(1R,4R,7Z,15R,17R)-N-cyclopropylsulfonyl-17-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxamide | 923604-59-5

• 物质功能分类: 生物 - 细胞培养 - 添加剂
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (1R,4R,7Z,15R,17R)-N-cyclopropylsulfonyl-17-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxamide
• CAS: 923604-59-5
• 化学式: C₃₈H₄₇N₅O₇S₂
• 分子量: 749.9
• InChiKey: JTZZSQYMACOLNN-CDZHZSKVSA-N

物化性质

• 密度：
  1.38
• 溶解度：
  不溶于水；不溶于乙醇； ≥18.75 mg/mL，溶于 DMSO
• 颜色/状态：
  White to almost white powder
• 熔点：
  225
• 蒸汽压力：
  5.9X10-27 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 2.68X10-28 atm-cu m/mol at 25 °C (est)
• 解离常数：
  pKa1 = 1.61 (imine); pKa2 = 3.77 (amine); pKa3 = 10.80 (secondary amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  52
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  194
• 氢给体数：
  2
• 氢受体数：
  10

ADMET

代谢

Simeprevir 经肝脏代谢。主要的代谢途径涉及CYP3A系统介导的氧化。不能排除CYP2C8和CYP2C19的参与。

Simeprevir undergoes hepatic metabolism. The primary metabolic pathway involves CYP3A system-mediated oxidation. Involvement of CYP2C8 and CYP2C19 cannot be excluded.

来源:DrugBank

代谢

在健康受试者单次口服200毫克（推荐剂量的1.3倍）的(14)C-西美瑞韦后，血浆中大部分的放射性（平均：83%）归因于未改变的药物，而血浆中的一部分放射性与代谢物有关（没有主要的代谢物）。在粪便中鉴定的代谢物是通过在大环部分或芳香部分或两者同时进行氧化形成的，以及通过O-脱甲基化后进行氧化形成的。

Following a single oral administration of 200 mg (1.3 times the recommended dosage) (14)C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

西美瑞韦在肝脏中被代谢。用人肝脏微粒体的体外实验表明，西美瑞韦主要通过肝脏的CYP3A系统进行氧化代谢。不能排除CYP2C8和CYP2C19的参与。与中等或强效的CYP3A抑制剂联合使用可能会显著增加西美瑞韦的血浆暴露量，而与中等或强效的CYP3A诱导剂联合使用可能会显著降低西美瑞韦的血浆暴露量。

Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of Olysio with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir.

来源:Hazardous Substances Data Bank (HSDB)

代谢

14C-TMC435的体外代谢在鼠、大鼠、兔、猴和人的肝细胞和肝微粒体中被研究。从动物和人体中报告的体外代谢活性较低。在肝细胞中形成了I相代谢物II相结合途径。在体外，母体TMC435的量比任何代谢物都要高得多。已鉴定出20多种代谢物。代谢I相最重要的途径是未改变药物的O-脱甲基化（特别是在动物中）、未改变药物和氧化代谢物的氧化（特别是在猴和人中），氧化代谢物的葡萄糖苷酸化是II相的主要途径（在人中较少）。在体外仅发现一种在大鼠或狗中没有见到的代谢物，即M22（氧化未改变的药物），但该代谢物在大鼠（粪便）中被鉴定。体内数据显示，在大鼠、狗和人血浆中的主要成分是母体TMC435。在动物和人体血浆中报告的体内主要代谢物是M18和M21。O-脱甲基-TMC435 M21是在大鼠、狗和人血浆中发现的唯一共同循环代谢物（M21：平均TMC435血浆的8%，狗中仅含少量痕迹），而M18是大鼠和狗血浆中常见的，但相对于母体化合物，它们的出现浓度较低（M18：在大鼠中为28.9%至12.5%，狗中仅含少量痕迹）。在狗血浆中仅报告了由芳香部分O-脱甲基化和氧化形成的代谢物M18、M21和M8的痕迹。M21代表未改变药物的不到10%，也代表总放射性的不到10%，因此在安全性评估研究中没有评估对M21的系统暴露。M21在人中没有出现累积。在大鼠胆汁中报告了较高水平的母体化合物（0.11至17.2%）。在这种基质中，TMC435的代谢物主要是由羟基化、O-脱甲基化和葡萄糖苷酸化形成的。

