奥利万星 | 171099-57-3

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 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: 奥利万星
• 英文名称: oritavancin
• 英文别名: LY333328；(1S,2R,18R,19R,22S,25R,28R,40S)-2-[(2R,4S,5R,6S)-4-amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-5,15-dichloro-48-[(2S,3R,4S,5S,6R)-3-[(2S,4S,5R,6S)-4-[[4-(4-chlorophenyl)phenyl]methylamino]-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-18,20,23,26,32,35,37,42,44-nonahydroxy-22-(2-hydroxy-2-iminoethyl)-19-[[(2R)-1-hydroxy-4-methyl-2-(methylamino)pentylidene]amino]-7,13-dioxa-21,24,27,41,43-pentazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8,10,12(48),14,16,20,23,26,29(45),30,32,34(39),35,37,41,43,46,49-icosaene-40-carboxylic acid
• CAS: 171099-57-3
• 化学式: C₈₆H₉₇Cl₃N₁₀O₂₆
• 分子量: 1793.13
• InChiKey: VHFGEBVPHAGQPI-LXKZPTCJSA-N

物化性质

• 密度：
  1.59±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜
• 沸点：
  810.3

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  125
• 可旋转键数：
  19
• 环数：
  15.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  561
• 氢给体数：
  20
• 氢受体数：
  29

ADMET

代谢

体外对人肝细胞的研究表明，奥利万星不被代谢，以原形排出体外。

In vitro studies on human hepatocytes suggest that oritavancin is not metabolized, and is excreted unchanged.[A185297,L8492]

来源:DrugBank

毒理性

• 肝毒性

在获得许可前的对照临床试验中，使用Dalbavancin、Oritavancin或Telavancin治疗期间血清ALT升高是常见的，发生在高达25%的患者中。然而，血清转氨酶升高超过正常上限三倍的情况并不常见，接受Dalbavancin、Oritavancin或Telavancin治疗的患者中，这种情况的发生率为0.8%至6%。此外，这些肝脏测试异常的发生率与比较组相比并没有太大差异。在糖肽类抗生素治疗期间ALT升高通常是暂时的、无症状的，并且严重程度仅为轻度到中度，很少导致剂量调整或提前终止。在这些药物的注册试验中没有报告出现黄疸的临床明显肝损伤。自从这些药物获得批准并更广泛使用以来，没有公开发表的报告将肝损伤归因于糖肽类抗生素，尽管有报告称过敏反应有时会伴随轻度到中度的肝损伤。尽管如此，这三种药物相对较新，使用并不广泛，且使用时治疗时间相对较短，没有任何药物被关联到严重的肝损伤案例。

In prelicensure controlled trials, serum ALT elevations during therapy with dalbvancin, oritavancin or telavancin were common, occurring in up to 25% of patients. Serum aminotransferase elevations above three times the upper limit of normal, however, were uncommon, occurring in 0.8% to 6% of patients receiving dalbavancin, oritavancin or telavancin. Furthermore, these rates of liver test abnormalities were not very different from those in comparator arms. The ALT elevations during glycopeptide antibiotic therapy were in general transient, asymptomatic and only mild-to-moderate in severity, rarely leading to dose modifications or early discontinuations. There were no reports of clinically apparent liver injury with jaundice in the registration trials of these agents. Since their approval and more wide scale use, there have been no published reports of liver injury attributed to glycopeptide antibiotics, although hypersensitivity reactions have been reported which can sometimes be associated with a mild-to-moderate degree of liver injury. Regardless, these three agents are relatively new, have not been widely used and when used, are given for a relatively short period of time and none have been linked to serious cases of liver injury.

来源:LiverTox

毒理性

• 毒性总结

奥里万星在大鼠的LD50大于500毫克/千克。[L12870] 处方信息表明在奥里万星的临床项目中没有过量的经验，然而，过量可能会导致不良反应风险增加，如头痛、恶心、呕吐和腹泻。这种药物不可通过透析清除，在过量情况下，应采取支持性措施。[L8492]

The LD50 of oritavancin in rats is >500m mg/kg.[L12870] Prescribing information indicates no experience with overdose during the clinical program for oritavancin, however, an overdose is likely to result in an increased risk of adverse effects, such as headache, nausea vomiting, and diarrhea. This drug is not dialyzable, and in the case of an overdose, supportive measures should be undertaken.[L8492]

来源:DrugBank

毒理性

• 蛋白质结合

奥里塔万星大约85%与血浆蛋白结合。[L8492]

Oritavancin is about 85% bound to plasma proteins.[L8492]

