entecavir | 142217-69-4

• 物质功能分类: 原料药 - 人工合成抗感染类药 - 抗病毒类药
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: entecavir
• 英文别名: ETV；2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-6,9-dihydro-3H-purin-6-one；2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one；BMS-200475；Baraclude；2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylene-cyclopentyl]-6H-purine-6-one；2-amino-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl)-1H-purin-6(9H)-one；Entecavir；2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-1H-purin-6-one
• CAS: 142217-69-4
• 化学式: C₁₂H₁₅N₅O₃
• 分子量: 277.283
• InChiKey: QDGZDCVAUDNJFG-FXQIFTODSA-N

物化性质

• 熔点：
  249-252°C
• 沸点：
  661.4±65.0 °C(Predicted)
• 密度：
  1.81±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少量）、甲醇（少量）
• 物理描述：
  Solid
• 颜色/状态：
  White to off white powder
• 蒸汽压力：
  4.6X10-18 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 1.6X10-21 atm-cu m/mole at 25 °C (est)
• 解离常数：
  pKa = 8.00 - (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  126
• 氢给体数：
  4
• 氢受体数：
  5

ADMET

代谢

恩替卡韦不是细胞色素P450（CYP450）酶系统的底物、抑制剂或诱导剂。恩替卡韦能有效磷酸化成活性三磷酸形式。

Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. Entecavir is efficiently phosphorylated to the active triphosphate form.

来源:DrugBank

代谢

在给予14C-恩替卡韦后，未观察到氧化或乙酰化代谢物。观察到少量II期代谢物（葡萄糖醛酸和硫酸共轭物）。恩替卡韦不是细胞色素P450酶系统的底物、抑制剂或诱导剂。

Following administration of 14C-entecavir, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 enzyme system.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

接受单次恩替卡韦剂量高达40毫克或多剂量高达20毫克/天，为期最多14天的健康受试者，未出现增加的或意外的不良事件。如果发生过量，必须监测患者是否有毒性证据，并根据需要应用标准支持性治疗。

Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

来源:DrugBank

毒理性

• 肝毒性

血清ALT水平升高发生在2%至10%使用恩替卡韦治疗的慢性乙型肝炎患者中。这些升高似乎是由于潜在的慢性乙型肝炎的短暂发作，并且在治疗期间和治疗结束后都会发生。在治疗期间，ALT发作通常发生在治疗的前1到2个月内，且通常是轻微的、无症状的、自限性的，并伴随着HBV DNA水平的快速下降。停药后ALT水平发作在8%至12%接受恩替卡韦治疗乙型肝炎并随后停止治疗的患者中发生。停药后的发作在停止治疗后的1到3个月内出现，并且通常之前会有HBV DNA水平向治疗前值急剧和突然的上升。乙型肝炎的停药发作可能是症状性的和严重的，有报道称患者在治疗1到3年后停药出现了急性肝衰竭。停止恩替卡韦后出现停药发作的报告很少，因为大多数患者无限期地继续治疗。然而，停止恩替卡韦后发作的率和严重程度可能与停止乙型肝炎的其他治疗后的情况相似。 在晚期乙型肝炎患者中，有报道称使用恩替卡韦治疗的患者出现了乳酸酸中毒的情况；然而，在开始使用恩替卡韦并前瞻性随访的肝硬化患者中，乳酸水平据报道是正常的，在大规模临床试验中也没有报告乳酸酸中毒。归因于恩替卡韦的乳酸酸中毒病例主要发生在患有严重晚期疾病的患者中，可能是由于败血症、低血压和/或肝衰竭，而不是对恩替卡韦的不良反应。恩替卡韦治疗与典型乳酸酸中毒、肝脂肪变性和肝衰竭综合征的发展无关，这种情况在使用司他夫定、地达诺辛和齐多夫定治疗的无严重预先存在肝病的患者中已有描述。因此，如果恩替卡韦直接导致临床上明显的肝毒性，那也一定是罕见的。 可能性评分：E*（疑似但未证实的临床上明显肝损伤原因）。