The in vitro metabolism of 14C-TMC435 was investigated in hepatocytes and liver microsomes of mouse, rat, rabbit, monkey and human. The metabolic activity reported in vitro from animals and man was low. Phase II conjugation pathways of Phase I metabolites were formed in hepatocytes. Parent TMC435 was found in much greater levels than any metabolite in vitro. More than 20 metabolites were identified. The metabolic Phase I route of highest importance were O-demethylation of unchanged drug (particularly in animals), oxidation of unchanged drug and oxidized metabolites (particularly in monkey and man) and glucuronidation was the major Phase II of oxidized metabolites (less in human). Only one human metabolite identified in vitro not seen in rat or dog was M22 (oxidized unchanged drug) but this metabolite was identified in rat (feces). In vivo data reveals that the main moiety present in plasma of rat, dog and man was parent TMC435. The major metabolites reported in vivo in plasma from animals and human were M18 and M21. O-desmethyl-TMC435 M21 was the only common circulating metabolite found in rat dog and human plasma (M21: 8% of the mean TMC435 plasma and only small traces in dogs), while M18 was common to plasma of rats and dogs but with respect to the parent compound they appeared with low concentrations (M18: between 28.9% and 12.5% in rats, with only small traces in dogs). Only traces of metabolites M18, M21 and M8 formed by O-demethylation and oxidation at the aromatic moiety were reported in dog plasma. M21 represents less than 10% of unchanged drug and also total radioactivity therefore systemic exposure to M21 was not assessed in the safety evaluation studies. M21 did not appear to accumulate in man. In bile from rats, moderately high levels of parent compound were reported (0.11 to 17.2%). TMC435 metabolites in this matrix were formed mainly by hydroxylation and O-demethylation and also by glucuronidation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠和狗体内，TMC435最重要的代谢途径是母药的O-脱甲基化，生成M18（大鼠雄性-雌性12.8%-6.4%；狗18.8%）。在大鼠中，其他代谢物是通过M18的氧化和未变化药物的氧化形成的。在狗中，M18进一步氧化为M14和M8，以及未变化药物氧化为M21、M16和M11也被报道为次要途径。人类的代谢轮廓表明，TMC435主要通过两个主要途径代谢：（1）未变化药物的氧化，可以在大环部分（M27、M21和M22），或在芳香部分（M26和M16），或两者都有（M23、M24、M25和M11）；（2）未变化药物O-脱甲基化生成M18，然后在大环部分氧化为M14，在芳香部分氧化为M5，这看起来是人类次要的代谢途径。M21和M22是人类粪便中最重要的代谢物。其他相关代谢物（剂量的1%）是M11、M16、M27和M18。在人类粪便中检测到的所有代谢物都在大鼠和/或狗的体外和/或体内粪便中检测到。参与TMC435代谢的主要CYP酶是CYP3A酶，尽管体外数据表明CYP2C8和CYP2C19的参与。

The most important metabolic route TMC435 in rat and dog was O-demethylation of the parent drug to M18 (12.8%- 6.4% male-female rats; 18.8% dogs). In rats other metabolites were formed by oxidation of M18 and oxidation of unchanged drug. In dogs, further oxidation of M18 to M14 and M8, and of the unchanged drug to M21, M16 and M11 were also reported as minor routes. The human metabolism profile suggests that TMC435 is mainly metabolized by two main routes, (1) oxidation of unchanged drug, either at the macrocyclic moiety (M27, M21 and M22), or at the aromatic moiety (M26 and M16), or both (M23, M24, M25 and M11) and (2) the O-demethylation of unchanged drug to M18, followed by oxidation on the macrocyclic moiety to M14 and by oxidation on the aromatic moiety to M5, appears to be the secondary metabolic pathway in man. M21 and M22 were the most important metabolites in human faeces. Other relevant metabolites (1% of the dose) were M11, M16, M27 and M18. All metabolites detected in human feces were detected in vitro and/or in vivo in rat and/or dog feces. The main CYP enzymes involved in TMC435 metabolism were CYP3A enzymes although in vitro data suggests the involvement of CYP2C8 and CYP2C19.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

与索非布韦联合治疗时，最常见报告的不良反应是乏力、头痛和恶心。在使用PEG-干扰素阿尔法-2A和利巴韦林进行三联疗法的情况下，最常见的不良反应包括皮疹（包括光敏性）、瘙痒和恶心。由于西美瑞韦抑制胆红素转运蛋白OATP1B1和MRP2，可能会观察到血清胆红素升高。

In a combination therapy with sofosbuvir, most common reported adverse effects is fatigue, headache and nausea. In case of triple therapy with PEG-Interferon Alfa-2A and ribavirin, most common adverse effects included rash (including photosensitivity), pruritus and nausea. Elevations of serum bilirubin may be observed due to inhibition of bilirubin transporters OATP1B1 and MRP2 by simeprevir.

