(1S,2R,5aS,7R,8aR,8bS)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-(4-fluorophenyl)-7-hydroxyoctahydrocyclopenta[a]pyrrolizin-5(1H)-one | 1254353-63-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (1S,2R,5aS,7R,8aR,8bS)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-(4-fluorophenyl)-7-hydroxyoctahydrocyclopenta[a]pyrrolizin-5(1H)-one
• 英文别名: (1S,2R,5aS,7R,8aR,8bS)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-1-(4-fluorophenyl)-7-hydroxyoctahydrocyclopenta[a]pyrrolizin-5(5aH)-one；(1S,2R,5aS,7R,8aR,8bS)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-1-(4-fluorophenyl)-7-hydroxy-2,3,5a,6,7,8,8a,8b-octahydro-1H-cyclopenta[a]pyrrolizin-5-one
• CAS: 1254353-63-3
• 化学式: C₂₆H₂₄F₇NO₃
• 分子量: 531.47
• InChiKey: IXAYPVHFYLGKGT-RSKZVPLKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  (1S,2R,5aS,8aR,8bS)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-(4-fluorophenyl)octahydrocyclopentyl[a]pyrrolizine-5,7-dione 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 5.0h， 以36%的产率得到(1S,2R,5aS,7S,8aR,8bS)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-(4-fluorophenyl)-7-hydroxyoctahydrocyclopenta[a]pyrrolizin-5(1H)-one
  参考文献：
  名称：

  Fused tricyclic pyrrolizinones that exhibit pseudo-irreversible blockade of the NK1 receptor

  摘要：

  Previously, we had disclosed a novel class of hNK(1) antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK(1) affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK(1) compounds and to improve functional activity, we have designed and synthesized a new class of hNK(1) antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK(1) antagonists maintain subnanomolar hNK(1) binding affinity with highly improved functional IP-1 activity (< 10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (< 2% SP remaining), hNK(1) binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID50 of 0.02 mpk at both 0 and 24 h, respectively. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.07.058

文献信息

• Fused tricyclic pyrrolizinones that exhibit pseudo-irreversible blockade of the NK1 receptor
  作者：Gregori J. Morriello、Gary Chicchi、Tricia Johnson、Sander G. Mills、Julie DeMartino、Marc Kurtz、K.L.C. Tsao、Song Zheng、Xinchun Tong、Emma Carlson、Karen Townson、Alan Wheeldon、Susan Boyce、Neil Collinson、Nadia Rupniak、Robert J. DeVita

  DOI：10.1016/j.bmcl.2010.07.058

  日期：2010.10

  Previously, we had disclosed a novel class of hNK(1) antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK(1) affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK(1) compounds and to improve functional activity, we have designed and synthesized a new class of hNK(1) antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK(1) antagonists maintain subnanomolar hNK(1) binding affinity with highly improved functional IP-1 activity (< 10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (< 2% SP remaining), hNK(1) binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID50 of 0.02 mpk at both 0 and 24 h, respectively. (C) 2010 Elsevier Ltd. All rights reserved.