Elevations in serum ALT levels occur in 2% to 10% patients with chronic hepatitis B treated with entecavir. These elevations appear to be due to a transient flare in the underlying chronic hepatitis B and occur both during and after therapy. On treatment, ALT flares typically occur during the first 1 to 2 months of therapy and are mild, asymptomatic and self-limited, accompanying the rapid declines in HBV DNA levels. Withdrawal flares in ALT levels occur in 8% to 12% of patients who receive entecavir therapy of hepatitis B and are subsequently withdrawn from treatment. The withdrawal flares arise within 1 to 3 months of stopping treatment and are usually preceded by marked and sudden rises in HBV DNA levels towards pretreatment values. Withdrawal flares of hepatitis B can be symptomatic and severe, and several instances of acute liver failure have been described in patients withdrawn from therapy after 1 to 3 years of treatment. There have been few reports of withdrawal flares after stopping entecavir, because the majority of patients have continued therapy indefinitely. However, the rate of flares and their severity are likely to be similar after stopping entecavir as after withdrawal of other therapies of hepatitis B. Several instances of lactic acidosis have been reported in patients with advanced hepatitis B who were treated with entecavir; however, lactate levels were reported to be normal in patients with cirrhosis started on entecavir and followed prospectively, and in large clinical trials lactic acidosis has not been reported. The cases of lactic acidosis attributed to entecavir occurred largely in patients with severe, advanced disease and may have been due to septicemia, hypotension and/or hepatic failure rather than an adverse reaction to entecavir. Therapy with entecavir has not been associated with development of the typical syndrome of lactic acidosis, hepatic steatosis and liver failure in patients without severe preexisting liver disease that has been described with stavudine, didanosine and zidovudine treatment. Thus, clinically apparent direct hepatotoxicity from entecavir must be rare, if it occurs at all. Likelihood score: E* (suspected but unproven cause of clinically apparent liver rinjury).

来源:LiverTox

毒理性

• 药物性肝损伤

恩替卡韦

Compound:entecavir

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：7

Severity Grade:7

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后，健康受试者中恩替卡韦达到峰值血浆浓度的时间在0.5到1.5小时之间。在健康受试者中，片剂的生物利用度相对于口服溶液为100%。

Absorption Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. In healthy subjects, the bioavailability of the tablet is 100% relative to the oral solution.

来源:DrugBank

吸收、分配和排泄

• 清除

renal cl=383.2 +/- 101.8 mL/min [肾功能正常] renal cl=197.9 +/- 78.1 mL/min [轻度肾功能损害] renal cl=135.6 +/- 31.6 mL/min [中度肾功能损害] renal cl=40.3 +/- 10.1 mL/min [重度肾功能损害] apparent oral cl=588.1 +/- 153.7 mL/min [肾功能正常] apparent oral cl=309.2 +/- 62.6 mL/min [轻度肾功能损害] apparent oral cl=226.3 +/- 60.1 mL/min [中度肾功能损害] apparent oral cl=100.6 +/- 29.1 mL/min [重度肾功能损害] apparent oral cl=50.6 +/- 16.5 mL/min [接受血液透析管理的重度肾功能损害] apparent oral cl=35.7 +/- 19.6 mL/min [接受CAPD管理的重度肾功能损害]

renal cl=383.2 +/- 101.8 mL/min [Unimpaired renal function] renal cl=197.9 +/- 78.1 mL/min [Mild impaired renal function] renal cl=135.6 +/- 31.6 mL/min [Moderate impaired renal function] renal cl=40.3 +/- 10.1 mL/min [severe impaired renal function] apparent oral cl=588.1 +/- 153.7 mL/min [Unimpaired renal function] apparent oral cl=309.2 +/- 62.6 mL/min [Mild impaired renal function] apparent oral cl=226.3 +/- 60.1 mL/min [Moderate impaired renal function] apparent oral cl=100.6 +/- 29.1 mL/min [severe impaired renal function] apparent oral cl=50.6 +/- 16.5 mL/min [severe impaired renal function amnaged with Hemodialysis] apparent oral cl=35.7 +/- 19.6 mL/min [severe impaired renal function amnaged with CAPD]