来源:DrugBank

毒理性

• 毒性总结

SIMCITRA-100 (simeprevir) 是一种白色至近白色的粉末。SIMCITRA-100（simeprevir）与聚乙二醇干扰素α和利巴韦林联合使用，用于治疗慢性丙型肝炎病毒（HCV）基因型1感染成人，伴补偿性肝病（包括肝硬化）的初治（之前未经治疗）患者，或经干扰素和利巴韦林治疗失败的患者（包括之前无应答、之前部分应答或之前复发的患者）。SIMCITRA-100（simeprevir）必须与聚乙二醇干扰素α（聚乙二醇干扰素α-2a或聚乙二醇干扰素α-2b）和利巴韦林联合使用，不应单独用于治疗慢性HCV感染。 人体暴露和毒性：关于SIMCITRA-100（simeprevir）过量的影响的数据非常有限。在健康成人受试者中，单次给药高达600 mg或每日一次给药高达400 mg、连续5天，以及成人HCV患者中每日一次给药200 mg、连续4周，SIMCITRA-100（simeprevir）普遍耐受性良好。 动物研究：在小鼠中单次给药高达500 mg/kg、大鼠中1000 mg/kg、犬中160 mg/kg和猴子中300 mg/kg后，SIMCITRA-100（simeprevir）普遍耐受性良好。在动物研究中，SIMCITRA-100（simeprevir）对生命功能（心脏、呼吸和中央神经系统）没有不良影响。对SIMCITRA-100（simeprevir）进行了小鼠（长达3个月）、大鼠（长达6个月）、犬（长达9个月）和猴子（长达28天）的重复剂量口服毒性研究。所有物种均观察到胃肠道影响。小鼠、大鼠和/或犬中出现软便、粘液便或苍白便的比例较高。在小鼠、大鼠和犬中，十二指肠和空肠的顶端肠上皮细胞出现肿胀/空泡化。由于胃排空延迟，小鼠和大鼠中出现了异常胃内容物和/或腹部膨胀。在小鼠、大鼠和犬中观察到肝脏影响。这些发现通常伴有血浆中胆红素和肝酶的增加。 在一项小鼠胚胎-胎儿研究中，SIMCITRA-100（simeprevir）在高达1000 mg/kg的剂量下，导致早期和晚期宫内胎儿死亡以及早期母体死亡，其暴露量大约是人类推荐150 mg每日剂量平均AUC的6倍。在暴露量大约是人类推荐每日剂量平均AUC的4倍时，观察到胎儿体重显著降低和胎儿骨骼变异增加。在一项大鼠围产期研究中，母体动物在妊娠和哺乳期间暴露于高达1000 mg/kg/日的SIMCITRA-100（simeprevir）。在妊娠大鼠中，SIMCITRA-100（simeprevir）在1000 mg/kg/日的剂量下导致早期死亡，其暴露量与人类推荐150 mg每日剂量平均AUC相似。在暴露量是人类推荐150 mg每日剂量平均AUC的0.7倍时，观察到体重增加显著减少。在子宫内（通过母体给药）和哺乳期（通过母体乳汁至哺乳仔鼠）暴露于SIMCITRA-100（simeprevir）的发育中大鼠后代体重显著降低，对身体生长（延迟和小尺寸）和发展（活动能力降低）产生负面影响。随后存活、行为和生殖能力未受影响。 在一项大鼠生育研究中，高达500 mg/kg/日的SIMCITRA-100（simeprevir）剂量下，3只雄性大鼠出现无活动精子、睾丸和附睾小，其中2只大鼠在约是人类平均AUC的0.2倍时出现不育。SIMCITRA-100（simeprevir）在一系列体外和体内试验中，包括 Ames 试验、小鼠淋巴瘤细胞的哺乳动物正向突变试验或体内哺乳动物微核试验中，均不具有致突变性。

