(2R,4S)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide | 1356351-76-2

• 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,4S)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide
• 英文别名: (2R,4S)-N-[4-(4-fluorophenoxy)phenyl]-4-[(4-fluorophenyl)methyl]-1-[2-(triazol-1-yl)acetyl]pyrrolidine-2-carboxamide
• CAS: 1356351-76-2
• 化学式: C₂₈H₂₅F₂N₅O₃
• 分子量: 517.535
• InChiKey: YVPVVMYVUCYNPA-RXFWQSSRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  89.4
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  D-焦谷氨酸 在 甲醇 、 4-二甲氨基吡啶 、 三乙基硼氢化锂 、 对甲苯磺酸 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 、 potassium hydroxide 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 60.58h， 生成 (2R,4S)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide
  参考文献：
  名称：

  Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists

  摘要：

  A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.

  DOI：

  10.1021/jm201533b

文献信息

• Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists
  作者：Mohamed A. Ibrahim、Henry W. B. Johnson、Joon Won Jeong、Gary L. Lewis、Xian Shi、Robin T. Noguchi、Matthew Williams、James W. Leahy、John M. Nuss、John Woolfrey、Monica Banica、Frauke Bentzien、Yu-Chien Chou、Anna Gibson、Nathan Heald、Peter Lamb、Larry Mattheakis、David Matthews、Aaron Shipway、Xiang Wu、WenTao Zhang、Sihong Zhou、Geetha Shankar

  DOI：10.1021/jm201533b

  日期：2012.2.9

  A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.