(7S)-6-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-butyl-7-(methoxycarbonyl)-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c]pyrimidin-2-ium bromide | 400045-26-3

• 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: (7S)-6-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-butyl-7-(methoxycarbonyl)-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c]pyrimidin-2-ium bromide
• 英文别名: methyl (7S)-2-butyl-6-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]-5-oxo-7,8-dihydroimidazo[1,5-c]pyrimidin-2-ium-7-carboxylate;bromide
• CAS: 400045-26-3
• 化学式: Br*C₁₉H₃₁N₄O₅
• 分子量: 475.383
• InChiKey: LSGCDDONYHNBSS-RSAXXLAASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.53
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  93.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (7S)-6-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-butyl-7-(methoxycarbonyl)-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c]pyrimidin-2-ium bromide 在 硫酸 作用下， 以 水 为溶剂， 反应 17.0h， 以82%的产率得到(2S)-2-[(2-Aminoethyl)amino]-3-(1-n-butyl-1H-imidazol-4-yl)propanoic acid
  参考文献：
  名称：

  Discovery of Potent & Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor for the Treatment of Thrombosis

  摘要：

  Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.

  DOI：

  10.1021/jm0702433
• 作为产物：
  描述：

  正溴丁烷 、 methyl (7S)-6-{2-[(tert-butoxycarbonyl)amino]ethyl}-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c]pyrimidine-7-carboxylate 以 乙腈 为溶剂， 反应 17.0h， 以46%的产率得到(7S)-6-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-butyl-7-(methoxycarbonyl)-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c]pyrimidin-2-ium bromide
  参考文献：
  名称：

  Discovery of Potent & Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor for the Treatment of Thrombosis

  摘要：

  Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.

  DOI：

  10.1021/jm0702433

文献信息

• Discovery of Potent & Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor for the Treatment of Thrombosis
  作者：Mark E. Bunnage、Julian Blagg、John Steele、Dafydd R. Owen、Charlotte Allerton、Andrew B. McElroy、Duncan Miller、Tracy Ringer、Ken Butcher、Kevin Beaumont、Karen Evans、Andrew J. Gray、Stephen J. Holland、Neil Feeder、Robert S. Moore、David G. Brown

  DOI：10.1021/jm0702433

  日期：2007.11.1

  Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.