5,6,7,8,9,10-hexahydro-4-hydroxy-3-(1-phenylpentyl)-2H-cyclooctapyran-2-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃
• 英文名称: 5,6,7,8,9,10-hexahydro-4-hydroxy-3-(1-phenylpentyl)-2H-cyclooctapyran-2-one
• 英文别名: 5,6,7,8,9,10-Hexahydro-4-hydroxy-3-(1-phenylpentyl)-2H-cycloocta[b]pyran-2-one；4-hydroxy-3-(1-phenylpentyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyran-2-one
• 化学式: C₂₂H₂₈O₃
• 分子量: 340.463
• InChiKey: CNSKLJKHQGIUGM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  苯戊醇 、 5,6,7,8,9,10-Hexahydro-4-hydroxy-2H-cyclooctapyran-2-on 在 3 A molecular sieve 、 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 反应 7.0h， 以22%的产率得到5,6,7,8,9,10-hexahydro-4-hydroxy-3-(1-phenylpentyl)-2H-cyclooctapyran-2-one
  参考文献：
  名称：

  Use of Medium-Sized Cycloalkyl Rings To Enhance Secondary Binding: Discovery of a New Class of Human Immunodeficiency Virus (HIV) Protease Inhibitors

  摘要：

  A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, K-1 = 0.800 mu M) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, K-i = 0.015 mu M) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).

  DOI：

  10.1021/jm00011a008

文献信息

• Use of Medium-Sized Cycloalkyl Rings To Enhance Secondary Binding: Discovery of a New Class of Human Immunodeficiency Virus (HIV) Protease Inhibitors
  作者：Karen R. Romines、Keith D. Watenpaugh、Paul K. Tomich、W. Jeffrey Howe、Jeanette K. Morris、Kristine D. Lovasz、Anne M. Mulichak、Barry C. Finzel、Janet C. Lynn

  DOI：10.1021/jm00011a008

  日期：1995.5

  A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, K-1 = 0.800 mu M) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, K-i = 0.015 mu M) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).