1-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylcarbonyl]-4-piperidinylacetic acid | 441712-10-3

• 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: 1-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylcarbonyl]-4-piperidinylacetic acid
• 英文别名: 2-[1-[(2S,4S)-4-fluoro-1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]pyrrolidine-2-carbonyl]piperidin-4-yl]acetic acid
• CAS: 441712-10-3
• 化学式: C₂₈H₃₁FN₄O₅
• 分子量: 522.576
• InChiKey: RNONHKYHQFSZDY-REWPJTCUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  ethyl 2-[1-[(2S,4S)-4-fluoro-1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]pyrrolidine-2-carbonyl]piperidin-4-yl]acetate 在 sodium hydroxide 、 水 、 盐酸 作用下， 以 四氢呋喃 为溶剂， 反应 15.0h， 生成 1-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylcarbonyl]-4-piperidinylacetic 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