(1S,2S,4R,6R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-6-[4-[(4-hydroxyphenyl)methyl]phenyl]-9,13-dimethyl-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one | 1337894-73-1

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: (1S,2S,4R,6R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-6-[4-[(4-hydroxyphenyl)methyl]phenyl]-9,13-dimethyl-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one
• CAS: 1337894-73-1
• 化学式: C₃₅H₃₆F₂O₇
• 分子量: 606.663
• InChiKey: YFRPXMQJHJXXJV-BFQQSILCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  44
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  113
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  醋酸氟轻松 在 tetrafluoroboric acid 、 三氟甲磺酸 、 水 、 magnesium sulfate 作用下， 以 1,4-二氧六环 为溶剂， 反应 31.0h， 生成 (1S,2S,4R,6R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-6-[4-[(4-hydroxyphenyl)methyl]phenyl]-9,13-dimethyl-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one
  参考文献：
  名称：

  Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma

  摘要：

  In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.07.106

文献信息

• Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma
  作者：David S. Millan、Stephen A. Ballard、Sara Chunn、Joseph A. Dybowski、Craig K. Fulton、Paul A. Glossop、Edouard Guillabert、Christopher A. Hewson、Rhys M. Jones、David J. Lamb、Carolyn M. Napier、Toby A. Payne-Cook、Emmanuelle R. Renery、Matthew D. Selby、Michelle F. Tutt、Michael Yeadon

  DOI：10.1016/j.bmcl.2011.07.106

  日期：2011.10

  In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma. (C) 2011 Elsevier Ltd. All rights reserved.