泰利霉素 | 191114-48-4

• 物质功能分类: 原料药 - 抗生素类药物 - 大环内酯类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 泰利霉素
• 中文别名: 红霉酮(特利霉素)
• 英文名称: telithromycin
• 英文别名: HMR 3467；HMR 3647；Ketek；3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-αlpha;-L-ribo-hexopyranosyl)oxy]-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]imino]]erythromycin；11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-((4-(4-(3-pyridinyl)-1H-imidazol-1-yl)butyl)imino))erythromycin；(1S,2R,5R,7R,8R,9R,11R,13R,14R)-8-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-9-methoxy-1,5,7,9,11,13-hexamethyl-15-[4-(4-pyridin-3-ylimidazol-1-yl)butyl]-3,17-dioxa-15-azabicyclo[12.3.0]heptadecane-4,6,12,16-tetrone
• CAS: 191114-48-4
• 化学式: C₄₃H₆₅N₅O₁₀
• 分子量: 812.017
• InChiKey: LJVAJPDWBABPEJ-PNUFFHFMSA-N

物化性质

• 熔点：
  176-188 C
• 沸点：
  966℃
• 密度：
  1.26±0.1 g/cm3(Predicted)
• 闪点：
  >110°(230°F)
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）、甲醇（少许）
• 颜色/状态：
  White to off-white crystalline powder
• 碰撞截面：
  269.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  58
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  172
• 氢给体数：
  1
• 氢受体数：
  13

ADMET

代谢

肝脏 - 估计有50%通过CYP3A4代谢，另外50%独立于细胞色素P450代谢。

Hepatic - estimated 50% metabolized by CYP3A4 and 50% metabolized independent of cytochrome P450

来源:DrugBank

代谢

大约70%（其中33%在系统前，37%在系统中）的口服剂量大约相等地由细胞色素P450（CYP）3A4和非CYP3A4同工酶代谢为4种主要代谢物。系统上可利用的泰利霉素以原药形式在粪便中消除（7%），在尿液中以原药形式消除（13%），并在肝脏中代谢37%。

About 70% (33% presystemic and 37% systemic) of an oral dose is metabolized about equally by cytochrome P450 (CYP) 3A4 and non-CYP3A4 isoenzymes to 4 major metabolites. The systemically available telithromycin is eliminated in the feces as unchanged drug (7%), in urine as unchanged drug (13%), and 37% is metabolized in the liver.

来源:Hazardous Substances Data Bank (HSDB)

代谢

生物转化：肝脏；剂量的37%通过肝脏代谢。代谢约占剂量的70%。主要代谢物占AUC的12.6%，而其他三种被定量分析的代谢物占特立曲霉素AUC的3%或更少。

Biotransformation: Hepatic; 37% of the dose is metabolized by the liver. Metabolism accounts for approximately 70% of the dose. The main metabolite represented 12.6% of the AUC while three other metabolites quantified represented 3% or less of the AUC of telithromycin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

总的来说，代谢过程约占剂量的70%。在血浆中，服用800毫克放射性标记剂量后，主要循环化合物是母化合物，占总放射性的56.7%。主要代谢物占泰利霉素AUC的12.6%。还有三种其他血浆代谢物被定量，每一种都占泰利霉素AUC的3%或更少。估计大约50%的代谢是通过CYP 450 3A4介导的，剩余的50%是CYP 450独立的。

In total, metabolism accounts for approximately 70% of the dose. In plasma, the main circulating compound after administration of an 800-mg radiolabeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin. It is estimated that approximately 50% of its metabolism is mediated by CYP 450 3A4 and the remaining 50% is CYP 450-independent.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

与其他大环内酯类抗生素一样，泰利霉素在治疗期间与低发生率（1%至2%）的短暂血清酶升高相关。然而，这些升高通常是暂时的，即使在继续用药的情况下也会解决，并且比较药物也可能出现相似的发生率的血清酶升高。更重要的是，泰利霉素与严重形式的急性、临床上明显的肝毒性有关，首次报告是在其在美国获得普遍使用批准后不久。肝损伤发病的典型潜伏期是迅速的，有些病例在治疗开始后一两天内出现，平均潜伏期为1周。肝损伤往往突然发生，伴有疲劳、虚弱、黄疸和发热。酶升高的模式通常是肝细胞型的，血清转氨酶水平可能非常高（>1000 U/L）。已经报道了归因于泰利霉素的轻度非黄疸性肝损伤病例，但有些病例非常严重，与腹水和肝性脑病快速发展的肝衰竭有关。嗜酸性粒细胞增多和皮疹可能会发生，但并不常见。重新接触后损伤复发的描述已经被提出。

