6-[(4S)-fluoro-1-[2-(2-methylphenyl)amino-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]hexanoic acid | 732240-15-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶唑类
• 英文名称: 6-[(4S)-fluoro-1-[2-(2-methylphenyl)amino-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]hexanoic acid
• 英文别名: 6-[[(2S,4S)-4-fluoro-1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]pyrrolidin-2-yl]methoxy]hexanoic acid
• CAS: 732240-15-2
• 化学式: C₂₇H₃₂FN₃O₅
• 分子量: 497.567
• InChiKey: SWCNXPKXNIGCDX-SFTDATJTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  6-[(4S)-fluoro-1-[2-(2-methylphenyl)amino-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]hexanoic acid 在 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 生成 6-[(4S)-fluoro-1-[2-(2-methylphenyl)amino-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]hexanoic acid sodium salt
  参考文献：
  名称：

  A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid

  摘要：

  During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-( 2- methylphenylamino) benzoxazole moiety which mimics the diphenylurea structure. However, this modi. cation resulted in a significant decrease ( 3, IC(50) = 19 nM) in VLA-4 inhibitory activity compared to 1 ( IC(50) = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50) = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties ( CL = 3.3ml/min/ kg, F = 51%) in rats. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.12.026
• 作为产物：
  描述：

  methyl 6-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)hexanoate 在 sodium hydroxide 、 水 、 盐酸 作用下， 以 四氢呋喃 为溶剂， 反应 17.0h， 生成 6-[(4S)-fluoro-1-[2-(2-methylphenyl)amino-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]hexanoic acid
  参考文献：
  名称：

  A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid

  摘要：

  During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-( 2- methylphenylamino) benzoxazole moiety which mimics the diphenylurea structure. However, this modi. cation resulted in a significant decrease ( 3, IC(50) = 19 nM) in VLA-4 inhibitory activity compared to 1 ( IC(50) = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50) = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties ( CL = 3.3ml/min/ kg, F = 51%) in rats. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.12.026

文献信息

• VLA-4 INHIBITORS
  申请人：DAIICHI PHARMACEUTICAL CO., LTD.

  公开号：EP1346982B1

  公开（公告）日：2011-09-14
• US7157487B2
  申请人：——

  公开号：US7157487B2

  公开（公告）日：2007-01-02