(2R)-4-hydroxypent-(Z)-2-enoic acid benzyl ester | 226916-21-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2R)-4-hydroxypent-(Z)-2-enoic acid benzyl ester
• 英文别名: 2-Pentenoic acid, 4-hydroxy-, phenylmethyl ester, (2Z,4R)-；benzyl (Z,4R)-4-hydroxypent-2-enoate
• CAS: 226916-21-8
• 化学式: C₁₂H₁₄O₃
• 分子量: 206.241
• InChiKey: XMOMNBGAUQVSCC-GQYWMQPJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  15
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (2R)-4-hydroxypent-(Z)-2-enoic acid benzyl ester 在 palladium on activated charcoal 、 四(三苯基膦)钯 盐酸 、 正丁基锂 、 氯化亚砜 、 氢气 、 三正丁基氢锡 、 4-吡咯烷基吡啶 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 乙酸乙酯 、 丙酮 、 甲苯 、 xylene 为溶剂， 215.0 ℃ 、101.33 kPa 条件下， 生成 (1R,3aR,4aS,8aS,9S,9aS)-1-methyl-9-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-1,3a,4,4a,6,7,8,8a,9,9a-decahydrobenzo[f][2]benzofuran-3,5-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
• 作为产物：
  描述：

  (R)-4-羟基-2-戊炔酸苄酯 在 Lindlar's catalyst 氢气 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 生成 (2R)-4-hydroxypent-(Z)-2-enoic acid benzyl ester
  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

文献信息

• Heterotricyclic Himbacine Analogs as Potent, Orally Active Thrombin Receptor (Protease Activated Receptor-1) Antagonists
  作者：Mariappan V. Chelliah、Samuel Chackalamannil、Yan Xia、Keith Eagen、Martin C. Clasby、Xiaobang Gao、William Greenlee、Ho-Sam Ahn、Jacqueline Agans-Fantuzzi、George Boykow、Yunsheng Hsieh、Matthew Bryant、Jairam Palamanda、Tze-Ming Chan、David Hesk、Madhu Chintala

  DOI：10.1021/jm070704k

  日期：2007.10.1

  Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet

  遵循我们在基于组氨酸的凝血酶受体拮抗剂领域的早期努力，我们合成了一系列在三环基序的C环中掺入杂原子的化合物。这项工作已导致鉴定出几种对凝血酶受体具有优异亲和力的有效杂环类似物。这些化合物中的几种在口服给药后在食蟹猴的离体模型中显示出对血小板聚集的强烈抑制。介绍了28b（本系列的基准化合物）的详细资料，Ki为4.3 nM。
• Thrombin receptor antagonists
  申请人：——

  公开号：US20040152736A1

  公开（公告）日：2004-08-05

  A series of compounds represented by the structural formulas 1 2 and pharmaceutically acceptable isomers, salts, solvates and polymorphs thereof are disclosed. Also disclosed are pharmaceutical compositions containing said compounds and their use as thrombin receptor antagonists and binders to cannabinoid receptors.

  本文披露了一系列化合物，其结构式表示为12，并且包括其药学上可接受的异构体、盐、溶剂合物和多晶形式。还披露了含有这些化合物的制药组合物，并将其用作凝血酶受体拮抗剂和大麻素受体结合剂。
• THROMBIN RECEPTOR ANTAGONISTS
  申请人：SCHERING CORPORATION

  公开号：EP1036072B1

  公开（公告）日：2004-05-06
• Derivatives of hexahydrobenzofuranone useful for the treatment of (inter alia) auto-immune or inflammatory disorders
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2301930B1

  公开（公告）日：2016-01-06
• EP2301930A1
  申请人：——

  公开号：EP2301930A1

  公开（公告）日：2011-03-30