| Description | Simeprevir (TMC435) is a potent HCV NS3/4A protease inhibitor, and inhibits HCV replication with EC50 of 8 nM. |
| In vitro | 在Huh7-Luc细胞中，Simeprevir的抗病毒活性与剂量呈依赖关系，其EC50和EC90值分别为8 nM和24 nM。Simeprevir对NS3/4A蛋白酶的抑制作用随时间依赖性增强，针对基因型1a和1b的总Kis估计值分别为0.5 nM和0.4 nM。Simeprevir是一种强效的HCV NS3/4A蛋白酶抑制剂（Ki=0.36 nM）以及病毒复制的抑制剂（复制子EC50=7.8 nM）。 |
| In vivo | 在大鼠中，TMC435350（40 mg/kg，p.o.）广泛分布于肝脏和肠道（组织/血浆浓度-时间曲线下面积比值>35），且绝对生物利用度为44%。 |
| Cell experiments | Huh7-Luc cells are seeded at a density of 2,500 cells/well in a 384-well plate in Dulbecco's modified Eagle's medium plus 10% fetal calf serum and incubated with a range of concentrations of serially diluted simeprevir, in a final DMSO concentration of 0.5% in the absence of G418. After 72 h of incubation, Steady Lite reagent is added in a 1:1 ratio to the medium, and luciferase signal is measured using a ViewLux reader. |
| Animal experiments | Twenty-four male specific-pathogen-free Sprague-Dawley rats, weighing between 200 and 300 g at the time of dosing, are divided into eight groups of three rats each. Seven groups are dosed orally (p.o.) by gastric intubation of a vitamin E acetate-d-α-tocopheryl polyethylene glycol 1000 succinate-polyethylene glycol 400 solution of Simeprevir (TMC435350) at 2 mL/kg body weight to provide a dose of 40 mg/kg. One group is dosed intravenously (i.v.) by slow bolus injection in a tail vein of a 20% 2-hydroxypropyl-β-cyclodextrin formulation of TMC435350 (containing TMC435350, 100 mg/mL 2-hydroxypropyl-β-cyclodextrin, 0.1 N NaOH to pH 8.0±0.1, and mannitol-and pyrogen-free water) at 2 mL/kg body weight to provide a dose of 4 mg/kg. Water and food are available ad libitum during the study. |
| Target activity | HCV:8 nM (EC50) |
| Synonyms | TMC435, 西咪匹韦, TMC-435350, Olysio |
| molecular weight | 749.94 |
| Molecular formula | C38H47N5O7S2 |
| CAS | 923604-59-5 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | DMSO: 55 mg/mL (73.34 mM) H2O: Insoluble |
| References | 1. Lin TI, et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor.Antimicrob Agents Chemother. 2009 Apr;53(4):1377-85. Epub 2009 Jan 26. 2. Raboisson P, et al. Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8. 3. Zhang X, et al. Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism. Eur J Med Chem. 2018 Jan 1;143:1053-1065. |
| Citations | 1. Sinokki A, Miinalainen A, Kiander W, et al.PREINCUBATION-DEPENDENT INHIBITION OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 2B1.European Journal of Pharmaceutical Sciences.2024: 106852. |