来源:DrugBank

吸收、分配和排泄

恩替卡韦片的生物利用度与口服溶液相当。

The bioavailability of /entecavir/ tablets was /equivalent/ to the oral solution.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服0.5毫克恩替卡韦，随标准高脂肪餐服用，会导致吸收延迟（餐后1至1.5小时vs空腹0.75小时），Cmax降低44%至46%，AUC降低18%至20%。

Oral administration of 0.5 mg of entecavir given with a standard high fat meal resulted in a delayed in absorption (1 to 1.5 hours fed vs. 0.75 hours fasted), a decrease in Cmax of 44% to 46%, and a decrease in AUC of 18% to 20%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

/估计的表观分布容积超过了总体水容积/，恩替卡韦在组织中广泛分布。

/The estimated apparent volume of distribution is in excess of total body water/, entecavir is extensively distributed into tissues.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  3
• 海关编码：
  2933990090
• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  -20°C freezer

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Entecavir
Synonyms:

---

Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Entecavir
CAS number: 142217-69-4

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

---

Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Storage: Store in closed vessels, refrigerated.

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

---

Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
Melting point: No data
Flash point: No data
Density: No data
Molecular formula: C12H15N5O3
Molecular weight: 277.3

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

---

Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

乙肝治疗一线药物：恩替卡韦

恩替卡韦是一种用于治疗乙型肝炎病毒感染的新一代鸟嘌呤核苷类似物口服药，主要用于治疗成人伴有病毒复制活跃和血清转氨酶持续增高、或肝组织学为活动性病变的慢性乙型肝炎。它是目前降病毒最快最强、变异几率最低的核苷类似物。

数据表明：不同的慢性乙肝患者，包括核苷初治、核苷经治以及肝硬化的患者，通过使用恩替卡韦片治疗可以迅速控制病情，轻松抵达治疗的现实终点，即乙肝病毒不可测；通过坚持治疗，相当一部分患者可以抵达治疗的最终目标，即血清转氨酶恢复到正常水平并持续下去。此外，部分患者还可以进一步达到乙肝表面抗原消失和e抗体阳转。

药理作用与机制 恩替卡韦在体内被细胞激酶转化为有活性的代谢产物阿德福韦二磷酸盐。该物质通过以下两种方式抑制HBV DNA多聚酶（逆转录酶）：一是与自然底物脱氧腺苷三磷酸竞争，二是整合到病毒DNA后引起链终止。恩替卡韦对HBV DNA多聚酶的抑制常数（Ki）是0.1μM。

阿德福韦酯

阿德福韦酯在体内快速转化为阿德福韦，在细胞激酶的作用下被磷酸化为有活性的代谢产物即阿德福韦二磷酸盐。该物质通过下列两种方式来抑制HBV DNA多聚酶（逆转录酶）：一是与自然底物脱氧腺苷三磷酸竞争，二是整合到病毒DNA后引起链终止。阿德福韦对HBV DNA多聚酶的抑制常数（Ki）是0.1μM。

生殖毒性 恩替卡韦在生殖毒性研究中未发现雄性和雌性大鼠的生育力受到影响。但当剂量至人体剂量35倍或以上时，啮齿类动物与狗出现了输精管的退行性变。在猴子实验中，未发现睾丸改变。

此外，在家兔实验中，恩替卡韦对胚胎—胎兔的毒性作用（吸收）、骨化水平降低（舌骨），并且第13根肋骨的发生率增加；但在家兔口服临床实验中，观察到用药量大于人体的94倍未对后代产生影响。这表明，恩替卡韦可从大鼠乳汁分泌。

肝损伤与停药反应 长期服用阿德福韦酯片后，一旦停药就会加重肝功能的损伤。因此，对于停止服用的病人应密切监测肝功能。此外，恩替卡韦和阿德福韦酯都适用于治疗慢性乙型肝炎患者，但选择药物时需考虑患者的既往用药史及其耐药性情况。

