(E)-7-[7-(4-tert-Butyl-benzyl)-2-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-5-hydroxy-3-oxo-hept-6-enoic acid ethyl ester | 153124-87-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (E)-7-[7-(4-tert-Butyl-benzyl)-2-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-5-hydroxy-3-oxo-hept-6-enoic acid ethyl ester
• CAS: 153124-87-9
• 化学式: C₃₃H₃₉FN₂O₄
• 分子量: 546.682
• InChiKey: ISRUJVCQMUGKHC-ISLYRVAYSA-N

物化性质

• 沸点：
  709.3±60.0 °C(predicted)
• 密度：
  1.16±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.26
• 重原子数：
  40.0
• 可旋转键数：
  10.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  81.42
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (E)-7-[7-(4-tert-Butyl-benzyl)-2-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-5-hydroxy-3-oxo-hept-6-enoic acid ethyl ester 在 sodium hydroxide 、 sodium tetrahydroborate 、 air 、 三乙基硼 作用下， 以 甲醇 为溶剂， 反应 3.0h， 生成 (E)-(3RS,5SR)-7-<7-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl>-3,5-dihydroxy-6-heptenoic acid sodium salt
  参考文献：
  名称：

  HMG-CoA reductase inhibitors: design, synthesis, and biological activity of tetrahydroindazole-substituted 3,5-dihydroxy-6-heptenoic acid sodium salts

  摘要：

  Compounds comprising a series of 7-[2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5-dihydroxy-6-heptenoic acid sodium salts (18) were synthesized and tested for their ability to inhibit HMG-CoA reductase in a partially purified enzyme preparation and cholesterol biosynthesis from acetate in cultured HEP-G2 cells. Changing the size of the saturated ring of the tetrahydroindazole nucleus did not improve potency, but incorporation of substituents at the 7-position resulted in up to 1700-fold improvement in inhibitory potency. Structure-activity studies revealed that the most potent compounds possess a substituted benzyl group at the 7-position, with a preference for steric bulk at the para position of the benzene ring. The most potent enzyme inhibitor (18t, IC50 = 3.0 nM) is approximately 3-fold more potent than lovastatin sodium salt (2). The most potent cholesterol biosynthesis inhibitor in HEP-G2 cells (18q, IC50 = 0.078 muM) is slightly less potent than 2 (sodium salt). Molecular modeling studies suggested that, when compared to the parent compound (18b) lacking the appropriate 7-substituent, 18t overlaps better with 2 and literature inhibitors 5 and 6 in a hydrophobic binding region adjacent to the enzyme active site.

  DOI：

  10.1021/jm00075a024
• 作为产物：
  描述：

  (E)-3-<7-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl>-2-propenol 在 manganese(IV) oxide 作用下， 以 四氢呋喃 、 苯 为溶剂， 反应 2.0h， 生成 (E)-7-[7-(4-tert-Butyl-benzyl)-2-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-5-hydroxy-3-oxo-hept-6-enoic acid ethyl ester
  参考文献：
  名称：

  HMG-CoA reductase inhibitors: design, synthesis, and biological activity of tetrahydroindazole-substituted 3,5-dihydroxy-6-heptenoic acid sodium salts

  摘要：

  Compounds comprising a series of 7-[2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5-dihydroxy-6-heptenoic acid sodium salts (18) were synthesized and tested for their ability to inhibit HMG-CoA reductase in a partially purified enzyme preparation and cholesterol biosynthesis from acetate in cultured HEP-G2 cells. Changing the size of the saturated ring of the tetrahydroindazole nucleus did not improve potency, but incorporation of substituents at the 7-position resulted in up to 1700-fold improvement in inhibitory potency. Structure-activity studies revealed that the most potent compounds possess a substituted benzyl group at the 7-position, with a preference for steric bulk at the para position of the benzene ring. The most potent enzyme inhibitor (18t, IC50 = 3.0 nM) is approximately 3-fold more potent than lovastatin sodium salt (2). The most potent cholesterol biosynthesis inhibitor in HEP-G2 cells (18q, IC50 = 0.078 muM) is slightly less potent than 2 (sodium salt). Molecular modeling studies suggested that, when compared to the parent compound (18b) lacking the appropriate 7-substituent, 18t overlaps better with 2 and literature inhibitors 5 and 6 in a hydrophobic binding region adjacent to the enzyme active site.

  DOI：

  10.1021/jm00075a024