Verubecestat (MK-8931) 是一种具有口服活性的,高亲和力BACE1和BACE2抑制剂,Ki值分别为 2.2 nM 和 0.38 nM。Verubecestat 可以有效降低 Aβ40,并具有用于阿尔茨海默氏病的潜力。
生物活性 | Verubecestat (MK-8931) is an orally active, high-affinityBACE1andBACE2inhibitor withKivalues of 2.2 nM and 0.38 nM. Verubecestat effectively reduces Aβ40 and has the potential for Alzheimer's Disease[1][2]. |
IC50& Target | Ki: 2.2 nM (BACE1) and 0.38 nM (BACE2)[1] |
体外研究 (In Vitro) | Verubecestat (MK-8931) is a β-site amyloid precursor protein cleaving enzyme 1/2 (BACE1/2) inhibitor. Verubecestat does not significantly inhibit human CYP isoforms 1A2, 2C9, 2C19, 2D6, and 3A4 (all IC50>40 μM), indicating that the compound is unlikely to be a perpetrator of CYP-mediated drug-drug interactions[1]. Verubecestat has IC50s of 2.1 nM, 0.7 nM, 4.4 nM for Aβ1-40, Aβ1-42, sAPPβ in HEK293 APPSwe/Loncells[1].
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体内研究 (In Vivo) | Verubecestat (MK-8931; 3 mg/kg; IV or oral) has a T1/2of 1.9 hours, a CL of 46 mL/min/kg, a Vssof 5.4 L/kg, a Cmaxof 0.27 μM and a AUC of 1.1 μMoh for Sprague-Dawley (SD) rats[1]. Verubecestat (1 mg/kg; IV) has a T1/2of 4.9 hours, a CL of 21 mL/min/kg, a Vssof 7.5 L/kg for cynomolgus monkeys[1]. Verubecestat (1 mg/kg; IV) has a T1/2of 9.7 hours, a CL of 4.3 mL/min/kg, a Vssof 2.7 L/kg for beagle dogs[1]. Verubecestat (30 mg/kg; orally; BID for 5 days) causes a modest (1.4-fold) induction of CYP 3A1 activity but does not significantly alter the expression of CYPs 1A1, 1A2, 2B, 3A2, or 4A in rats[1]. Verubecestat dose-dependently reduces CSF and cortex Aβ40 with ED50values of 5 and 8 mg/kg, respectively, corresponding to unbound plasma EC50values of 48 and 81 nM, respectively[1]. Verubecestat (3 and 10 mg/kg; orally) reduces profound, sustained of CSF Aβ40 levels and has peak effects on CSF Aβ lowering (72 and 81% reduction at 3 and 10 mg/kg, respectively) 12 h after dosing[1].
Animal Model: | Sprague-Dawley (SD) rats[1] | Dosage: | 3 mg/kg (Pharmacokinetic Analysis) | Administration: | IV or oral | Result: | Had a T1/2of 1.9 hours, a CL of 46 mL/min/kg, a Vssof 5.4 L/kg, a Cmaxof 0.27 μM and a AUC of 1.1 μMoh. |
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运输条件 | Room temperature in continental US; may vary elsewhere. |
储存方式 | Powder | -20°C | 3 years | | 4°C | 2 years | In solvent | -80°C | 6 months | | -20°C | 1 month |
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溶解性数据 | In Vitro: DMSO : ≥ 35 mg/mL(85.49 mM) *"≥" means soluble, but saturation unknown. 配制储备液 1 mM | 2.4425 mL | 12.2127 mL | 24.4254 mL | 5 mM | 0.4885 mL | 2.4425 mL | 4.8851 mL | 10 mM | 0.2443 mL | 1.2213 mL | 2.4425 mL |
*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℃, 6 months; -20℃, 1 month。-80℃ 储存时,请在 6 个月内使用,-20℃ 储存时,请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液,再依次添加助溶剂: ——为保证实验结果的可靠性,澄清的储备液可以根据储存条件,适当保存;体内实验的工作液,建议您现用现配,当天使用;
以下溶剂前显示的百 分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂: 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.5 mg/mL (6.11 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (6.11 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂: 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.5 mg/mL (6.11 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (6.11 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。 3. 请依序添加每种溶剂: 10% DMSO 90%corn oil Solubility: ≥ 2.5 mg/mL (6.11 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (6.11 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。 *以上所有助溶剂都可在本网站选购。
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