格佐匹韦 | 1350514-68-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 格佐匹韦
• 中文别名: 格佐普韦；戈雷瑞韦
• 英文名称: grazoprevir
• 英文别名: MK-5172；(1aR,5S,8S,10R,22aR)-N-[(1R,2S)-1-[(cyclopropylsulfonamido)carbonyl]-2-ethenylcyclopropyl]-14-methoxy-5-(2-methylpropan-2-yl)-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide；(1R,18R,20R,24S,27S)-24-tert-butyl-N-[(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]-7-methoxy-22,25-dioxo-2,21-dioxa-4,11,23,26-tetrazapentacyclo[24.2.1.03,12.05,10.018,20]nonacosa-3,5(10),6,8,11-pentaene-27-carboxamide
• CAS: 1350514-68-9
• 化学式: C₃₈H₅₀N₆O₉S
• 分子量: 766.916
• InChiKey: OBMNJSNZOWALQB-NCQNOWPTSA-N

物化性质

• 密度：
  1.38±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO 中≥38.35 mg/mL；不溶于水； ≥24 mg/mL，乙醇溶液，温和加热和超声波

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  54
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  204
• 氢给体数：
  3
• 氢受体数：
  11

ADMET

代谢

grazoprevir部分通过CYP3A介导的氧化代谢消除[美国食品药品监督管理局标签]。在人体血浆中没有检测到循环代谢物。

Grazoprevir is partially eliminated by oxidative metabolism meditated by CYP3A [FDA Label]. No circulating metabolites of have been detected in human plasma.

来源:DrugBank

毒理性

• 肝毒性

在大规模随机对照试验中，使用Zepatier治疗的患者的血清转氨酶水平超过正常上限（ULN）的5倍的发生率为1%，而安慰剂接受者中很少出现这种情况。这些升高通常是无症状的和短暂的，经常在治疗的前4周后出现，并在剂量调整与否的情况下解决，很少需要提前终止。在某些情况下，ALT水平上升到超过正常上限的10倍，但这些升高并没有伴随症状或黄疸，并且总是自限性的。在许多预注册试验中，Zepatier并未与临床上明显的肝损伤案例有关联。 然而，有两种形式的肝损伤与用于治疗慢性丙型肝炎的直接作用抗病毒药物有关，这些反应似乎与所有治疗方案都有关系。第一种是丙型肝炎相关肝硬化的急性失代偿。肝损伤通常在开始抗病毒治疗后的2到6周内出现，但可能在更晚的时间出现，甚至是在停药之后。损伤的特点是黄疸加重和肝衰竭的迹象出现，如腹水或肝性脑病，血清转氨酶水平通常很少有或没有变化。早期可能会出现乳酸酸中毒。病程变化不一，但需要立即停止治疗，尽管成功抑制了HCV RNA水平。一些案例导致了死亡或需要紧急肝移植。因此，接受像Zepatier这样的强效直接作用药物进行抗病毒治疗的肝硬化患者，应被仔细监测，尤其是在治疗的前几周。这种综合征并未明确与使用 grazoprevir 和 elbasvir 的治疗方案有关联，但该方案尚未在患有晚期丙型肝炎肝硬化的患者中进行评估。 慢性丙型肝炎治疗的第二种肝并发症是乙型肝炎的再激活。这最常见于血清中有HBsAg的患者，但在没有HBsAg而只有anti-HBc的受试者中也有罕见案例。在治疗丙型肝炎期间乙型肝炎再激活的原因尚不清楚，但可能与在HCV复制期间抑制HBV复制有关。因此，准备接受抗病毒治疗的丙型肝炎患者应筛查HBsAg和anti-HBc。HBsAg阳性的患者最好通过同时使用对HBV有效的抗病毒药物（如恩替卡韦或替诺福韦）进行治疗。没有HBsAg而只有anti-HBc的受试者很少经历再激活，可以通过在治疗期间密切监测HBV DNA水平并在水平出现新发或显著上升时对HBV进行治疗来进行管理。乙型肝炎的再激活已经有很多种治疗方案被描述，尽管并未特别与grazoprevir和elbasvir有关。 可能性评分：E*（未证实但怀疑是临床上明显肝损伤的原因）。

