tert-butyl [(2R)-2-[6-(acetylamino)-3-pyridinyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl][2-[3'-ethoxy-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]carbamate | 945548-87-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl [(2R)-2-[6-(acetylamino)-3-pyridinyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl][2-[3'-ethoxy-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]carbamate
• 英文别名: tert-butyl N-[(2R)-2-(6-acetamidopyridin-3-yl)-2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-[2-[4-[3-ethoxy-4-(methylsulfonylcarbamoyl)phenyl]phenyl]ethyl]carbamate
• CAS: 945548-87-8
• 化学式: C₃₈H₅₄N₄O₈SSi
• 分子量: 755.02
• InChiKey: YTUWZMKKBATTRE-XIFFEERXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.34
• 重原子数：
  52
• 可旋转键数：
  17
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  162
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl [(2R)-2-[6-(acetylamino)-3-pyridinyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl][2-[3'-ethoxy-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]carbamate 在 水 、 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 18.0h， 生成
  参考文献：
  名称：

  Discovery of Highly Potent and Selective Biphenylacylsulfonamide-Based β₃-Adrenergic Receptor Agonists and Evaluation of Physical Properties as Potential Overactive Bladder Therapies: Part 5

  摘要：

  As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC50 values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.

  DOI：

  10.1021/jm9000709
• 作为产物：
  描述：

  2-ethoxy-N-(methylsulfonyl)-4-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-benzamide 、 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 1,1'-bis(diphenylphosphino)ferrocene 、 sodium carbonate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以259 mg的产率得到tert-butyl [(2R)-2-[6-(acetylamino)-3-pyridinyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl][2-[3'-ethoxy-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]carbamate
  参考文献：
  名称：

  Discovery of Highly Potent and Selective Biphenylacylsulfonamide-Based β₃-Adrenergic Receptor Agonists and Evaluation of Physical Properties as Potential Overactive Bladder Therapies: Part 5

  摘要：

  As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC50 values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.

  DOI：

  10.1021/jm9000709

文献信息

• Discovery of Highly Potent and Selective Biphenylacylsulfonamide-Based β₃-Adrenergic Receptor Agonists and Evaluation of Physical Properties as Potential Overactive Bladder Therapies: Part 5
  作者：Kouji Hattori、Susumu Toda、Masashi Imanishi、Shinji Itou、Yutaka Nakajima、Kenichi Washizuka、Takanobu Araki、Hitoshi Hamashima、Yasuyo Tomishima、Minoru Sakurai、Shigeo Matsui、Emiko Imamura、Koji Ueshima、Takao Yamamoto、Nobuhiro Yamamoto、Hirofumi Ishikawa、Keiko Nakano、Naoko Unami、Kaori Hamada、Yasuhiro Matsumura、Fujiko Takamura

  DOI：10.1021/jm9000709

  日期：2009.5.14

  As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC50 values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.