[(1S,4R)-4-[2-amino-6-(cyclopropylamino)-7H-purin-9-ium-9-yl]cyclopent-2-en-1-yl]methanol;sulfate | 188062-50-2

• 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: [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-7H-purin-9-ium-9-yl]cyclopent-2-en-1-yl]methanol;sulfate
• CAS: 188062-50-2
• 化学式: C28H38N12O6S
• 分子量: 670.7
• InChiKey: WMHSRBZIJNQHKT-FFKFEZPRSA-N

物化性质

• 熔点：
  222-225°C
• 溶解度：
  H2O：≥17mg/mL
• 颜色/状态：
  White to off-white solid

计算性质

• 辛醇/水分配系数(LogP)：
  1.53
• 重原子数：
  47
• 可旋转键数：
  8
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  287
• 氢给体数：
  8
• 氢受体数：
  16

ADMET

代谢

阿巴卡韦部分通过醇脱氢酶（形成5'-羧酸）和葡萄糖醛酸化（形成5'-葡萄糖醛酸苷）进行代谢。

Abacavir is partially metabolized by alcohol dehydrogenase (to form the 5'-carboxylic acid) and glucuronidation (to form the 5'-glucuronide).

来源:Hazardous Substances Data Bank (HSDB)

代谢

阿巴卡韦的代谢命运尚未完全确定，但该药物在肝脏中代谢。阿巴卡韦通过醇脱氢酶代谢形成5-羧酸，通过葡萄糖醛酸转移酶代谢形成5-葡萄糖苷酸；这些代谢物似乎没有抗病毒活性。细胞色素P450同工酶在阿巴卡韦代谢中的参与是有限的。

The metabolic fate of abacavir has not been fully determined, but the drug is metabolized in the liver. Abacavir is metabolized by alcohol dehydrogenase to form the 5-carboxylic acid and by glucuronyltransferase to form the 5-glucuronide; these metabolites do not appear to have any antiviral activity. Any involvement of cytochrome p450 isoenzymes in the metabolism of abacavir is limited.

来源:Hazardous Substances Data Bank (HSDB)

代谢

细胞内，阿巴卡韦通过腺苷酸转移酶磷酸化生成阿巴卡韦单磷酸盐；然后阿巴卡韦单磷酸盐在细胞质酶催化的反应中转化为卡波维单磷酸盐，接着通过细胞激酶转化为卡波维三磷酸盐。阿巴卡韦到卡波维三磷酸盐的细胞内（宿主细胞）转化是药物发挥抗病毒活性的必要条件。在CD4+ CEM细胞中，卡波维三磷酸盐的体外半衰期为3.3小时。

Intracellularly, abacavir is phosphorylated to abacavir monophosphate by adenosine phosphotransferase; abacavir monophosphate is then converted to carbovir monophosphate in a reaction catalyzed by cytosolic enzymes and then to carbovir triphosphate by cellular kinases. Intracellular (host cell) conversion of abacavir to carbovir triphosphate is necessary for the antiviral activity of the drug. The in vitro intracellular half-life of carbovir triphosphate in CD4+ CEM cells is 3.3 hours.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：阿巴卡韦在母乳中以小量出现。关于其在哺乳期使用的安全性信息非常有限。在美国和其他可以获取清洁水源和负担得起的替代喂养的国家，建议感染HIV的母亲不要母乳喂养婴儿，以避免HIV-1感染的后天传播。通过抗逆转录病毒治疗实现并维持病毒载量抑制，可以将母乳喂养传播风险降低到小于1%，但并非零。在抗逆转录病毒治疗下，病毒载量持续不可检测的HIV感染者如果选择母乳喂养，应支持这一决定。 ◉ 对母乳喂养婴儿的影响：一名HIV阳性母亲每天服用一次含有多替拉韦50mg、硫酸阿巴卡韦600mg和拉米夫定300mg（特鲁迈克）的复合片剂。她的婴儿大约纯母乳喂养了30周，然后又部分母乳喂养了大约20周。未观察到明显的副作用。 ◉ 对泌乳和母乳的影响：在接受高效抗逆转录病毒治疗的男性中报告了男性乳房发育。男性乳房发育最初是单侧的，但在大约一半的病例中进展为双侧。未观察到血清催乳素的变化，即使继续用药，通常也会在一年内自发解决。一些病例报告和体外研究建议蛋白酶抑制剂可能会在某些男性患者中引起高催乳素血症和乳汁分泌过多，尽管这一点存在争议。这些发现与哺乳母亲的相关性尚不清楚。已建立泌乳的母亲催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Abacavir appears in breastmilk in small quantities. Very little information is available on the safety of its use during breastfeeding. In the US and other countries where access to clean water and affordable replacement feeding are available, it is recommended that mothers living with HIV not breastfeed their infants to avoid postnatal transmission of HIV-1 infection. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. ◉ Effects in Breastfed Infants:An HIV-positive mother took a combination tablet containing dolutegravir 50 mg, abacavir sulfate 600 mg and lamivudine 300 mg (Triumeq) once daily. Her infant was exclusively breastfed for about 30 weeks and partially breastfed for about 20 weeks more. No obvious side effects were noted. ◉ Effects on Lactation and Breastmilk:Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