来源:DrugBank

吸收、分配和排泄

• 吸收

奥立万星药代动力学分析显示，其Cmax为138 μg/mL，AUC0-∞为2800 μg•h/mL。[L8492]在一项针对健康志愿者的研究中，800毫克剂量的AUC0-t为1,1111 μg•h/mL。[A2932] 另一项药代动力学研究报告称，Cmax为4.7-7.6微克/毫升，通常在给药后24小时内达到。[A2933]

Pharmacokinetic analysis of oritavancin revealed a Cmax of 138 and μg/mL and an AUC0-∞ of 2800 μg•h/mL.[L8492] The AUC0-t in a study of healthy volunteers after an 800 mg dose 1,1111 μg•h/mL.[A2932] was also be Another pharmacokinetic study reported a Cmax of 4.7-7.6 micrograms/mL, generally achieved within 24 hours of administration.[A2933]

来源:DrugBank

吸收、分配和排泄

• 消除途径

奥里塔万星以未改变的药物形式在尿液和粪便中排泄。在尿液中的回收率不到5%，在粪便中的回收率为1%。

Oritavancin is excreted as unchanged drug in both the urine and feces. Less than 5% has been recovered in the urine, and 1% has been recovered in the feces.[A2933,L8492]

来源:DrugBank

吸收、分配和排泄

• 分布容积

奥立伐链的分布体积估计为87.6升，这表明其在组织中广泛分布。

The volume of distribution of oritavancin is estimated at 87.6 L, suggesting extensive tissue distribution.[L8492]

来源:DrugBank

吸收、分配和排泄

• 清除

奥里万星（Oritavancin）的清除率大约为0.445升/小时。[L8492] 一项研究表明肾清除率为0.457毫升/分钟。[A2933]

The clearance of oritavancin is approximately 0.445 L/h.[L8492] One study revealed a renal clearance of 0.457 mL/min.[A2933]

来源:DrugBank

制备方法与用途

简介

奥利万星（Orbactiv）是FDA批准的第一个也是唯一一个用于治疗ABSSSIs（急性细菌性皮肤和皮肤结构感染）的单剂量抗生素。患者只需接受一次Orbactiv输液，整个疗程即告完成。此次获批标志着在治疗细菌性皮肤和皮肤结构感染方面取得了重大进步，远超当前临床标准。

用途

FDA已批准奥利万星（Oritavancin，Orbactiv）注射液用于治疗由敏感的革兰氏阳性菌（包括耐甲氧西林金黄色葡萄球菌，MRSA）引起的成人急性细菌性皮肤和皮肤结构感染。

反应信息

• 作为反应物：
  描述：

  烯丙基琥珀酰亚胺基碳酸酯 、 奥利万星 在 碳酸氢钠 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 以93%的产率得到
  参考文献：
  名称：

  Synthesis and in vitro evaluation of bisphosphonated glycopeptide prodrugs for the treatment of osteomyelitis

  摘要：

  As therapeutic agents of choice in the treatment of complicated infections, glycopeptide antibiotics are often preferentially used in cases of osteomyelitis, an infection located in bone and notoriously difficult to successfully manage. Yet frequent and heavy doses of these systemically administered antibiotics are conventionally prescribed to obtain higher antibiotic levels in the bone and reduce the high recurrence rates. Targeting antibiotics to the bone after systemic administration would present at least three potential advantages: (i) greater efficacy, by concentrating the therapeutic agent in bone; (ii) greater convenience, through a reduction in the frequency of administration; and (iii) greater safety, by reducing the levels of systemic drug exposure. We present here the design, synthesis and in vitro evaluation of eight prodrugs of the glycopeptide antibacterial agents vancomycin and oritavancin taking advantage of the affinity of the bisphosphonate group for bone for delivery to osseous tissues. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.01.006
• 作为产物：
  描述：

  (1S,2R,18R,19R,22S,25R,28R,40S)-2-[(2R,4S,5R,6S)-4-amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-22-(2-amino-2-oxoethyl)-5,15-dichloro-48-[(2S,3R,4S,5S,6R)-3-[(2S,4S,5R,6S)-4-[[4-(4-chlorophenyl)phenyl]methylamino]-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-18,32,35,37-tetrahydroxy-19-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8,10,12(48),14,16,29(45),30,32,34(39),35,37,46,49-pentadecaene-40-carboxylic acid;phosphoric acid 、 碳酸氢钠 、 在 crude product 、 乙腈 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 48.0h， 以to give 12 (102 mg, 24%) as a white solid的产率得到奥利万星
  参考文献：
  名称：

