methyl (3S)-3-amino-2-hydroxy-7-[(2-methylpropan-2-yl)oxycarbonylamino]heptanoate | 740067-13-4

• 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 (3S)-3-amino-2-hydroxy-7-[(2-methylpropan-2-yl)oxycarbonylamino]heptanoate
• CAS: 740067-13-4
• 化学式: C₁₃H₂₆N₂O₅
• 分子量: 290.36
• InChiKey: HYOVUHWJNQAQDT-RGURZIINSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  20
• 可旋转键数：
  10
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl (3S)-3-amino-2-hydroxy-7-[(2-methylpropan-2-yl)oxycarbonylamino]heptanoate 在 sodium hydroxide 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 Boc-D-Cha-Pro-Lys(Boc)-carboxy
  参考文献：
  名称：

  Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

  摘要：

  Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg(.)min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.

  DOI：

  10.1021/jm011110z
• 作为产物：
  描述：

  Nε-Boc-Nα-Cbz-L-赖氨酸 在 10percent Pd/C 盐酸 、 苄基三乙基氯化铵 、 氢气 、 二异丁基氢化铝 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 乙醚 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 methyl (3S)-3-amino-2-hydroxy-7-[(2-methylpropan-2-yl)oxycarbonylamino]heptanoate
  参考文献：
  名称：

  Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

  摘要：

  Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg(.)min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.

  DOI：

  10.1021/jm011110z

文献信息

• Practical synthesis of a peptidomimetic thrombin inhibitor
  作者：Serge Wilmouth、Christel Bufferne-Perret、Christine Flouzat、Grégoire Humblot、Christiane Ray、Nadine Simbille

  DOI：10.1016/j.tet.2009.01.078

  日期：2009.3

  Compound 1 is a low molecular weight thrombin inhibitor developed for treatment of deep vein thrombosis and cardiovascular diseases. We herein report our efforts to develop a robust, efficient and reproducible process suitable for large-scale synthesis of compound 1.

  化合物1是开发用于治疗深静脉血栓形成和心血管疾病的低分子量凝血酶抑制剂。我们在此报告了我们为开发适用于大规模合成化合物1的稳健，有效和可重现方法的努力。
• WO2008/97676
  申请人：——

  公开号：——

  公开（公告）日：——
• COMPOUNDS AND COMPOSITIONS AS CHANNEL ACTIVATING PROTEASE INHIBITORS
  申请人：Tully David C.

  公开号：US20100056756A1

  公开（公告）日：2010-03-04

  The invention provides compounds and pharmaceutical compositions thereof, which are useful for modulating channel activating proteases, and methods for, using such compounds to treat, ameliorate or prevent a condition associated with a channel activating protease, including but not limited to prostasin, PRSS22, TMPRSS11 (e.g., TMPRSS11B, TMPRSS11E), TMPRSS2, TMPRSS3, TMPRSS4 (MTSP-2), matriptase (MTSP-1), CAP2, CAP3, trypsin, cathepsin A, or neutrophil elastase.
• US8293915B2
  申请人：——

  公开号：US8293915B2

  公开（公告）日：2012-10-23
• Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics
  作者：Anton E. P. Adang、Adrianus P. A. de Man、Gerard M. T. Vogel、Peter D. J. Grootenhuis、Martin J. Smit、Co A. M. Peters、Arie Visser、Jos B. M. Rewinkel、Theo van Dinther、Hans Lucas、Jan Kelder、Sjoerd van Aelst、Dick G. Meuleman、Constant A. A. van Boeckel

  DOI：10.1021/jm011110z

  日期：2002.9.1

  Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg(.)min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.