In large randomized controlled trials, serum aminotransferase elevations more than 5 times the upper limit of normal (ULN) occurred in 1% of Zepatier treated patients, but were infrequent in placebo recipients. The elevations were generally asymptomatic and short-lived, often arising after the first 4 weeks of therapy and resolving with or without dose modification and only rarely requiring early discontinuation. In some instances, ALT levels rose above 10 times the upper limit of normal, but these elevations were not accompanied by symptoms or jaundice and were invariably self-limited. In the many preregistration trials, Zepatier was not associated with instances of clinically apparent liver injury. However, two forms of liver injury have been associated with direct-acting antiviral agents used to treat chronic hepatitis C, and these reactions appear to occur with all regimens. The first is acute decompensation of HCV-related cirrhosis. The liver injury usually arises within 2 to 6 weeks of starting antiviral therapy, but can occur later and even after discontinuation. The injury is marked by worsening jaundice and appearance of signs of hepatic failure such as ascites or hepatic encephalopathy, often with little or no change in serum aminotransferase levels. Lactic acidosis may be present early. The course is variable but calls for prompt discontinuation of treatment despite successful suppression of HCV RNA levels. Some instances have led to death or need for emergency liver transplantation. For this reason, patients with cirrhosis undergoing antiviral therapy with potent direct acting agents, such as Zepatier, should be monitored carefully, particularly during the first few weeks of treatment. This syndrome has not been clearly linked to therapy with grazoprevir and elbasvir, but this regimen has not been evaluated in patients with advanced cirrhosis due to hepatitis C. A second, liver complication of therapy of chronic hepatitis C is reactivation of hepatitis B. This occurs most frequently in patients who have HBsAg in serum but rare instances have arisen in subjects with anti-HBc without HBsAg. The cause of the reactivation of hepatitis B during antiviral therapy of hepatitis C is unknown, but may relate to the inhibition of HBV replication during HCV replication. For this reason, patients with hepatitis C who are to receive antiviral therapy should be screened for HBsAg and anti-HBc. Those with HBsAg are best managed by concurrent treatment with an antiviral agent active against HBV, such as entecavir or tenofovir. Subjects with anti-HBc without HBsAg rarely experience reactivation and can be managed by careful monitoring for HBV DNA levels during treatment and institution of therapy for HBV if levels appear de novo or rise significantly. Reactivation of hepatitis B has been described with many regimens, although not specifically with grazoprevir and elbasvir. Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 毒性总结

所有强度中最常见的不良反应（在安慰剂对照试验中大于或等于5%）是疲劳、头痛和恶心【FDA标签】。

The most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea [FDA Label].

来源:DrugBank

毒理性

• 蛋白质结合

Grazoprevir与血浆蛋白的结合率超过98.8% [FDA标签]。它既与人血清白蛋白和α1-酸性糖蛋白结合。

Grazoprevir is more than 98.8% bound to plasma proteins [FDA Label]. It binds both human serum albumin and α1-acid glycoprotein.

来源:DrugBank

吸收、分配和排泄

• 吸收

Grazoprevir在服用后0.5-3小时达到血浆峰值浓度[FDA标签]。Grazoprevir的绝对生物利用度为27%。与食物同服时，Grazoprevir的峰值浓度增加2.8倍，但这种暴露增加在临床上并未被认为有显著意义。

Grazoprevir reaches peak plasma concentration 0.5-3 hours after administration [FDA Label]. Grazoprevir has an absolute bioavailability of 27%. When taken with food the peak concentration of Grazoprevir increases 2.8 fold but this increase in exposure has not been deemed clinically relevant.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Grazoprevir 主要通过粪便排出（90%），通过尿液排出的非常少（<1%）[FDA 标签]。

Grazoprevir is mainly eliminated in the feces (90%) with very little eliminated in the urine (<1%) [FDA Label].

来源:DrugBank

吸收、分配和排泄

• 分布容积

grazoprevir的估计表观分布容积为1250升(美国食品药品监督管理局标签)。据认为，它主要分布在肝脏，其摄取由有机阴离子转运多肽1B1/3介导。

Grazoprevir has an estimated apparent volume of distribution of 1250 liters [FDA Label]. It is thought to distribute primarily to the liver with its uptake facilitated by organic anion transporting polypeptide 1B1/3.

来源:DrugBank

吸收、分配和排泄

• 清除

grazoprevir的清除率尚未确定。

The clearance of Grazoprevir has not been determined [FDA Label].

来源:DrugBank

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20℃

制备方法与用途

生物活性

Grazoprevir anhydrous (MK5172) 是一种针对 Hepatitis C Virus NS3/4A Protease 的抑制剂，其对 HCV genotype 1a、1B 和 4 的 IC50 值分别为 7pM、4pM 和 62pM。

靶点

Target	Value
gt1b (细胞自由测定)	0.01 nM (Ki)
gt1a (细胞自由测定)	0.01 nM (Ki)
gt1b R155K (细胞自由测定)	0.07 nM (Ki)
gt2a (细胞自由测定)	0.08 nM (Ki)
gt1b D168V (细胞自由测定)	0.14 nM (Ki)

反应信息

• 作为反应物：
  描述：

  格佐匹韦 在 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 3.0h， 生成 Grazoprevir sodium
  参考文献：
  名称：

