methyl 4-(tetrahydropyranyloxy)-2-butenoate | 62222-75-7

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: methyl 4-(tetrahydropyranyloxy)-2-butenoate
• 英文别名: 2-Butenoic acid, 4-[(tetrahydro-2H-pyran-2-yl)oxy]-, methyl ester, (Z)-；methyl 4-(oxan-2-yloxy)but-2-enoate
• CAS: 62222-75-7
• 化学式: C₁₀H₁₆O₄
• 分子量: 200.235
• InChiKey: SNJOVVNSRJRUCZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 4-(tetrahydropyranyloxy)-2-butenoate 、 N-[3,4-Dihydro-2H-naphthalen-(1E)-ylidene]-N'-(4-fluoro-phenyl)-hydrazine 在 lithium diisopropyl amide 作用下， 生成 (E)-3-[2-(4-Fluoro-phenyl)-4,5-dihydro-2H-benzo[g]indazol-3-yl]-acrylic acid methyl 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

文献信息

• Tetrahydroindazole, tetrahydrocyclopentapyrazole, and
  申请人：Ortho Pharmaceutical Corporation

  公开号：US05134155A1

  公开（公告）日：1992-07-28

  Compounds of the general formula I: ##STR1## are disclosed as useful in the treatment or prevention of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Novel intermediate compounds used to make the compound of formula I are also disclosed.

  通式I的化合物：##STR1## 被披露为在治疗或预防高胆固醇血症、高脂蛋白血症和动脉粥样硬化方面有用。还披露了用于制备通式I化合物的新型中间体化合物。
• HMG-CoA reductase inhibitors: design, synthesis, and biological activity of tetrahydroindazole-substituted 3,5-dihydroxy-6-heptenoic acid sodium salts
  作者：Peter J. Connolly、Claudia D. Westin、Deborah A. Loughney、Lisa K. Minor

  DOI：10.1021/jm00075a024

  日期：1993.11

  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.