(3R,3aS,4S,4aR,8aS,9aR)-3-methyl-4-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)octahydronaphtho[2,3-c]furan-1,6(3H,4H)-dione | 226914-53-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并呋喃类
• 英文名称: (3R,3aS,4S,4aR,8aS,9aR)-3-methyl-4-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)octahydronaphtho[2,3-c]furan-1,6(3H,4H)-dione
• CAS: 226914-53-0
• 化学式: C₂₇H₂₆F₃NO₃
• 分子量: 469.504
• InChiKey: PYXVYOXAUKLNHO-WOYHNBARSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.96
• 重原子数：
  34.0
• 可旋转键数：
  3.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  56.26
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (3R,3aS,4S,4aR,8aS,9aR)-3-methyl-4-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)octahydronaphtho[2,3-c]furan-1,6(3H,4H)-dione 在 sodium tetrahydroborate 作用下， 以 乙醇 为溶剂， 生成 (3R,3aS,4S,4aR,6R,8aS,9aR)-6-hydroxy-3-methyl-4-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3H-benzo[f][2]benzofuran-1-one 、 (+)-(3R,3aS,4S,4aR,6S,8aS,9aR)-decahydro-6-hydroxy-3-methyl-4-[(E)-2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]-naphtho[2,3-c]furan-1(3H)-one
  参考文献：
  名称：

  Metabolism-Based Identification of a Potent Thrombin Receptor Antagonist

  摘要：

  The metabolism of our prototypical thrombin receptor antagonist 1, K-i = 2.7 nM, was studied and three major metabolites (2,4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a K-i = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.

  DOI：

  10.1021/jm061043e
• 作为产物：
  描述：

  1,4-二氧杂螺[4.5]癸-7-烯-8-基三氟甲磺酸酯 在 bis-triphenylphosphine-palladium(II) chloride 、 palladium on activated charcoal 、 四(三苯基膦)钯 盐酸 、 sodium hydroxide 、 正丁基锂 、 氯化亚砜 、 氢气 、 4-吡咯烷基吡啶 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 、 甲苯 、 xylene 为溶剂， 215.0 ℃ 、101.33 kPa 条件下， 反应 10.0h， 生成 (3R,3aS,4S,4aR,8aS,9aR)-3-methyl-4-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)octahydronaphtho[2,3-c]furan-1,6(3H,4H)-dione
  参考文献：
  名称：

  Metabolism-Based Identification of a Potent Thrombin Receptor Antagonist

  摘要：

  The metabolism of our prototypical thrombin receptor antagonist 1, K-i = 2.7 nM, was studied and three major metabolites (2,4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a K-i = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.

  DOI：

  10.1021/jm061043e