其他注意事项 恩替卡韦较新且抗病毒作用较强，但如果没有服用过拉米夫定，则产生耐药的可能性最小；然而如果曾服用来那他韦再使用恩替卡韦则产生耐药的几率较大。因此，在选择药物时需综合考虑患者的个体差异和用药历史。

总之，恩替卡韦是目前治疗慢性乙型肝炎的有效药物之一。在实际应用中应根据患者的具体情况合理选择并遵循医嘱进行治疗。同时需要注意药物可能带来的副作用及特殊人群（如孕妇）的使用限制。

反应信息

• 作为反应物：
  描述：

  entecavir 在 盐酸 作用下， 以 四氢呋喃 、 水 、 二甲基亚砜 为溶剂， 反应 2.0h， 生成 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-1H-purin-6-one;hydrochloride
  参考文献：
  名称：

  Process for Preparing Entecavir and its Intermediates

  摘要：

  制备恩替卡韦的过程包括将化合物转化为恩替卡韦，其中公式（M5）中的两个PG一起取代形成一个可选择取代的六元或七元环。

  公开号：

  US20110201809A1
• 作为产物：
  描述：

  在 titanium(IV) isopropylate 、 potassium fluoride 、 sodium tetrahydroborate 、 甲烷磺酸 、 caesium hydride 、 (2S,3S)-tartaric acid diethyl ester 、 双氧水 、 乙酸酐 、 potassium carbonate 、 对甲苯磺酸 、 溶剂黄146 、 三乙胺 、 特丁基对苯二酚 、 lithium chloride 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 149.0h， 生成 entecavir
  参考文献：
  名称：

  恩替卡韦中间体及其制备方法

  摘要：

  本发明公开了一种恩替卡韦中间体及其制备方法。本发明提供了一种恩替卡韦中间体化合物8的制备方法，其包括以下步骤：在溶剂中，酸性条件下，将化合物9进行脱除羟基保护基的反应，得到化合物8。本发明还提供了一种恩替卡韦中间体化合物9的制备方法，其包括以下步骤：在非质子有机溶剂中，碱性条件下，将化合物10与羟基保护试剂进行上羟基保护基的反应，得到化合物9。本发明的制备方法原料廉价易得，反应条件温和，产品收率较高。原子经济性好，环境友好，适合于工业化生产。

  公开号：

  CN104177398B

文献信息

• [EN] VIRAL POLYMERASE INHIBITORS<br/>[FR] INHIBITEURS DE POLYMERASE VIRALE
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2004065367A1

  公开（公告）日：2004-08-05

  An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein wherein A, B, R2, R3, L, M1, M2, M3, M4, Y1, Y0, Z and Sp are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase.

  化合物的异构体、对映体、非对映异构体或互变异构体，由式(I)所代表：其中A、B、R2、R3、L、M1、M2、M3、M4、Y1、Y0、Z和Sp如权利要求1中定义，或其盐，作为HCV NS5B聚合酶的抑制剂。
• [EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2017046658A1

  公开（公告）日：2017-03-23

  Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

  Amernita毒素的衍生物的化学式（I），其中，化学式（a）中的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、X、L、m、n和Q在此处被定义。这些衍生物的制备。这些衍生物在靶向治疗癌症、自身免疫性疾病和传染病中的治疗用途。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• [EN] CYCLIC SULFAMIDE COMPOUNDS AND METHODS OF USING SAME<br/>[FR] COMPOSÉS DE SULFAMIDE CYCLIQUE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：ASSEMBLY BIOSCIENCES INC

  公开号：WO2018160878A1

  公开（公告）日：2018-09-07

  The present disclosure provides, in part, cyclic sulfamide compounds, and pharmaceutical compositions thereof, useful as modulators of Hepatitis B (HBV) core protein, and methods of treating Hepatitis B (HBV) infection.

  本公开提供了部分环磺胺化合物及其药物组合物，可用作乙型肝炎（HBV）核心蛋白的调节剂，并用于治疗乙型肝炎（HBV）感染的方法。