IDENTIFICATION AND USE: Simeprevir is a white to almost white powder. Simeprevir is used in conjunction with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in adults with compensated liver disease (including cirrhosis) who are treatment-naive (previously untreated) or in whom prior treatment with interferon and ribavirin failed (including those with prior null response, prior partial response, or prior relapse). Simeprevir must be used in conjunction with peginterferon alfa (peginterferon alfa-2a or peginterferon alfa-2b) and ribavirin and should not be used alone for the treatment of chronic HCV infection. HUMAN EXPOSURE AND TOXICITY: Very few data are available on the effects of overdose to simeprevir. Simeprevir was generally well tolerated when given as single doses up to 600 mg or once daily doses up to 400 mg for 5 days in healthy adult subjects, and as 200 mg once daily for 4 weeks in adult patients with HCV. ANIMAL STUDIES: Simeprevir was well tolerated after single doses up to 500 mg/kg in mice, 1000 mg/kg in rats, 160 mg/kg in dogs and 300 mg/kg in monkeys. There were no adverse effects of simeprevir on vital functions (cardiac, respiratory and central nervous system) in animal studies. Repeat dose oral toxicity studies with simeprevir were conducted in mice (up to 3 months), rats (up to 6 months), dogs (up to 9 months), and monkeys (up to 28 days). Gastrointestinal effects were observed in all species. A higher incidence of soft, mucoid or pale feces was seen in mice, rats and/or dogs. The presence of swelling/vacuolization of apical enterocytes in the duodenum and jejunum was noted in mice, rats and dogs. The compound formulation caused abnormal stomach contents and/or abdominal distention, in mice and rats, as a result of delayed gastric emptying. Liver effects were observed in mice, rats and dogs. These findings were often accompanied by increases in bilirubin, and liver enzymes in plasma. In a mouse embryofetal study at doses up to 1000 mg/kg, simeprevir resulted in early and late in utero fetal losses and early maternal deaths at an exposure approximately 6 times higher than the mean AUC in humans at the recommended 150 mg daily dose. Significantly decreased fetal weights and an increase in fetal skeletal variations were seen at exposures approximately 4 times higher than the mean AUC in humans at the recommended daily dose. In a rat pre- and postnatal study, maternal animals were exposed to simeprevir during gestation and lactation at doses up to 1000 mg/kg/day. In pregnant rats, simeprevir resulted in early deaths at 1000 mg/kg/day corresponding to exposures similar to the mean AUC in humans at the recommended 150 mg once daily dose. Significant reduction in body weight gain was seen at an exposure 0.7 times the mean AUC in humans at the recommended 150 mg once daily dose. The developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at a maternal exposure similar to the mean AUC in humans at the recommended 150 mg once daily dose. Subsequent survival, behavior and reproductive capacity were not affected. In a rat fertility study at doses up to 500 mg/kg/day, 3 male rats treated with simeprevir (2/24 rats at 50 mg/kg/day and 1/24 rats at 500 mg/kg/day) showed no motile sperm, small testes and epididymides, and resulted in infertility in 2 out of 3 of the male rats at approximately 0.2 times the mean AUC in humans. Simeprevir was not genotoxic in a series of in vitro and in vivo tests including the Ames test, the mammalian forward mutation assay in mouse lymphoma cells or the in vivo mammalian micronucleus test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模随机对照试验中，simeprevir并未与治疗期间血清酶水平升高或临床明显肝损伤的案例增多有关联。Simeprevir会导致血清间接胆红素轻微升高，一些患者出现了明显的黄疸，但胆红素升高通常是轻微的、暂时的，并且与血清转氨酶或碱性磷酸酶水平的变化无关。然而，在获得批准并更广泛使用后，simeprevir至少与一例急性肝炎（案例1）有关。发病潜伏期为7周，损伤模式为肝细胞型，没有免疫过敏或自身免疫特征。停止治疗后，恢复迅速而完全。 此外，simeprevir与其他药物联合使用时，还与急性、看似自发的丙型肝炎相关肝硬化失代偿案例有关。simeprevir相对于其他联合使用的丙型肝炎抗病毒药物的角色常常不明确。在使用聚乙二醇干扰素和利巴韦林联合治疗丙型肝炎肝硬化时，simeprevir联合治疗期间肝功能失代偿的比率大约为2%至3%，而与索非布韦联合使用时为0.5%至1.0%。由于存在失代偿的风险，接受抗病毒方案治疗（包括所有口服和干扰素基础方案）的肝硬化患者应在治疗的前4周内特别监测肝脏疾病恶化的迹象。这种并发症在肝脏疾病更严重的患者、Child B级肝硬化和有肝功能失代偿既往史的患者中可能更为常见。 损伤机制的几率评分：D（可能的罕见原因，容易在易感个体中引起临床明显的肝损伤）。 损伤机制 simeprevir可能引起肝损伤的机制尚不清楚。它主要通过肝细胞色素P450系统代谢，主要是CYP 3A，并且是药物转运蛋白P-糖蛋白和OATP1Ba/3以及外排转运蛋白MDR1、MRP2和BSEP的抑制剂，这可能是某些患者出现间接高胆红素血症的原因。Simeprevir与药物相互作用有关，并且可以提高一些他汀类药物的水平。simeprevir联合治疗时发生的失代偿可能是药物的直接作用，或者是快速根除丙型肝炎感染的常见并发症。最后，失代偿的发作可能是偶然的，与抗病毒治疗无关。