As with other macrolide antibiotics, telithromycin has been associated with a low rate (1% to 2%) of transient serum enzyme elevations during therapy. These elevations, however, are usually transient and resolve even with drug continuation and a similar rate of serum enzyme elevations can occur with comparator agents. More importantly, telithromycin has been linked to severe forms of acute, clinically apparent hepatotoxicity, first reported within a short time of its general approval for use in the United States. The typical latency to onset of liver injury is rapid, some cases presenting within a day or two of initiation of therapy, the average latency being 1 week. The liver injury is often abrupt in onset with fatigue, weakness, jaundice and fever. The pattern of enzyme elevations is typically hepatocellular and serum aminotransferase levels can be quite high (>1000 U/L). Mild and anicteric cases of liver injury attributed to telithromycin have been reported, but some cases are very severe and associated with rapid development of hepatic failure with ascites and hepatic encephalopathy. Eosinophilia and rash can occur, but are not common. Recurrence of injury with reexposure has been described.

来源:LiverTox

毒理性

• 药物性肝损伤

泰利霉素

Compound:telithromycin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

绝对生物利用度大约为57%。口服给药后0.5-4小时达到最大浓度。食物摄入不影响吸收。

Absolute bioavailability is approximately 57%. Maximal concentrations are reached 0.5 - 4 hours following oral administration. Food intake does not affected absorption.

来源:DrugBank

吸收、分配和排泄

• 消除途径

系统性地摄入的泰利霉素通过多种途径被消除，如下所示：7%的剂量通过胆汁和/或肠道分泌以原形在粪便中排出；13%的剂量通过肾脏排泄以原形在尿液中排出；而37%的剂量在肝脏中被代谢。

The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver.

来源:DrugBank

吸收、分配和排泄

• 分布容积

2.9升/千克

2.9 L/kg

来源:DrugBank

吸收、分配和排泄

泰利霉素在白细胞中的浓度超过血浆中的浓度，并且从白细胞中消除的速度比从血浆中慢。在连续5天每天一次600毫克的重复给药后，泰利霉素在白细胞中的平均浓度在6小时时达到72.1微克/毫升的峰值，并在24小时后保持在14.1微克/毫升。在连续10天每天一次600毫克的重复给药后，白细胞中的浓度在最后一次给药后48小时保持在8.9微克/毫升。

Telithromycin concentration in white blood cells exceeds the concentration in plasma and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 ug/mL at 6 hours, and remained at 14.1 ug/mL 24 hours after 5 days of repeated dosing of 600 mg once daily. After 10 days, repeated dosing of 600 mg once daily, white blood cell concentrations remained at 8.9 ug/mL 48 hours after the last dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

分布容积 - 2.9 L/kg 静脉输注后。广泛分布于全身。泰利霉素会分布到大鼠的乳汁中。

Volume of distribution - 2.9 L/kg following an intervenous infusion. Widely distributed throughout the body. Telithromycin is distributed into breast milk of rats.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  9
• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• RTECS号：
  KF4674500
• 危险类别：
  9

制备方法与用途

大环内酯类抗生素——泰利霉素

近年来，人们研发出一种新的大环内酯类抗生素——泰利霉素。它是林可酰胺—链阳霉素B（MLSB）家族中的第一个抗菌药物，并且是首个获准应用于临床的酮内酯类抗生素，由法国赛诺菲-安万特集团研发成功。泰利霉素具有广谱抗菌活性和较低的选择性耐药性，对肺炎链球菌及其耐青霉素和红霉素菌株、嗜血流感杆菌和莫拉汉菌均有良好疗效，其抗菌作用比阿奇霉素等大环内酯类抗生素更强。主要用于治疗呼吸道感染、支气管炎、咽炎、扁桃体炎以及肺炎等。

泰利霉素的作用机制与大环内酯类抗生素相似，主要通过直接与细菌核糖体的50s亚基结合，抑制蛋白质合成，并阻抑其翻译和装配。它还可与23s核糖体RNA的Ⅱ和Ⅴ结构区的核苷酸结合。不过，泰利霉素对野生型核糖体的结合力较红霉素和克拉霉素分别强约10倍和6倍。这种微小差异使其对细菌的耐受能力提高了20倍，并使其对大环内酯的所有耐药菌株有效。