  Glycopeptide and lipoglycopeptide antibiotics with improved solubility

  摘要：

  本发明涉及与母体糖肽或脂肽糖肽抗生素具有不同离子化状态的糖肽衍生物和脂肽糖肽衍生物，并具有在生理条件下再生为母体糖肽或脂肽糖肽抗生素的能力。这些化合物可用作预防和/或治疗细菌感染的抗生素。

  公开号：

  US08901072B2

文献信息

• GLYCOPEPTIDE AND LIPOGLYCOPEPTIDE ANTIBIOTICS WITH IMPROVED SOLUBILITY
  申请人：Rafai Far Adel

  公开号：US20120149632A1

  公开（公告）日：2012-06-14

  The invention relates to derivatives of glycopeptide and lipoglycopeptide antibiotics possessing an altered ionization state with respect to the parent glycopeptide or lipoglycopeptide antibiotic, and having the ability to be regenerated as the parent glycopeptide or lipoglycopeptide antibiotic under physiological conditions. These compounds are useful as antibiotics for the prevention and/or the treatment of bacterial infections.

  这项发明涉及具有与母体糖肽或脂质糖肽抗生素相比具有改变的电离状态的糖肽和脂质糖肽抗生素衍生物，并且具有在生理条件下能够再生为母体糖肽或脂质糖肽抗生素的能力。这些化合物可用作预防和/或治疗细菌感染的抗生素。
• PHOSPHONATED GLYCOPEPTIDE AND LIPOGLYCOPEPTIDE ANTIBIOTICS AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
  申请人：Tanaka Kelly

  公开号：US20100113333A1

  公开（公告）日：2010-05-06

  The present invention is directed to antimicrobial compounds which have an affinity for binding bones. More particularly, the invention is directed to phosphonated derivatives of glycopeptide or lipoglycopeptide antibiotics. These compounds are useful as antibiotics for the prevention or treatment of bone and joint infections, especially for the prevention and treatment of osteomyelitis.

  本发明涉及具有与骨骼结合亲和力的抗微生物化合物。更具体地，该发明涉及磷酸酯化的糖肽类或脂质糖肽类抗生素的衍生物。这些化合物可用作抗生素，用于预防或治疗骨骼和关节感染，特别是用于预防和治疗骨髓炎。
• Reductive Alkylation of Glycopeptide Antibiotics: Synthesis and Antibacterial Activity.
  作者：ROBIN D. G. COOPER、NANCY J. SNYDER、MARK J. ZWEIFEL、MICHAEL A. STASZAK、STEPHEN C. WILKIE、THALIA I. NICAS、DEBORAH L. MULLEN、THOMAS F. BUTLER、MICHAEL J. RODRIGUEZ、BRET E. HUFF、RICHARD C. THOMPSON

  DOI：10.7164/antibiotics.49.575

  日期：——

  Reductive alkylation of the A82846 family of glycopeptide antibiotics has the potential of producing seven products. N-Alkylation of the disaccharide amino function can be accomplished selectively, and offers the greatest increase in antibacterial activity. Products resulting from N-alkylation of LY264826 (A82846B) provide the most potent derivatives as compared to other members of this class of antibiotics. Two of these derivatives, LY307599 and LY333328 are approximately 500 times more active than vancomycin against vancomycin-resistant enterococci.

  A82846类糖肽抗生素的还原烷基化有潜力产生七种产物。二糖氨基功能的N-烷基化可以选择性地完成，并提供最大的抗菌活性提升。与这一类抗生素的其他成员相比，由N-烷基化的LY264826（A82846B）产生的产物提供了最强效的衍生物。这些衍生物中的两个，LY307599和LY333328，相比于万古霉素对万古霉素耐药肠球菌的活性约高出500倍。
• METHOD OF INHIBITING CLOSTRIDIUM DIFFICILE BY ADMINISTRATION OF ORITAVANCIN
  申请人：Wilcox Mark Harvey

  公开号：US20100311646A1

  公开（公告）日：2010-12-09

  Glycopeptide antibiotics, such as oritavancin, demonstrate significant activity against both a vegetative form of C. difficile and C. difficile spores. Methods for the treatment, prophylaxis and prevention of C. difficile infection and disease in animals, including humans, are described.
• METHODS OF TREATMENT USING SINGLE DOSES OF ORITAVANCIN
  申请人：Targanta Therapeutics Corp.

  公开号：US20130172237A1

  公开（公告）日：2013-07-04

  Glycopeptide antibiotics, such as oritavancin, demonstrate significant activity against a wide range of bacteria. Methods for the treatment, prophylaxis and prevention of bacterial infection and disease in animals, including humans, using a single dose of oritavancin over the course of therapy, are described.