In large randomized controlled trials, simeprevir was not linked to an increased rate of serum enzyme elevations during treatment or with instances of clinically apparent liver injury. Simeprevir causes a mild increase in serum indirect bilirubin and some patients became visibly jaundiced, but the bilirubin elevations were generally mild, transient and not associated with changes in serum aminotransferase or alkaline phosphatase levels. After its approval and more wide scale use, however, simeprevir has been implicated in at least one case of an acute hepatitis (Case 1). The latency to onset was 7 weeks and pattern of injury was hepatocellular without immunoallergic or autoimmune features. Recovery was rapid and complete once therapy was stopped. In addition, simeprevir, in combination with other agents, has been linked to instances of acute, seemingly spontaneous decompensation of HCV related cirrhosis. The role of simeprevir as opposed to the other HCV antivirals used in combination was often unclear. Rates of hepatic decompensation during simeprevir combination therapy of cirrhosis due to hepatitis C was approximately 2% to 3% when combined with peginterferon and ribavirin, and 0.5% to 1.0% when used with sofosbuvir. Because of the risk of decompensation, patients with cirrhosis who are treated with antiviral regimens (both all-oral and interferon based) should be monitored for evidence of worsening liver disease, particularly during the first 4 weeks of treatment. This complication is probably more common in patients with more advanced liver disease, Child’s Class B cirrhosis and those with a previous history of liver decompensation. Likelihood score: D (possible rare cause of clinically apparent liver injury in susceptible individuals). Mechanism of Injury The mechanism by which simeprevir might cause liver injury is not known. It is metabolized in the liver largely via the cytochrome P450 system, predominantly CYP 3A and it is an inhibitor of the drug transporters P-glycoprotein and OATP1Ba/3 and the efflux transporters MDR1, MRP2 and BSEP, perhaps accounting for the indirect hyperbilirubinemia that occurs in some patients. Simeprevir is associated with drug-drug interactions and it can raise levels of some statins. The decompensation that occurs with simeprevir combination therapy may be due to a direct effect of the agent, or else represent a usual complication of the rapid eradication of HCV infection. Finally, the episodes of decompensation may be incidental and unrelated to the antiviral therapy.

来源:LiverTox

毒理性

• 相互作用

体外实验中，西美瑞韦是P-糖蛋白（P-gp）的底物和抑制剂。同时使用西美瑞韦和P-gp底物的药物可能会导致这些药物浓度增加。

In vitro, simeprevir is a substrate and inhibitor of P-glycoprotein (P-gp) transport. Concomitant use of simeprevir with drugs that are P-gp substrates may result in increased concentrations of such drugs.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与环孢素的药代动力学相互作用（增加环孢素浓度）。与simeprevir同时使用时，不需要调整环孢素的剂量；建议常规监测环孢素浓度。

Pharmacokinetic interaction with cyclosporine (increased cyclosporine concentrations). Cyclosporine dosage adjustments are not needed when used concomitantly with simeprevir; routine monitoring of cyclosporine concentrations is recommended.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

在进食条件下，单次口服150毫克西美普韦胶囊后，西美普韦的平均绝对生物利用度为62%。口服给药后，通常在4到6小时内达到最高血浆浓度（Cmax）。

The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of simeprevir capsule in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours following the oral administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

西美瑞韦主要通过胆汁排泄。在一项放射性研究中，91%的放射性标记药物在粪便中被检测到，而在尿液中的检测量不到1%。从粪便中回收的药物中，西美瑞韦的未改变形式占总给药剂量的31%。

Simeprevir is predominantly eliminated through biliary excretion. In a radioactivity study, 91% of radiolabeled drug was detected in the feces and less than 1% was detected in the urine. From the recovered drug in the feces, the unchanged form of simeprevir accounted for 31% of the total administered dose.

