Simeprevir (TMC435; TMC435350) 是一种有效、高特异性且具有口服活性的丙型肝炎病毒 (HCV) NS3/4A蛋白酶抑制剂,Ki值为 0.36 nM,并抑制 HCV 复制,EC50值为 7.8 nM。Simeprevir 还能有效抑制SARS-CoV-2的复制,并与瑞德西韦 (Remdesivir) 具有协同作用。Simeprevir 可抑制 SARS-CoV-2 的主要蛋白酶 (Mpro) 和 RNA 依赖性 RNA 聚合酶 (RdRp),并调节宿主免疫反应。
生物活性 | Simeprevir (TMC435; TMC435350) is an oral, potent and highly specifichepatitis C virus (HCV) NS3/4A proteaseinhibitor with aKiof 0.36 nM. Simeprevir inhibitsHCVreplication with anEC50of 7.8 nM. Simeprevir also potently suppressesSARS-CoV-2replication and synergizes with Remdesivir. Simeprevir inhibits the main protease (Mpro) and the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, and also modulates host immune responses[1][4]. |
IC50& Target | Ki: 0.36 nM (HCV NS3/4A protease)[1] EC50: 7.8 nM (HCV replication)[1] IC50: 9.6±2.3 μM (SARS-CoV-2 Mpro), 5.5±0.2 μM (SARS-CoV-2 RdRp)[4] |
体外研究 (In Vitro) | Simeprevir (TMC435) inhibits HCV in a dose-dependent manner in Huh7-Luc cells, with EC50and EC90values of 8 nM and 24 nM, respectively[2]. Simeprevir (TMC435) inhibits NS3/4A proteases from HCV genotypes 1 to 6 with IC50s of 1/0.9/7/30/1.5/2.2/1.6 nM for 1a/1b/2b/3a/4/5/6, respectively[3]. Simeprevir inhibits SARS-CoV-2 in Vero E6 cells with IC50s of 9.6±2.3 μM and 5.5±0.2 μM for Mproand RdRp, respectively[4].
|
体内研究 (In Vivo) | Simeprevir (TMC435) has moderate terminal elimination half-life (t1/2=1.5 h and 4.1 h for rat (3 mg/kg, p.o.), monkey (3 mg/kg, p.o.))[3]. Simeprevir (TMC435350) exhibits a medium-slow rate of absorption, well distribution with the high concentration observed in the liver, and a low clearance[1]. Pharmacokinetic Parameters of Simeprevir (TMC435350) in male Sprague-Dawley rats[1].
| IV (2 mg/kg) | PO (10 mg/kg) | CL (L/h/kg) | 0.505 | | Vdss(h) | 0.49 | | AUC0-24(μM·h) | 5.21 | 2.79 | Cmax(μM) | | 0.73 | Tmax(h) | | 3.0 | T1/2(h) | | 2.8 | F (%) | | 11 | Liver/plasma ratio at 6 h | 63.5 | 32 |
Animal Model: | Sprague-Dawley (SD) rats and cynomolgus monkeys[3] | Dosage: | 3 mg/kg | Administration: | Oral administration | Result: | Time at which peak concentration (Tmax) of 1 hour and 2 hour for rat and monkey, respectively. Concentration at 24 h after dosing (C24 h) of 0.9 and 2.3 ng/mL for rat and monkey, respectively. AUC0-24h=1173 and1409 ng o h/mL for rat and monkey, respectively. |
|
Clinical Trial | |
分子量 | |
性状 | |
Formula | |
CAS 号 | |
中文名称 | |
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 |
|
溶解性数据 | In Vitro: DMSO : 14.29 mg/mL(19.05 mM;Need ultrasonic) 配制储备液 1 mM | 1.3334 mL | 6.6672 mL | 13.3344 mL | 5 mM | 0.2667 mL | 1.3334 mL | 2.6669 mL | 10 mM | 0.1333 mL | 0.6667 mL | 1.3334 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: 5% DMSO 40%PEG300 5%Tween-80 50% saline Solubility: 2.5 mg/mL (3.33 mM); Suspended solution; Need ultrasonic 2. 请依序添加每种溶剂: 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 1.43 mg/mL (1.91 mM); Clear solution
此方案可获得 ≥ 1.43 mg/mL (1.91 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 14.3 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。 3. 请依序添加每种溶剂: 10% DMSO 90%corn oil Solubility: ≥ 1.43 mg/mL (1.91 mM); Clear solution
此方案可获得 ≥ 1.43 mg/mL (1.91 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 14.3 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。
|