同时使用乙醇与阿巴卡韦可能会导致阿巴卡韦的浓度和半衰期增加，这是由于酒精脱氢酶通过共同代谢途径竞争所致。

Concurrent use /of ethanol/ with abacavir may result in increased concentrations and half-life of abacavir as a result of competition for common metabolic pathways via alcohol dehydrogenase.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在接受口服美沙酮维持治疗的稳定患者中，开始每日两次600毫克阿巴卡韦治疗，美沙酮的清除率增加了22%；在大多数患者中，清除率的增加在临床上不会显著；少数患者可能需要增加美沙酮的剂量。

Methadone clearance increased 22% in patients stabilized on oral methadone maintenance therapy who started abacavir therapy with 600 mg twice daily; increase in clearance will not be clinically significant in the majority of patients; methadone dosage increase may be required in a small number of patients.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要进行治疗……。监测休克，如有必要进行治疗……。预见并处理癫痫发作……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用生理盐水连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

高级治疗：对于无意识、严重肺水肿或呼吸停止的患者，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。监测心率和必要时治疗心律失常。 ... 开始静脉输液，使用D5W/SRP：“保持开放”，最低流量/。如果出现低血容量的迹象，使用乳酸钠林格氏液。注意液体过载的迹象。考虑使用药物治疗肺水肿。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象。用地西泮（安定）治疗癫痫。使用丙美卡因氢氯化物协助眼部冲洗。/毒药A和B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在口服600毫克放射性阿巴卡韦后，82.2%的剂量通过尿液排出，16%的剂量通过粪便排出。尿液中的5-羧酸代谢物、5-葡萄糖苷酸代谢物和未改变的阿巴卡韦分别占回收放射性活性的30%、36%和1.2%；未识别的次要代谢物占尿液回收放射性活性的15%。

Following oral administration of a 600-mg dose of radiolabeled abacavir, 82.2% of the dose is excreted in urine and 16% of the dose is excreted in feces. The 5-carboxylic acid metabolite, 5-glucuronide metabolite, and unchanged abacavir accounted for 30, 36, and 1.2%, respectively, of recovered radioactivity in urine; unidentified minor metabolites accounted for 15% of recovered radioactivity in urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚不清楚阿巴卡韦是否分布到人乳中；该药物在大鼠乳汁中有分布。

It is not known whether abacavir is distributed into human milk; the drug is distributed into milk in rats.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Abacavir 在大鼠体内可穿过胎盘。

Abacavir crosses the placenta in rats.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

阿巴卡韦的口服生物利用度很高，无论是否与食物同服；脑脊液与血浆的AUC比值大约为0.3。

The oral bioavailability of abacavir is high with or without food; the CSF-to-plasma AUC ratio is approximately 0.3.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S36/37
• 危险类别码：
  R40,R63
• WGK Germany：
  3
• 海关编码：
  2933595960
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P280,P305+P351+P338
• 危险品运输编号：
  2811
• 危险性描述：
  H317,H319,H341,H350,H360

制备方法与用途

硫酸阿巴卡韦简介

硫酸阿巴卡韦是抗病毒药物阿巴卡韦的硫酸盐，药理作用与阿巴卡韦相同，由英国葛兰素威康（GLAxo-Wellcome）公司研发成功。1998年12月，美国食品与药品管理局（FDA）批准其上市销售，商品名为Ziagen。本品是一种核苷类逆转录酶抑制剂（NRTI），通过抑制HIV逆转录酶，引起断链，阻止病毒复制而起效。研究显示，本品与其他核苷类逆转录酶抑制剂如地丹诺辛 (didanosine)、扎西他宾 (zalcitabine)、拉米夫定 (LAmivudine) 和司他夫定 (stavudine) 合用时，疗效具有相加作用；与齐多夫定 (zidovudine) 合用有协同作用。这为治疗HIV感染提供了一种三重治疗的新方法，并使得蛋白酶抑制剂和非核苷逆转录酶抑制剂在临床用药中保持可选择性。

不良反应

2004年4月，美国FDA批准硫酸阿巴卡韦联合其他药物用于抗HIV的感染。2003年，其销售收入为1.67亿英镑。2008年2月份，美国食品与药品管理局修订了艾滋病抗病毒治疗指南，阿巴卡韦成为初次治疗患者中的一种首选抗病毒药物。该选择除了因其抗病毒效果与泰诺福韦相近、对线粒体损害较小、从而减少脂肪消耗、胰腺炎、神经炎和乳酸酸中毒等不良反应外，还在于用药前筛查超敏反应的基因HLA-B5701，在国外应用于临床时，阴性者应用该药后一般不会发生超敏反应，安全性大大提高。2008年5月，美国食品药品管理局（FDA）发布了关于阿巴卡韦（Abacavir）和去羟肌苷（Didanosine）的早期安全性警示，称服用这两种药物的患者存在心脏病发作、心肌梗死的风险。然而，阿巴卡韦制药商葛兰素史克公司收到D:A:D研究分析初步结果后，并未发现该药会增加心脏病发作或心肌梗死的风险。

