1-(4-((1R,2R,3R)-2,3,4-trihydroxy-1-methoxybutyl)-1H-imidazol-2-yl)ethanone | 1160957-52-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(4-((1R,2R,3R)-2,3,4-trihydroxy-1-methoxybutyl)-1H-imidazol-2-yl)ethanone
• 英文别名: 1-[5-[(1R,2R,3R)-2,3,4-trihydroxy-1-methoxybutyl]-1H-imidazol-2-yl]ethanone
• CAS: 1160957-52-7
• 化学式: C₁₀H₁₆N₂O₅
• 分子量: 244.247
• InChiKey: GRKOGNKZPVFUDR-IWSPIJDZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.1
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  116
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-乙氧基丙烯腈 、 在 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 7.0h， 以22 mg的产率得到1-(4-((1R,2R,3R)-2,3,4-trihydroxy-1-methoxybutyl)-1H-imidazol-2-yl)ethanone
  参考文献：
  名称：

  Inhibition of Sphingosine-1-Phosphate Lyase for the Treatment of Autoimmune Disorders

  摘要：

  During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S I P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

  DOI：

  10.1021/jm900278w

文献信息

• Inhibition of Sphingosine-1-Phosphate Lyase for the Treatment of Autoimmune Disorders
  作者：Jeffrey T. Bagdanoff、Michael S. Donoviel、Amr Nouraldeen、James Tarver、Qinghong Fu、Marianne Carlsen、Theodore C. Jessop、Haiming Zhang、Jill Hazelwood、Huy Nguyen、Simon D. P. Baugh、Michael Gardyan、Kristen M. Terranova、Joseph Barbosa、Jack Yan、Mark Bednarz、Suman Layek、Lawrence F. Courtney、Jerry Taylor、Ann Marie Digeorge-Foushee、Suma Gopinathan、Debra Bruce、Traci Smith、Liam Moran、Emily O’Neill、Jeff Kramer、Zhong Lai、S. David Kimball、Qingyun Liu、Weimei Sun、Sean Yu、Jonathan Swaffield、Alan Wilson、Alan Main、Kenneth G. Carson、Tamas Oravecz、David J. Augeri

  DOI：10.1021/jm900278w

  日期：2009.7.9

  During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S I P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.