  Inhibitors of nedd8-activating enzyme

  摘要：

  该发明涉及一种包含晶型I的{(1S,2S,4R)-4-[(6-{[(1R,2S)-5-氯-2甲氧基-2,3-二氢-1H-茚-1-基]氨基}嘧啶-4-基)氧基]-2-羟基环戊基}甲基磺酰胺(I-216)盐酸盐的管理单元，以及包括该管理单元的包装。

  公开号：

  EP2764866A1
• 作为产物：
  描述：

  (1aR,5S,8S,10R,22aR)-18,19-二去氢-5-(叔丁基)-1,1a,3,4,5,6,9,10,20,21,22,22a-十二氢-14-甲氧基-3,6-二氧代-8H-7,10-甲桥环丙烯并[18,19][1,10,3,6]二氧杂二氮杂环十九碳九烯并[11,12-b]喹喔啉-8-羧酸甲酯 在 吡啶 、 甲醇 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 为溶剂， -5.0~45.0 ℃ 、344.75 kPa 条件下， 反应 16.0h， 生成 格佐匹韦
  参考文献：
  名称：

  用于治疗丙型肝炎病毒的强效NS3 / 4a蛋白酶抑制剂Grazoprevir的合成

  摘要：

  据报道，grazoprevir的有效合成。从四个容易获得的结构单元开始，制备格拉佐泼韦的总收率为51％，纯度大于99.9％，可用于制药用途。

  DOI：

  10.1021/acs.orglett.8b03173

文献信息

• [EN] METHODS AND INTERMEDIATES FOR PREPARING MACROLACTAMS<br/>[FR] PROCÉDÉS ET INTERMÉDIAIRES POUR PRÉPARER DES MACROLACTAMES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015057611A1

  公开（公告）日：2015-04-23

  The present invention includes compounds useful as intermediates in the preparation of macrolactams, methods for preparing the intermediates, and methods for preparing macrolactams. One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity. HCV NS3 inhibitory compounds have therapeutic and research applications.

  本发明包括作为大环内酰胺制备中间体有用的化合物，制备这些中间体的方法，以及制备大环内酰胺的方法。本文描述的方法和中间体的一个用途是生产能够抑制HCV NS3蛋白酶活性的大环内酰胺化合物。HCV NS3抑制化合物具有治疗和研究应用。
• Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
  申请人：Harper Steven

  公开号：US20100029666A1

  公开（公告）日：2010-02-04

  The present invention relates to macrocyclic a compound of formula (I) and its use as inhibitors of the hepatitis C virus (HCV) NS3 protease, and in treating or preventing HCV infections.

  本发明涉及一种具有化学式(I)的大环化合物，以及其作为丙型肝炎病毒（HCV）NS3蛋白酶抑制剂的用途，用于治疗或预防HCV感染。
• [EN] SUBSTITUTED BENZOFURAN COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES<br/>[FR] COMPOSÉS BENZOFURANES SUBSTITUÉS ET LEURS MÉTHODES D'UTILISATION POUR LE TRAITEMENT DE MALADIES VIRALES
  申请人：MERCK SHARP & DOHME

  公开号：WO2014209727A1

  公开（公告）日：2014-12-31

  The present invention relates to compounds of formula I that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system. (I)

  本发明涉及式I的化合物，可用作丙型肝炎病毒（HCV）NS5B聚合酶抑制剂，以及这类化合物的合成，以及用这类化合物来抑制HCV NS5B聚合酶活性，用于治疗或预防HCV感染，并在基于细胞的系统中抑制HCV病毒复制和/或病毒产生。
• PROCESS FOR MAKING HCV PROTEASE INHIBITORS
  申请人：ABBVIE INC.

  公开号：US20130178630A1

  公开（公告）日：2013-07-11

  Efficient processes for making HCV protease inhibitors are described. In one embodiment, the process uses novel idazolide derivatives of vinyl-ACCA.

  描述了制造HCV蛋白酶抑制剂的高效过程。在一种实施例中，该过程使用了新型咪唑酰乙烯基-ACCA衍生物。
• [EN] MACROCYCLIC QUINOXALINE COMPOUNDS AS HCV NS3 PROTEASE INHIBITORS<br/>[FR] COMPOSÉS DE QUINOXALINE MACROCYCLIQUES EN TANT QU'INHIBITEURS DE PROTÉASE NS3 DU VIRUS DE L'HÉPATITE C (HCV)
  申请人：MERCK & CO INC

  公开号：WO2010011566A1

  公开（公告）日：2010-01-28

  The present invention relates to macrocyclic a compound of formula (I) and its use as inhibitors of the hepatitis C virus (HCV) NS3 protease, and in treating or preventing HCV infections. Formula (I)

  本发明涉及一种式为（I）的大环化合物及其作为丙型肝炎病毒（HCV）NS3蛋白酶抑制剂的用途，并用于治疗或预防HCV感染。式（I）如下：