[3aR-(3aalpha,4alpha,6aalpha)]-4-[[[(1,1-二甲基乙基)二苯基硅烷基]氧基]甲基]六氢-2H-环戊[b]呋喃-2-酮 | 140690-09-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 中文名称: [3aR-(3aalpha,4alpha,6aalpha)]-4-[[[(1,1-二甲基乙基)二苯基硅烷基]氧基]甲基]六氢-2H-环戊[b]呋喃-2-酮
• 中文别名: [3aR-（3aα，4α，6aα）]-4-[[[[（（1,1-二甲基乙基）二苯基甲硅烷基]氧基]甲基]六氢-2H-环戊[b]呋喃-2-酮
• 英文名称: (3aR,4S,6aS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)hexahydro-2H-cyclopenta[b]furan-2-one
• 英文别名: [3aR-(3aalpha,4alpha,6aalpha)]-4-[[[(1,1-Dimethylethyl)diphenylsilyl]oxy]methyl]hexahydro-2H-cyclopenta[b]furan-；(3aR,4S,6aS)-4-[[tert-butyl(diphenyl)silyl]oxymethyl]-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-one
• CAS: 140690-09-1
• 化学式: C₂₄H₃₀O₃Si
• 分子量: 394.586
• InChiKey: SZEYRRMRYKLNOX-QIJUGHKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  [3aR-(3aalpha,4alpha,6aalpha)]-4-[[[(1,1-二甲基乙基)二苯基硅烷基]氧基]甲基]六氢-2H-环戊[b]呋喃-2-酮 在 吡啶 、 盐酸 、 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 三丁基膦 、 四丁基氟化铵 、 三氧化硫吡啶 、 双(三甲基硅烷基)氨基钾 、 potassium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醇 、 水 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 11.83h， 生成 2-[(2-{(1R,2R,5S)-2-[(1E)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-hydroxycyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid
  参考文献：
  名称：

  Synthesis and evaluation of a potent, well-balanced EP 2 /EP 3 dual agonist

  摘要：

  A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (> 2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.11.035

文献信息

• EP1707208
  申请人：——

  公开号：——

  公开（公告）日：——
• EP1886693
  申请人：——

  公开号：——

  公开（公告）日：——
• Synthesis and evaluation of a potent, well-balanced EP 2 /EP 3 dual agonist
  作者：Akihiro Kinoshita、Masato Higashino、Koji Yoshida、Yoshiyuki Aratani、Akito Kakuuchi、Keisuke Hanada、Hiroyuki Takeda、Atsushi Naganawa、Hidekazu Matsuya、Kazuyuki Ohmoto

  DOI：10.1016/j.bmc.2017.11.035

  日期：2018.1

  A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (> 2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB. (C) 2017 Elsevier Ltd. All rights reserved.