生物活性

阿巴卡韦（1592U89）是一种常用的核苷类似物，具有抗HIV-1病毒活性。阿巴卡韦是鸟嘌呤的类似物，其靶点为病毒的反转录酶。

Target	Value
HIV-1 reverse-transcriptase

靶点

阿巴卡韦以病毒逆转录酶为靶点，是一种鸟苷（一种嘌呤）类似物。

反应信息

• 作为产物：
  描述：

  (-)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide 、 、 sodium hydroxide 、 硫酸 以 异丙醇 为溶剂， 反应 1.0h， 以Abacavir hemisulfate (0.56 g, 60%) was obtained as a white powder的产率得到[(1S,4R)-4-[2-amino-6-(cyclopropylamino)-7H-purin-9-ium-9-yl]cyclopent-2-en-1-yl]methanol;sulfate
  参考文献：
  名称：

  Process for the preparation of abacavir

  摘要：

  使用水和醇的混合物中的无机碱，去除式子(II)的N-酰化{(1S,4R)-4-[2-氨基-6-(环丙基氨基)-9H-嘌呤-9-基]-环戊-2-烯基}甲醇的氨基保护基，其中R═H或(C1-C4)-烷基，从而产生阿巴卡韦或其盐。该过程进行非常快，产物可以高收率和高纯度地得到。

  公开号：

  US08183370B2

文献信息

• [EN] SPIROCYCLIC HETEROCYCLE COMPOUNDS USEFUL AS HIV INTEGRASE INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES SPIROCYCLIQUES UTILES COMME INHIBITEURS DU VIH
  申请人：MERCK SHARP & DOHME

  公开号：WO2016094198A1

  公开（公告）日：2016-06-16

  The present invention relates to Spirocyclic Heterocycle Compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein A, B, X, R1, R2, R3 and R4 are as defined herein. The present invention also relates to compositions comprising at least one Spirocyclic Heterocycle Compound, and methods of using the Spirocyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.

  本发明涉及式(I)的螺环杂环化合物及其药学上可接受的盐，其中A、B、X、R1、R2、R3和R4如本文所定义。本发明还涉及包含至少一种螺环杂环化合物的组合物，以及使用螺环杂环化合物治疗或预防受试者的HIV感染的方法。
• [EN] AZADECALIN DERIVATIVES AS INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION<br/>[FR] DÉRIVÉS D'AZADÉCALINE EN TANT QU'INHIBITEURS DE LA RÉPLICATION DU VIRUS DE L'IMMUNODÉFICIENCE HUMAINE
  申请人：VIIV HEALTHCARE UK (NO 5) LTD

  公开号：WO2018002848A1

  公开（公告）日：2018-01-04

  Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, azadecaline derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula (I). These compounds are useful for the treatment of HIV and AIDS.

  具有药物和生物影响特性的化合物，其药物组合物和使用方法已列出。具体来说，提供了具有独特抗病毒活性的阿扎德卡林衍生物，作为HIV成熟抑制剂，如化合物(I)的公式所代表的那样。这些化合物对于治疗HIV和艾滋病是有用的。
• IRAK DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20190192668A1

  公开（公告）日：2019-06-27

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。
• [EN] AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION<br/>[FR] DÉGRONIMÈRES DE C3-GLUTARIMIDE LIÉS À UNE AMINE POUR LA DÉGRADATION DE PROTÉINES CIBLES
  申请人：C4 THERAPEUTICS INC

  公开号：WO2017197051A1

  公开（公告）日：2017-11-16

  This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.

  这项发明提供了胺连接的C3-戊二酰亚胺Degronimers和Degrons，用于治疗应用，如本文进一步描述的，以及它们的使用方法、组合物以及它们的制备方法。
• [EN] PYRIDINE CARBOXAMIDE AND METHODS FOR INHIBITING HIV INTEGRASE<br/>[FR] CARBOXAMIDE DE PYRIDINE ET METHODES PERMETTANT D'INHIBER L'INTEGRASE DU VIH
  申请人：VIROCHEM PHARMA INC

  公开号：WO2005042524A1

  公开（公告）日：2005-05-12

  Compounds of formula (I): wherein R1, R2, R4, R10, R11, and Q are as defined herein, and their pharmaceutically acceptable salts, are useful in the prevention or treatment of HIV infections.

  式(I)的化合物：其中R1、R2、R4、R10、R11和Q如本文所定义，并且它们的药用盐，在预防或治疗HIV感染方面是有用的。