cethromycin | 285129-45-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: cethromycin
• 英文别名: (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-1,5,7,9,11,13-hexamethyl-9-[(E)-3-quinolin-3-ylprop-2-enoxy]-3,17-dioxa-15-azabicyclo[12.3.0]heptadecane-4,6,12,16-tetrone
• CAS: 285129-45-5
• 化学式: C₄₂H₅₉N₃O₁₀
• 分子量: 765.945
• InChiKey: PENDGIOBPJLVBT-ONLVEXIXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  55
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  163
• 氢给体数：
  2
• 氢受体数：
  12

ADMET

代谢

尽管尚未对赛托霉素的代谢进行广泛研究，但一项研究在给予单次150毫克口服剂量的患者的粪便中识别出七种代谢物。主要回收产物是未改变的赛托霉素和一个无活性的N-去甲基代谢物。大多数代谢可能发生在肝脏，至少部分由CYP3A4介导。

Extensive studies of cethromycin metabolism have not been conducted, although one study identified seven metabolites within feces of patients administered a single 150 mg oral dose. The major recovered products were unchanged cethromycin and an inactive N-desmethyl metabolite. It is likely that most of the metabolism occurs in the liver and is mediated, at least in part, by CYP3A4.

来源:DrugBank

毒理性

• 蛋白质结合

塞思罗霉素在0.1至30.0微克/毫升浓度范围内的人血浆蛋白结合率为86.7%至95.6%。

Cethromycin displays 86.7 to 95.6% human plasma protein binding over a range of concentrations between 0.1 to 30.0 μg/ml.

来源:DrugBank

吸收、分配和排泄

• 吸收

赛克罗霉素显示出非线性吸收动力学。在健康成年人中，口服一次150毫克赛克罗霉素，每日一次，连续五剂，计算得出的Cmax（最大血药浓度）为0.181 ± 0.084微克/毫升，Tmax（达到最大血药浓度的时间）为2.01 ± 1.30小时，AUC0-24（0到24小时药时曲线下面积）为0.902 ± 0.469微克*小时/毫升。同样，300毫克剂量的相应值分别为0.500 ± 0.168微克/毫升，2.09 ± 0.03小时，3.067 ± 1.205微克*小时/毫升。在另一项研究中，使用单次口服150毫克赛克罗霉素，Cmax为318 ± 161纳克/毫升，Tmax为1.79 ± 0.50小时，AUC0-24为1596 ± 876纳克*小时/毫升，AUC0-∞（从0到无穷大的药时曲线下面积）为1662 ± 907纳克*小时/毫升。

Cethromycin displays non-linear absorption kinetics. In healthy adults administered 150 mg cethromycin orally once daily for five doses, the calculated Cmax, Tmax, and AUC0-24 values were 0.181 ± 0.084 μg/ml, 2.01 ± 1.30 hrs, and 0.902 ± 0.469 μg\*h/ml, respectively. Similarly, the corresponding values for a 300 mg dose were 0.500 ± 0.168 μg/ml, 2.09 ± 0.03 hrs, and 3.067 ± 1.205 μg\*h/ml, respectively. In another study using a single oral dose of 150 mg cethromycin, the Cmax was 318 ± 161 ng/ml, the Tmax was 1.79 ± 0.50, the AUC0-24 was 1596 ± 876 ng\*h/ml, and the AUC0-∞ was 1662 ± 907 ng\*h/ml.

来源:DrugBank

吸收、分配和排泄

• 消除途径

塞思洛霉素主要通过胆汁排泄，初次剂量的87.2%在粪便中回收，仅有7.0%在尿液中。未改变的塞思洛霉素占粪便中回收放射性活性的35.7%，而N-去甲基代谢物占39.8%；剩余的放射性活性大致均匀分布在三种次要代谢物和一个未明确的其他产物组中。

Cethromycin is primarily excreted by the biliary route, with 87.2% of an initial dose recovered in feces and only 7.0% in urine. Unchanged cethromycin accounted for 35.7% of the radioactivity recovered in feces and an N-desmethyl metabolite for 39.8%; the remaining radioactivity was approximately evenly divided between three minor metabolites and a group of uncharacterized additional products.

来源:DrugBank

吸收、分配和排泄

• 分布容积

塞思罗霉素以五个150毫克口服剂量给药时，在末端消除相的表观分布体积为1433 ± 843升，稳态表观分布体积为1453 ± 997升。相应地，300毫克剂量的值为761 ± 293升和769 ± 272升。已知塞思罗霉素会在上皮衬液、肺泡细胞以及多形核白细胞内积聚。

Cethromycin given in five 150 mg oral doses had an apparent volume of distribution at the terminal elimination phase of 1433 ± 843 L, and an apparent steady-state volume of distribution of 1453 ± 997 L. The corresponding values for a 300 mg dose was 761 ± 293 L and 769 ± 272 L. Cethromycin is known to accumulate in the epithelial lining fluid and alveolar cells, as well as within polymorphonuclear leukocytes.

