| 规格 | 价格 | 库存 | 数量 |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 靶点 |
ExVivo: It was demonstrated that BIA 10-2474 is a strong FAAH inhibitor in several brain areas, with an IC50 of 50–70 mg/kg (ip). The corresponding IC50 values for the cerebellum, cortex, remainder of the brain, and hypothalamus are 52, 67, and 68 mg/kg, respectively [1].
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| 体外研究 (In Vitro) |
ExVivo：已证明 BIA 10-2474 在多个大脑区域是一种强效 FAAH 抑制剂，IC50 为 50-70 mg/kg (ip)。小脑、皮质、大脑其余部分和下丘脑相应的 IC50 值分别为 52、67 和 68 mg/kg [1]。
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| 体内研究 (In Vivo) |
2016 年 1 月，一项涉及 BIA 10-2474 药物的 I 期临床试验发生了重大不良事件 (SAE)，导致一人死亡。我们将寻找试验失败的潜在原因，例如脱靶效应、剂量估计、不可预见的免疫反应、物种差异和累积剂量毒性[2]。
在大鼠体内，于放射性示踪剂注射前40分钟腹腔注射0.5 mg/kg或5 mg/kg剂量的BIA 10-2474，能够完全阻断FAAH选择性示踪剂[¹⁸F]-DOPP在所有脑区的结合，表明在此剂量下大鼠脑内FAAH活性被完全抑制[1] 使用更低剂量范围（1-500 µg/kg，腹腔注射）来表征BIA 10-2474的体内效力。该药物剂量依赖性地抑制了[¹⁸F]-DOPP与多个脑区FAAH的结合。测得的大鼠脑内FAAH抑制IC₅₀值在52至71 µg/kg之间[1] |
| 动物实验 |
Groups of male Sprague-Dawley rats (n=4 per group) were pre-treated with solutions of BIA 10-2474 (dissolved in 5% Tween 80 in saline) or vehicle via intraperitoneal injection, 40 minutes prior to the intravenous injection of the radiotracer [¹⁸F]-DOPP [1]
The drug doses used in the study ranged from 1 to 5000 µg/kg (i.p.) [1] Rats were sacrificed by decapitation 40 minutes after radiotracer administration. Brains were removed, dissected into regions (cortex, hypothalamus, cerebellum, rest of brain), and the radioactivity was measured to calculate the standard uptake value [1] |
| 药代性质 (ADME/PK) |
Plasma concentrations of BIA 10-2474 were measured in rats at the time of sacrifice (40 minutes post-dose) for the three highest dose groups: 100, 500, and 5000 µg/kg [1]
The corresponding plasma levels were 25 ± 3 ng/mL, 116 ± 22 ng/mL, and 1380 ± 71 ng/mL, which equate to approximately 83 nM, 386 nM, and 4595 nM, respectively [1] Plasma levels in groups receiving lower doses of BIA 10-2474 (below 100 µg/kg) were below the detection limit of the assay (<15 ng/mL) [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In the Phase I clinical trial, administration of multiple ascending doses (MAD) up to 50 mg daily for 10 days led to severe neurological toxicity in several subjects.
Clinical symptoms included headache, cerebellar syndrome, loss of consciousness, memory impairment, diplopia, and hemiparesis. Magnetic resonance imaging (MRI) revealed deep cerebral hemorrhage, necrosis, and bilateral symmetrical lesions affecting areas such as the hippocampus, pons, thalamus, and cerebral cortex. One volunteer died (brain death), and four others suffered irreversible brain damage The toxicity appeared to be cumulative, as it manifested on the 5th and 6th days of multiple dosing at 50 mg, but was not observed with a single 100 mg dose. In animal studies, cynomolgus monkeys receiving 100 mg/kg/24 h showed damage to the medulla oblongata in the form of axonal dystrophy. |
| 参考文献 | |
| 其他信息 |
BIA 10-2474 is a putative Fatty Acid Amide Hydrolase (FAAH) inhibitor [1]
This compound was involved in a Phase I clinical trial that resulted in severe adverse events (SAEs), including one death [1] The study was conducted to determine the in vivo potency of BIA 10-2474 at inhibiting FAAH in the rat central nervous system, as such information was lacking prior to the clinical trial [1] The results demonstrate that BIA 10-2474 is a potent FAAH inhibitor in the rat brain, with an IC₅₀ (50-70 µg/kg) comparable to other established FAAH inhibitors [1] The authors suggest that very high levels of FAAH inhibition were likely achieved in the CNS of subjects in the Phase I trial, and that assessing target engagement in the CNS using techniques like PET imaging prior to dose escalation might have helped prevent the SAEs [1] |
| 分子式 |
C16H20N4O2
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|---|---|---|
| 分子量 |
300.36
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| 精确质量 |
300.158
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| CAS号 |
1233855-46-3
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| 相关CAS号 |
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| PubChem CID |
46831476
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.3±0.1 g/cm3
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| 沸点 |
568.3±52.0 °C at 760 mmHg
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| 闪点 |
297.5±30.7 °C
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| 蒸汽压 |
0.0±1.6 mmHg at 25°C
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| 折射率 |
1.642
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| LogP |
-0.41
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| tPSA |
63.6
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| 氢键供体(HBD)数目 |
0
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| 氢键受体(HBA)数目 |
3
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| 可旋转键数目(RBC) |
2
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| 重原子数目 |
22
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| 分子复杂度/Complexity |
386
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| 定义原子立体中心数目 |
0
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| InChi Key |
DOWVMJFBDGWVML-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H20N4O2/c1-18(14-7-3-2-4-8-14)16(21)19-11-15(17-12-19)13-6-5-9-20(22)10-13/h5-6,9-12,14H,2-4,7-8H2,1H3
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| 化学名 |
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| 别名 |
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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 |
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| 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) |
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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 | 3.3293 mL | 16.6467 mL | 33.2934 mL | |
| 5 mM | 0.6659 mL | 3.3293 mL | 6.6587 mL | |
| 10 mM | 0.3329 mL | 1.6647 mL | 3.3293 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) 。
Inhibition of [18F]-DOPP binding to FAAH in rat brain regions by pre-treatment with PF-04457845 (0.1 mg/kg) or BIA 10-2474.J Cereb Blood Flow Metab.2017 Nov;37(11):3635-3639. |
Brain regional inhibition of FAAH by doses of BIA 10-2474 as measured by inhibition of [18F]-DOPP.J Cereb Blood Flow Metab.2017 Nov;37(11):3635-3639. |
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