3,8-diamino-6,7,8,8a-tetrahydro-8a-hydroxyimidazo[1,5a]pyridin-1(5H)-one | 185744-62-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并吡啶类
• 英文名称: 3,8-diamino-6,7,8,8a-tetrahydro-8a-hydroxyimidazo[1,5a]pyridin-1(5H)-one
• 英文别名: (8S,8aR)-3,8-diamino-8a-hydroxy-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-1-one
• CAS: 185744-62-1
• 化学式: C₇H₁₂N₄O₂
• 分子量: 184.198
• InChiKey: PZDQQIJFFSPHBS-MHTLYPKNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3,8-diamino-6,7,8,8a-tetrahydro-8a-hydroxyimidazo[1,5a]pyridin-1(5H)-one 在 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：

  3-(benzyloxycarbonylamino)-6-(dibenzyloxycarbonylguanidino)-2-oxo-hexanoic acid methylester 在 10percent Pd/C 盐酸 、 氢气 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以100%的产率得到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

文献信息

• 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.