methyl (2R)-1-[((2S,4R)-4-tert-butoxy-1-[3,3,3-tris(4-fluorophenyl)propanoyl]pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carboxylate | 1053610-06-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl (2R)-1-[((2S,4R)-4-tert-butoxy-1-[3,3,3-tris(4-fluorophenyl)propanoyl]pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carboxylate
• 英文别名: methyl (2R)-1-[(2S,4R)-4-[(2-methylpropan-2-yl)oxy]-1-[3,3,3-tris(4-fluorophenyl)propanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxylate
• CAS: 1053610-06-2
• 化学式: C₃₆H₃₉F₃N₂O₅
• 分子量: 636.711
• InChiKey: PEVFWMFGNUNYFZ-OLUZHXLYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  46
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  76.2
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl (2R)-1-[((2S,4R)-4-tert-butoxy-1-[3,3,3-tris(4-fluorophenyl)propanoyl]pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carboxylate 在 sodium hydroxide 、 WSC*HCl 、 sodium cyanoborohydride 、 1-羟基苯并三唑 、 三氟乙酸 、 zinc(II) chloride 作用下， 以 甲醇 、 氯仿 、 水 为溶剂， 反应 26.0h， 生成 (2R)-1-((2S,4R)-4-hydroxy-1-{3,3,3-tris(4-fluorophenyl)-propanoyl}pyrrolidin-2-yl)carbonyl-N-(1-methyl-4-piperidylmethyl)-pyrrolidine-2-carboxamide
  参考文献：
  名称：

  Identification of a Novel 4-Aminomethylpiperidine Class of M₃ Muscarinic Receptor Antagonists and Structural Insight into Their M₃ Selectivity

  摘要：

  Identification of a novel class of potent and highly selective M-3 muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M-3 selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M-3 antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M-3 selective antagonist that had > 100-fold selectivity versus the M-1, M-2, M-4, and M-5 receptors (M-3: K-i = 0.30 nM, M-1/M-3 = 570-fold, M-2/M-3 = 1600-fold, M-4/M-3 = 140-fold, M-5/M-3 = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M-3 antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M-3 receptors.

  DOI：

  10.1021/jm051205r
• 作为产物：
  描述：

  1-苄基2-甲基1,2-吡咯烷二羧酸酯 在 palladium dihydroxide WSC*HCl 、 氢气 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 60.0h， 生成 methyl (2R)-1-[((2S,4R)-4-tert-butoxy-1-[3,3,3-tris(4-fluorophenyl)propanoyl]pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carboxylate
  参考文献：
  名称：

  Identification of a Novel 4-Aminomethylpiperidine Class of M₃ Muscarinic Receptor Antagonists and Structural Insight into Their M₃ Selectivity

  摘要：

  Identification of a novel class of potent and highly selective M-3 muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M-3 selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M-3 antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M-3 selective antagonist that had > 100-fold selectivity versus the M-1, M-2, M-4, and M-5 receptors (M-3: K-i = 0.30 nM, M-1/M-3 = 570-fold, M-2/M-3 = 1600-fold, M-4/M-3 = 140-fold, M-5/M-3 = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M-3 antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M-3 receptors.

  DOI：

  10.1021/jm051205r