3-(benzyloxycarbonylamino)-6-(dibenzyloxycarbonylguanidino)-2-oxo-hexanoic acid methylester | 185744-61-0

• 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: 3-(benzyloxycarbonylamino)-6-(dibenzyloxycarbonylguanidino)-2-oxo-hexanoic acid methylester
• CAS: 185744-61-0
• 化学式: C₃₂H₃₄N₄O₉
• 分子量: 618.643
• InChiKey: KJCDNUXBCLMQTB-SANMLTNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  45.0
• 可旋转键数：
  13.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  173.42
• 氢给体数：
  3.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  3-(benzyloxycarbonylamino)-6-(dibenzyloxycarbonylguanidino)-2-oxo-hexanoic acid methylester 在 10percent Pd/C 盐酸 、 氢气 、 1-羟基苯并三唑 、 苯甲醚 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.75h， 生成 N⁸(D-phenylalanyl-prolyl)-3,8-diamino-6,7,8,8a-tetrahydro-8a-hydroxyimidazo[1,5a]pyridin-1(5H)-one
  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：

  2-acetoxy-3-(benzyloxycarbonylamino)-6-(dibenzyloxycarbonylguanidino)hexanenitril 在 盐酸 、 硫酸 、 铬酸 作用下， 以 甲醇 、 乙醚 为溶剂， 反应 17.0h， 生成 3-(benzyloxycarbonylamino)-6-(dibenzyloxycarbonylguanidino)-2-oxo-hexanoic acid methylester
  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