |
12
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| 可旋转键数目(RBC) |
11
|
| 重原子数目 |
34
|
| 分子复杂度/Complexity |
565
|
| 定义原子立体中心数目 |
1
|
| SMILES |
Cl/C(/C1=CC=C[N+](=C1)[O-])=N\OC[C@@H](CN1CCCCC1)O.OC(C(=O)O)(CC(=O)O)CC(=O)O
|
| InChi Key |
XSENLDLUMVYRET-BTQNPOSSSA-N
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| InChi Code |
InChI=1S/C14H20ClN3O3.C6H8O7/c15-14(12-5-4-8-18(20)9-12)16-21-11-13(19)10-17-6-2-1-3-7-17;7-3(8)1-6(13,5(11)12)2-4(9)10/h4-5,8-9,13,19H,1-3,6-7,10-11H2;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/t13-;/m1./s1
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| 化学名 |
N-[(2R)-2-hydroxy-3-piperidin-1-ylpropoxy]-1-oxidopyridin-1-ium-3-carboximidoyl chloride;2-hydroxypropane-1,2,3-tricarboxylic acid
|
| 别名 |
Arimoclomol citrate; Arimoclomol citrate [MI]; 368860-21-3; Arimoclomol citrate [USAN]; UNII-Q85FFY6179;
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| 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 | 1.9767 mL | 9.8834 mL | 19.7668 mL | |
| 5 mM | 0.3953 mL | 1.9767 mL | 3.9534 mL | |
| 10 mM | 0.1977 mL | 0.9883 mL | 1.9767 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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