2-[(4R,6R)-2,2-dimethyl-6-(2-phenylethyl)-1,3-dioxan-4-yl]acetic acid | 91285-73-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-[(4R,6R)-2,2-dimethyl-6-(2-phenylethyl)-1,3-dioxan-4-yl]acetic acid
• CAS: 91285-73-3
• 化学式: C₁₆H₂₂O₄
• 分子量: 278.348
• InChiKey: JBLVLPWHJKKKNL-ZIAGYGMSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-[(4R,6R)-2,2-dimethyl-6-(2-phenylethyl)-1,3-dioxan-4-yl]acetic acid 在 camphor-10-sulfonic acid 作用下， 以 甲醇 为溶剂， 反应 0.08h， 生成 (3R,5R)-3,5-Dihydroxy-7-phenyl-heptanoic acid
  参考文献：
  名称：

  Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

  摘要：

  A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.

  DOI：

  10.1021/jm00173a013
• 作为产物：
  描述：

  1,3-Dioxane-4-acetic acid, 2,2-dimethyl-6-(2-phenylethenyl)-,1,1-dimethylethyl ester 在 palladium on activated charcoal 麻黄素 、 氢气 作用下， 生成 2-[(4R,6R)-2,2-dimethyl-6-(2-phenylethyl)-1,3-dioxan-4-yl]acetic acid
  参考文献：
  名称：

  HMG-CoA还原酶的有效，组织选择性合成抑制剂。

  摘要：

  DOI：

  10.1021/jm00129a004

文献信息

• Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
  作者：S. Y. Sit、R. A. Parker、I. Motoc、W. Han、N. Balasubramanian、J. D. Catt、P. J. Brown、W. E. Harte、M. D. Thompson、J. J. Wright

  DOI：10.1021/jm00173a013

  日期：1990.11

  A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.
• A potent, tissue-selective, synthetic inhibitor of HMG-CoA reductase
  作者：N. Balasubramanian、P. J. Brown、J. D. Catt、W. T. Han、R. A. Parker、S. Y. Sit、J. J. Wright

  DOI：10.1021/jm00129a004

  日期：1989.9