| Description | Asunaprevir (BMS-650032) is an effective hepatitis C virus (HCV) NS3 protease inhibitor. |
| In vitro | Asunaprevir抑制基因型1a（H77株）和基因型1b（J4L6S株）的NS3蛋白酶活性，其IC50分别为0.7和0.3 nM。针对编码NS3蛋白酶领域的基因型1a、1b和4a的复制子，ASV的EC50值在1.2到4.0 nM之间[2]。在以10倍和30倍EC50值（分别为50或150 nM最终浓度）的Asunaprevir浓度下，维持复制子细胞的选择性压力。对于基因型1b的抗性选择，以10倍或30倍EC50值（分别为30或90 nM最终浓度）的Asunaprevir浓度维持复制子细胞[3]。单次或多次给药，每日两次，剂量从200到600 mg的Asunaprevir通常被患者良好耐受，能在慢性感染基因型1 HCV的受试者中快速且大幅降低HCV RNA水平[4]。 |
| In vivo | Asunaprevir（3-15 mg/kg，p.o.）在多种动物种类中表现出肝脏靶向性质，肝脏至血浆比例在不同物种间从40至359倍不等。在给药后24小时，所有测试物种的肝脏暴露度普遍达到或超过抑制剂EC50（针对HCV基因型1复制子）的110倍以上[2]。 |
| Cell experiments | Cytotoxicity is determined by incubating cells (3,000 to 10,000 cells/well) with serially diluted test compounds or DMSO for 5 days (MT-2 cells) or 4 days (all other cell types). Cell viability is quantitated using an MTS assay for MT-2 or a Cell-Titer Blue reagent assay for HEK-293, HuH-7, HepG2, and MRC5 cells, and 50% cytotoxic concentrations (CC50s) are calculated. |
| Animal experiments | Mice (n=9 per group; overnight fast) receive Asunaprevir (ASV) by oral gavage (5 mg/kg; a vehicle of PEG-400-ethanol, 9:1). Blood samples (-0.2 mL) are obtained by retro-orbital bleeding at 0.25, 0.5, 1, 3, 6, 8, and 24 h after dosing. Within each group, three animals are bled at 0.25, 3, and 24 h, three at 0.5 and 6 h, and three at 1 and 8 h, resulting in a composite pharmacokinetic profile. Livers and brains are also removed from mice at the terminal sampling points. Rats (n=3 per group; overnight fast) receive ASV (amorphous free acid) by oral gavage (3, 5, 10, and 15 mg/kg) in PEG-400-ethanol (9:1). Serial blood samples (-0.3 mL) are obtained from the jugular vein predosing (0 h) and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 24, and 48 h post dosing. To assess tissue exposure, rats are orally administered ASV (5 or 15 mg/kg, same vehicle as above), and blood, liver, and heart samples from two rats/group are obtained at 0.17, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 h after dosing. |
| Target activity | HCV 1a H77:0.7 nM, 6a (HK-6A):0.9 nM, 1b J4L6S:0.3 nM, 4a (ED43):1.6 nM, 5a (SA13):1.7 nM |
| Synonyms | BMS-650032, 阿那匹韦 |
| molecular weight | 748.29 |
| Molecular formula | C35H46ClN5O9S |
| CAS | 630420-16-5 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | H2O: Insoluble Ethanol: 20 mg/mL DMSO: 50 mg/mL (66.82 mM) |
| References | 1. Pelosi LA, et al. Effect on HCV Replication by Combinations of Direct Acting Antivirals Including NS5A Inhibitor Daclatasvir. Antimicrob Agents Chemother. 2012 Jul 30. 2. McPhee F, et al. Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032). Antimicrob Agents Chemother. 2012 Aug 6. 3. McPhee F, et al. Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir. Antimicrob Agents Chemother. 2012 Jul;56(7):3670-81. 4. Pasquinelli C, et al. Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C. Antimicrob Agents Chemother. 2012 Apr;56(4):1838-44. |