6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylic acid | 590367-64-9

• 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: 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylic acid
• 英文别名: (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(2,2,3,3-tetramethylcyclopropanecarbonyl)oxy-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-17-carboxylic acid
• CAS: 590367-64-9
• 化学式: C₂₉H₃₈F₂O₆
• 分子量: 520.614
• InChiKey: HSWXMMJATQJVOH-VUPQKAQSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylic acid 、 溴乙腈 在 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以485 mg的产率得到GSK-870086
  参考文献：
  名称：

  Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile

  摘要：

  Background and PurposeGlucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti‐inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti‐inflammatory activity.Experimental ApproachThe pharmacological properties of GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling.Key ResultsGW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV‐driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid‐regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase‐mediated damage. In murine models of irritant‐induced contact dermatitis and ovalbumin‐induced allergic inflammation, GW870086 showed comparable anti‐inflammatory efficacy to FP.Conclusion and ImplicationsGW870086 is a potent anti‐inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.

  DOI：

  10.1111/bph.12232
• 作为产物：
  描述：

  2,2,3,3-四甲基环丙甲酸 在 吡啶 、 N,N-二乙基甲酰胺 、 草酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylic acid
  参考文献：
  名称：

  Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile

  摘要：

  Background and PurposeGlucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti‐inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti‐inflammatory activity.Experimental ApproachThe pharmacological properties of GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling.Key ResultsGW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV‐driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid‐regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase‐mediated damage. In murine models of irritant‐induced contact dermatitis and ovalbumin‐induced allergic inflammation, GW870086 showed comparable anti‐inflammatory efficacy to FP.Conclusion and ImplicationsGW870086 is a potent anti‐inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.

  DOI：

  10.1111/bph.12232

文献信息

• [EN] SPECIFIC GLUCOCORTICOSTEROID COMPOUND HAVING ANTI- INFLAMMATORY ACTIVITY<br/>[FR] COMPOSE DE GLUCOCORTICOSTEROIDE SPECIFIQUE PRESENTANT UNE ACTIVE ANTI-INFLAMMATOIRE
  申请人：GLAXO GROUP LTD

  公开号：WO2005005451A1

  公开（公告）日：2005-01-20

  A compound of formula (I): (I) wherein X represents O or S; R1 represents C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylmethyl or C3-8 cycloalkenyl any of which optionally may be substituted by one or more methyl groups or halogen atoms or R1 represents aryl, substituted aryl, heteroaryl or substituted heteroaryl; R2 represents hydrogen, methyl, which may be in either the α or β configuration, or methylene; R3 and R4 are the same or different and each independently represents hydrogen, halogen or a methyl group; and represents a single or a double bond; or a physiologically acceptable salt or solvate thereof.

  式(I)的化合物：(I)其中X代表O或S; R1代表C1-6烷基，C3-8环烷基，C3-8环烷基甲基或C3-8环烯基，其中任何一种都可以选择性地被一个或多个甲基基团或卤原子取代，或者R1代表芳基，取代芳基，杂环芳基或取代杂环芳基; R2代表氢，甲基，可以是α或β构型中的任意一种，或亚甲基; R3和R4相同或不同，每个独立地代表氢，卤素或甲基; 表示单键或双键; 或其生理上可接受的盐或溶剂化物。
• Specific glucocorticosteriod compound having anti-inflamatory activity
  申请人：Biggadike Keith

  公开号：US20060247219A1

  公开（公告）日：2006-11-02

  A compound of formula (I): (I) wherein X represents O or S; R1 represents C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylmethyl or C3-8 cycloalkenyl any of which optionally may be substituted by one or more methyl groups or halogen atoms or R1 represents aryl, substituted aryl, heteroaryl or substituted heteroaryl; R2 represents hydrogen, methyl, which may be in either the α or β configuration, or methylene; R3 and R4 are the same or different and each independently represents hydrogen, halogen or a methyl group; and represents a single or a double bond; or a physiologically acceptable salt or solvate thereof.

  化合物的式子为（I）：（I）其中X代表O或S；R1代表C1-6烷基，C3-8环烷基，C3-8环烷基甲基或C3-8环烯基，其中任何一个都可以选择性地被一个或多个甲基基团或卤素原子取代，或者R1代表芳基，取代芳基，杂环芳基或取代杂环芳基；R2代表氢，甲基，可以是α或β构型中的任意一种，或亚甲基；R3和R4相同或不同，每个独立地代表氢，卤素或一个甲基基团；代表单键或双键；或其生理上可接受的盐或溶剂化物。
• SPECIFIC GLUCOCORTICOSTEROID COMPOUND HAVING ANTI-INFLAMMATORY ACTIVITY
  申请人：BIGGADIKE KEITH

  公开号：US20080070880A1

  公开（公告）日：2008-03-20

  A compound of formula (I): wherein X represents O or S; R 1 represents C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylmethyl or C 3-8 cycloalkenyl any of which optionally may be substituted by one or more methyl groups or halogen atoms or R 1 represents aryl, substituted aryl, heteroaryl or substituted heteroaryl; R 2 represents hydrogen, methyl, which may be in either the α or β configuration, or methylene; R 3 and R 4 are the same or different and each independently represents hydrogen, halogen or a methyl group; and represents a single or a double bond; or a physiologically acceptable salt or solvate thereof, and pharmaceutical formulations and methods of use thereof.

  化合物的化学式为(I)，其中X代表O或S；R1代表C1-6烷基，C3-8环烷基，C3-8环烷基甲基或C3-8环烯基，其中任意一个可以选择性地被一个或多个甲基基团或卤素原子取代，或者R1代表芳基，取代芳基，杂环芳基或取代杂环芳基；R2代表氢，甲基（可以是α或β构型）或亚甲基；R3和R4相同或不同，每个独立地代表氢，卤素或一个甲基基团；并表示单键或双键；或其生理上可接受的盐或溶剂化合物，以及其制剂和使用方法。
• Specific glucocorticosteroid compounds having anti-inflammatory activity
  申请人：Biggadike Keith

  公开号：US20070043007A1

  公开（公告）日：2007-02-22

  A compound of formula (I): or a physiologically acceptable solvate thereof.

  公式（I）的化合物，或其生理上可接受的溶剂化合物。
• Novel compounds
  申请人：JOHN PETER MATTHEW

  公开号：US20080015360A1

  公开（公告）日：2008-01-17

  A compound of formula (I): wherein X represents O or S; R 1 represents C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylmethyl or C 3 - 8 cycloalkenyl any of which optionally may be substituted by one or more methyl groups or halogen atoms or R 1 represents aryl, substituted aryl, heteroaryl or substituted heteroaryl; R 2 represents hydrogen, methyl, which may be in either the α or β configuration, or methylene; R 3 and R 4 are the same or different and each independently represents hydrogen, halogen or a methyl group; and represents a single or a double bond; or a physiologically acceptable salt or solvate thereof.

  化合物的化学式为(I)：其中X代表O或S；R1代表C1-6烷基，C3-8环烷基，C3-8环烷基甲基或C3-8环烯基，其中任何一个可以选择性地被一个或多个甲基基团或卤素原子取代，或者R1代表芳基，取代芳基，杂环芳基或取代杂环芳基；R2代表氢，甲基（可以是α或β构型）或亚甲基；R3和R4相同或不同，每个独立地代表氢，卤素或甲基基团；和代表单键或双键；或其生理上可接受的盐或溶剂化物。