泰利霉素口服吸收良好，口服生物利用度约为57%，食物不会影响其吸收。药物在肝脏被CYP3A4代谢为泰利醇、泰利酸、N-去甲脱氧酰胺衍生物、N-氧吡啶衍生物。半衰期（T1/2）为9.81小时，肾清除率为12.5L/h。药物通过多种途径排泄：约13%以原形从尿中排出，3%以原形从粪便中排出，代谢产物有37%从肝脏排泄。肝功能不全者，Cmax降低约20%，T1/2较正常人延长1.4倍，代谢率亦减少。在社区获得性肺炎(CAP)患者中的药动学参数平均为：Cmax为2.89 mg/L，Cmin为0.19 mg/L，AUC为13.9 mg/(L·h)。

2007年2月12日，美国食品和药物管理局宣布对赛诺菲-安万特生产的抗生素泰利霉素（又称肯立克）的药品标签作出修改，将急性细菌性鼻窦炎、慢性支气管炎的急性细菌性恶化两项适应症从说明书上移除，并提醒患者注意安全使用泰利霉素。

生物活性：Telithromycin(HMR3647)是一种可作用于社区获得性肺炎的抗生素。

反应信息

• 作为反应物：
  描述：

  泰利霉素 在 咪唑 、 N-fluorosulfonimide 、 potassium tert-butylate 作用下， 以 四氢呋喃 为溶剂， 生成
  参考文献：
  名称：

  β-Keto-ester chemistry and ketolides. synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3 enol-ether ketolides

  摘要：

  The effect of 2,3 modifications on the antibacterial activity of ketolides was evaluated by introducing substituents in position 2 and converting the C-1, C-2, C-3 beta-keto-ester into stable 2,3 enol-ether or 2,3 anhydro derivatives. Introduction of a fluorine in C-2. is beneficial with regard to the overall antibacterial spectrum whereas the enol-ether and 2,3 unsaturated compounds, as well as the bulky gem dimethyl or 2-chloro derivatives, are less active particularly against erythromycin resistant strains. A 2-fluoro ketolide derivative demonstrates good antibacterial activity and in vivo efficacy against multi-resistant Streptococcus pneumoniae. Compared to azithromycin against Haemophilus influenzae, this compound is equivalent in vitro and slightly more active in vivo. These results demonstrate that within the ketolide class, to retain good antibacterial activity, position needs to remain tetrahedral and tolerates only very small substituents such as fluorine. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(00)00392-9
• 作为产物：
  描述：

  克拉霉素 在 吡啶 、 盐酸 、 四磷十氧化物 、 水 、 sodium hexamethyldisilazane 、 二甲基亚砜 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 52.5h， 生成 泰利霉素
  参考文献：
  名称：

  Novel Synthesis of Telithromycin

  摘要：

  基于 11,12-Cylic carbonate 保护策略，开发了一种新的替红霉素合成路线，以防止生成 9,12-Hymiacetal 副产物。通过11,12-碳酸酯-6- O-甲基红霉素中间体，经过五个步骤从6- O-甲基红霉素合成了泰利霉素，总产率为33%。

  DOI：

  10.3184/174751913x13574995608294

文献信息

• [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] ANTIBACTERIAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIBACTÉRIENS
  申请人：MASSACHUSETTS GEN HOSPITAL

  公开号：WO2019199979A1

  公开（公告）日：2019-10-17

  The present application provides compounds of formula: Methods of using these compounds for killing bacterial growth and treating bacterial infections are also provided.

  本申请提供了以下化合物的公式：还提供了使用这些化合物杀灭细菌生长和治疗细菌感染的方法。
• [EN] FUSED POLYCYCLIC 2-PYRIDINONE ANTIBACTERIAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIBACTÉRIENS DE 2-PYRIDINONE POLYCYCLIQUE
  申请人：PTC THERAPEUTICS INC

  公开号：WO2016109706A1

  公开（公告）日：2016-07-07

  The present description relates to fused polycyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae or N. meningitides. A compound of Formula (la), Formula (lb) or Formula (Ic), or a form thereof, wherein the dashed lines represent one or more double bonds optionally present where allowed by available valences.

  本描述涉及融合的多环2-吡啶酮化合物及其形式和药物组合物，以及使用这些化合物、形式或组合物治疗或改善N. gonorrhoeae或N. meningitides的野生型或耐药型的方法。其中，化合物的化学式为（la）、（lb）或（Ic），或其形式，其中虚线代表一个或多个双键，根据可用的价键允许的情况下可选择地存在。