来源:DrugBank

吸收、分配和排泄

• 清除

每天一次口服300毫克赛托霉素的患者的清除率据报道大约为63升/小时。

Cethromycin clearance in patients receiving a once-daily oral dose of 300 mg is reported to be approximately 63 L/h.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  cethromycin 在 N-碘代丁二酰亚胺 作用下， 以 乙腈 为溶剂， 反应 12.0h， 以70%的产率得到(1S,2R,5R,7R,8R,9R,11R,13R,14R)-2-ethyl-8-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)oxan-2-yl]oxy-1,5,7,9,11,13-hexamethyl-9-[(E)-3-quinolin-3-ylprop-2-enoxy]-3,17-dioxa-15-azabicyclo[12.3.0]heptadecane-4,6,12,16-tetrone
  参考文献：
  名称：

  通过选择性的N-去甲基化反应仿生合成大环内酯/酮内酯代谢物。

  摘要：

  DOI：

  10.1021/jo000055j
• 作为产物：
  描述：

  acetic acid 2-(11-allyloxy-4-ethyl-8-hydroxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-tetradecahydro-3,5-dioxa-1-aza-cyclopentacyclotetradecen-10-yloxy)-4-dimethylamino-6-methyl-tetrahydro-pyran-3-yl ester 在 甲醇 、 palladium diacetate 、 N-氯代丁二酰亚胺 、 二甲基硫 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 51.5h， 生成 cethromycin
  参考文献：
  名称：

  具有连接至C-6位置的芳基的新型红霉素衍生物是有效的蛋白质合成抑制剂，可有效抵抗多种药物引起的呼吸道病原体。

  摘要：

  已经发现了一系列新的红霉素衍生物，它们对关键的呼吸道病原体具有有效的活性，包括对红霉素具有抗性的病原体。这些化合物的特征在于具有连接至赤藓醇内酯骨架的C-6位的芳基。C-6部分的广泛结构修饰导致发现了几种具有前景的化合物，这些化合物具有针对mef和erm介导的耐药性肺炎链球菌的有效活性。初步的机理研究表明，新的大环内酯类是有效的蛋白质合成抑制剂，可与从抗性生物体中分离出的甲基化核糖体相互作用。在实验动物模型中，这些化合物表现出出色的体内功效和平衡的药代动力学特征。

  DOI：

  10.1021/jm0102349

文献信息

• ACTIVE AGENT DELIVERY SYSTEMS AND METHODS FOR PROTECTING AND ADMINISTERING ACTIVE AGENTS
  申请人：Mickle Travis

  公开号：US20090253792A1

  公开（公告）日：2009-10-08

  The present invention relates to active agent delivery systems and more specifically to compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents and methods for administering conjugated active agent compositions.

  本发明涉及活性剂递送系统，更具体地涉及包含氨基酸（作为单个氨基酸或肽）与活性剂共价连接的组合物以及给予共轭活性剂组合物的方法。
• ACTIVE AGENT DELIVERY SYSTEMS AND METHODS FOR PROTECTING AND ADMINISTERING ACTIVE AGENTS
  申请人：Mickle Travis

  公开号：US20090306228A1

  公开（公告）日：2009-12-10

  The present invention relates to active agent delivery systems and more specifically to compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents and methods for administering conjugated active agent compositions.

  本发明涉及活性剂递送系统，更具体地涉及包含氨基酸，作为单个氨基酸或肽，与活性剂共价结合的组合物以及用于给予共轭活性剂组合物的方法。
• Active agent delivery sytems and methods for protecting and administering active agents
  申请人：Shire LLC

  公开号：EP2266590A2

  公开（公告）日：2010-12-29

  The present invention relates to active agent delivery systems and more specifically to compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents and methods for administering conjugated active agent compositions.

  本发明涉及活性剂给药系统，更具体地说，涉及由与活性剂共价连接的氨基酸（作为单个氨基酸或肽）组成的组合物以及给药共轭活性剂组合物的方法。
• Delivery system and methods for protecting and administering dextroamphetamine
  申请人：Shire LLC

  公开号：EP2316469A1

  公开（公告）日：2011-05-04

  The present invention relates to active agent delivery systems and more specifically to compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents and methods for administering conjugated active agent compositions.

  本发明涉及活性剂给药系统，更具体地说，涉及由与活性剂共价连接的氨基酸（作为单个氨基酸或肽）组成的组合物以及给药共轭活性剂组合物的方法。
• Synthesis and antibacterial activity of desosamine-modified macrolide derivatives
  作者：Nicolas LeTourneau、Pavan Vimal、Dorota Klepacki、Alexander Mankin、Artem Melman

  DOI：10.1016/j.bmcl.2012.05.110

  日期：2012.7

  Structural factors behind erm macrolide resistance were studied through synthesis of new macrolide derivates possessing truncated desosamine sugar moieties and subsequent determination of their antibacterial activity. Synthesized compounds with 2'-deoxy and 3'-desmethyl desosamine rings demonstrated decreased antibacterial activity on the native Staphylococcus aureus strain and were inactive against constitutively resistance S. aureus. The obtained results indicate that steric repulsion between the dimethylated A2058 and desosamine ring cannot be considered as a primary reason for erm-resistance. (C) 2012 Published by Elsevier Ltd.