(4aR,10aR)-4a-ethyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-1H-phenanthren-2-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: (4aR,10aR)-4a-ethyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-1H-phenanthren-2-one
• 英文别名: (4aR,10aR)-4a-ethyl-7-hydroxy-1,3,4,9,10,10a-hexahydrophenanthren-2-one
• 化学式: C₁₆H₂₀O₂
• 分子量: 244.334
• InChiKey: DKAIETXDHPNEQS-MLGOLLRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (4aR,10aR)-4a-ethyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-1H-phenanthren-2-one 在 咪唑 、 sodium ethanolate 作用下， 以 二氯甲烷 为溶剂， 反应 6.0h， 生成 (4aR,10aR,E)-3-benzylidene-7-((tert-butyldimethylsilyl)oxy)-4a-ethyl-1,4,4a,9,10,10a-hexahydrophenanthren-2(3H)-one
  参考文献：
  名称：

  2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as Potent Dissociated Glucocorticoid Receptor Agonists

  摘要：

  A significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy assay measuring repression of IL-1 induced MMP-13 expression was 3.5 nM, exhibiting 87% of the maximal effect of dexamethasone (DEX). It displayed a dissociated profile by exhibiting 42% of the maximal effect of DEX in a mouse mammary tumor virus (MMTV) luciferase reporter transactivation assay. Compound 13 and analogues containing heterocyclic replacements for the C2 phenyl and modified B rings showed high repression of TNF alpha production in human whole blood, with IC50 values (43-167 nM) approaching the level of DEX (21 nM). On the basis of X-ray structures and force field calculations, the overall potency of this series was attributed to a favorable conformation of the C2 alpha phenyl, induced by the neighboring C3 alpha methyl.

  DOI：

  10.1021/jm501601b
• 作为产物：
  描述：

  在 盐酸 、 水 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 (4aR,10aR)-4a-ethyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-1H-phenanthren-2-one 、
  参考文献：
  名称：

  Octahydrophenanthrene-2,7-diol Analogues as Dissociated Glucocorticoid Receptor Agonists: Discovery and Lead Exploration

  摘要：

  As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.

  DOI：

  10.1021/jm801512v

文献信息

• [EN] MODULATORS OF THE GLUCOCORTICOID RECEPTOR<br/>[FR] MODULATEURS DU RECEPTEUR GLUCOCORTICOIDE
  申请人：PFIZER PROD INC

  公开号：WO2004005229A1

  公开（公告）日：2004-01-15

  The present invention provides compounds of the formula wherein A is of the formula and X, Y, n, R1-R25 are as described in the specification which are modulators of the glucocorticoid receptor and are thus useful for the treatment of animals requiring glucocorticoid receptor ágonist.therapy. Glucocorticoid-receptor modulators are useful in the treatment of certain inflammatory conditions.

  本发明提供了以下式中A为该式，X、Y、n、R1-R25如说明书中所述的化合物，这些化合物是糖皮质激素受体的调节剂，因此对需要糖皮质激素受体激动剂治疗的动物有用。糖皮质激素受体调节剂在治疗某些炎症性疾病中是有用的。
• US7138406B2
  申请人：——

  公开号：US7138406B2

  公开（公告）日：2006-11-21
• US7553877B2
  申请人：——

  公开号：US7553877B2

  公开（公告）日：2009-06-30
• 2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as Potent Dissociated Glucocorticoid Receptor Agonists
  作者：Yves A. Chantigny、John C. Murray、Edward F. Kleinman、Ralph P. Robinson、Michael A. Plotkin、Matthew R. Reese、Leonard Buckbinder、Patricia A. McNiff、Michele L. Millham、Jean F. Schaefer、Yuriy A. Abramov、Jon Bordner

  DOI：10.1021/jm501601b

  日期：2015.3.26

  A significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy assay measuring repression of IL-1 induced MMP-13 expression was 3.5 nM, exhibiting 87% of the maximal effect of dexamethasone (DEX). It displayed a dissociated profile by exhibiting 42% of the maximal effect of DEX in a mouse mammary tumor virus (MMTV) luciferase reporter transactivation assay. Compound 13 and analogues containing heterocyclic replacements for the C2 phenyl and modified B rings showed high repression of TNF alpha production in human whole blood, with IC50 values (43-167 nM) approaching the level of DEX (21 nM). On the basis of X-ray structures and force field calculations, the overall potency of this series was attributed to a favorable conformation of the C2 alpha phenyl, induced by the neighboring C3 alpha methyl.
• Octahydrophenanthrene-2,7-diol Analogues as Dissociated Glucocorticoid Receptor Agonists: Discovery and Lead Exploration
  作者：Ralph P. Robinson、Leonard Buckbinder、Amber I. Haugeto、Patricia A. McNiff、Michele L. Millham、Matthew R. Reese、Jean F. Schaefer、Yuriy A. Abramov、Jon Bordner、Yves A. Chantigny、Edward F. Kleinman、Ellen R. Laird、Bradley P. Morgan、John C. Murray、Eben D. Salter、Matthew D. Wessel、Sue A. Yocum

  DOI：10.1021/jm801512v

  日期：2009.3.26

  As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.