来源:DrugBank

吸收、分配和排泄

• 分布容积

simeprevir的分布体积尚未确定。在动物研究中，simeprevir广泛分布于肠道和肝脏组织（在大鼠中肝脏：血液的比例为29:1）。

The volume of distribution for simeprevir has yet to be determined. In animal studies, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues.

来源:DrugBank

吸收、分配和排泄

• 清除

西美瑞韦的清除尚未确定。

The clearance of simeprevir has yet to be determined.

来源:DrugBank

吸收、分配和排泄

西美瑞韦与血浆蛋白广泛结合（大于99.9%），主要与白蛋白结合，其次是与α1-酸性糖蛋白结合。在肾或肝功能损害的患者中，血浆蛋白结合并没有明显改变。

Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

生物活性

Simeprevir（TMC-435, TMC-435350）是一种竞争性、可逆的、非共价结合的大环HCV NS3/4A蛋白酶抑制剂，直接抑制HCV病毒。它对genotypes 1a、1b、2、4、5和6的HCV NS3/4A的平均IC50值小于13 nM，而对genotype 3的IC50值为37 nM。

靶点

Target	Value
HCV NS3/4A protease	()

文献信息

• AMORPHOUS SALT OF A MACROCYCLIC INHIBITOR OF HCV
  申请人：Janssen Pharmaceuticals, Inc.

  公开号：EP3150596A1

  公开（公告）日：2017-04-05

  The amorphous form of the sodium salt of the macrocyclic inhibitor of HCV of formula: as well as processes for manufacturing this salt.

  式中的 HCV 大环抑制剂钠盐的无定形形式： 以及制造这种盐的工艺。
• Chimeric antigen receptor (CAR) modulation
  申请人：TRUSTEES OF BOSTON UNIVERSITY

  公开号：US11059864B2

  公开（公告）日：2021-07-13

  The technology described herein is directed to CAR polypeptides and systems comprising repressible proteases. In combination with a specific protease inhibitor, the activity of said CAR polypeptides and systems and cells comprising them can be modulated. Also described herein are methods of using said CAR polypeptides and systems, for example to treat various diseases and disorders.

  本文所述技术针对的是包含可抑制蛋白酶的 CAR 多肽和系统。结合特定的蛋白酶抑制剂，可以调节所述 CAR 多肽和系统以及包含它们的细胞的活性。本文还描述了使用所述 CAR 多肽和系统的方法，例如用于治疗各种疾病和失调。
• Regulated synthetic gene expression systems
  申请人：TRUSTEES OF BOSTON UNIVERSITY

  公开号：US11530246B2

  公开（公告）日：2022-12-20

  The technology described herein is directed to regulated synthetic gene expression systems. In one aspect described herein are synthetic transcription factors (synTFs) comprising a DNA binding domain, a transcriptional effector domain, and a regulator protein. In other aspects described herein are gene expression systems comprising said synTFs and methods of treating diseases and disorders using said synTFs.

  本文所述技术针对的是受调控的合成基因表达系统。一方面，本文所述的合成转录因子（synTFs）包括 DNA 结合结构域、转录效应结构域和调节蛋白。在其他方面，本文所述的基因表达系统包括所述的合成转录因子和使用所述合成转录因子治疗疾病和失调的方法。
• Methods for Treating HCV
  申请人：AbbVie Inc.

  公开号：US20170360783A1

  公开（公告）日：2017-12-21

  The present invention features interferon-free therapies for the treatment of HCV. Preferably, the treatment is over a shorter duration of treatment, such as no more than 16 weeks, alternatively no more than 12 weeks, or alternatively no more than 8 weeks. In one aspect, the treatment comprises administering at least two direct acting antiviral agents to a subject with HCV infection, wherein the treatment lasts for 16, 12, or 8 weeks and does not include administration of either interferon or ribavirin, and said at least two direct acting antiviral agents comprise (a) Compound 1 or a pharmaceutically acceptable salt thereof and (b) Compound 2 or a pharmaceutically acceptable salt thereof.
• CHIMERIC ANTIGEN RECEPTOR (CAR) MODULATION
  申请人：TRUSTEES OF BOSTON UNIVERSITY

  公开号：US20200308234A1

  公开（公告）日：2020-10-01

  The technology described herein is directed to CAR polypeptides and systems comprising repressible proteases. In combination with a specific protease inhibitor, the activity of said CAR polypeptides and systems and cells comprising them can be modulated. Also described herein are methods of using said CAR polypeptides and systems, for example to treat various diseases and disorders.