6-[(4-氟苯基)(4-甲基-1-哌啶基)甲基]-α-甲基-4'-(三氟甲基)-[1,1'-联苯]-3-乙酸 | 1257395-14-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二芳基庚烷
• 中文名称: 6-[(4-氟苯基)(4-甲基-1-哌啶基)甲基]-α-甲基-4'-(三氟甲基)-[1,1'-联苯]-3-乙酸
• 英文名称: 2-(6-((4-fluorophenyl)(4-methylpiperidin-1-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)propanoic acid
• 英文别名: 6-[(4-Fluorophenyl)(4-methyl-1-piperidinyl)methyl]-a-methyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-acetic acid；2-[4-[(4-fluorophenyl)-(4-methylpiperidin-1-yl)methyl]-3-[4-(trifluoromethyl)phenyl]phenyl]propanoic acid
• CAS: 1257395-14-4
• 化学式: C₂₉H₂₉F₄NO₂
• 分子量: 499.548
• InChiKey: ONYWALXTZFPKAS-UHFFFAOYSA-N

物化性质

• 沸点：
  563.4±50.0 °C(Predicted)
• 密度：
  1.226±0.06 g/cm3(Predicted)
• 溶解度：
  在 DMSO 中溶解度为 100 mM，在乙醇中溶解度为 100 mM

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  7

制备方法与用途

(Rac)-BIB042(化合物10)是γ-分泌酶的调节剂，能够降低淀粉样蛋白-β42水平，其EC50值为0.39µM，并且适用于阿尔茨海默病的研究。

反应信息

• 作为反应物：
  描述：

  6-[(4-氟苯基)(4-甲基-1-哌啶基)甲基]-α-甲基-4'-(三氟甲基)-[1,1'-联苯]-3-乙酸 在 二氧化碳 作用下， 以 甲醇 、 异丙醇 为溶剂， 以188 mg的产率得到(R)-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-1-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)propanoic acid
  参考文献：
  名称：

  Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator

  摘要：

  We have investigated a novel series of acid-derived gamma-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent gamma-secretase modulator, which lowered A beta 42, increased A beta 38, but had little to no effect on A beta 40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain A beta 42 levels in CF-1 mice and Fischer rats, as well as plasma A beta 42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

  DOI：

  10.1021/ml200175q
• 作为产物：
  描述：

  2-(3-羟基苯基)丙酸甲酯 在 吡啶 、 四(三苯基膦)钯 、 水 、 sodium carbonate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 甲苯 、 2,3,4-三氟甲苯 为溶剂， 反应 7.17h， 生成 6-[(4-氟苯基)(4-甲基-1-哌啶基)甲基]-α-甲基-4'-(三氟甲基)-[1,1'-联苯]-3-乙酸
  参考文献：
  名称：

  Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator

  摘要：

  We have investigated a novel series of acid-derived gamma-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent gamma-secretase modulator, which lowered A beta 42, increased A beta 38, but had little to no effect on A beta 40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain A beta 42 levels in CF-1 mice and Fischer rats, as well as plasma A beta 42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

  DOI：

  10.1021/ml200175q

文献信息

• [EN] CARBOXYLIC ACID-CONTAINING COMPOUNDS, DERIVATIVES THEREOF, AND RELATED METHODS OF USE<br/>[FR] COMPOSÉS CONTENANT DE L'ACIDE CARBOXYLIQUE, LEURS DÉRIVÉS ET PROCÉDÉS D'UTILISATION ASSOCIÉS
  申请人：BIOGEN IDEC INC

  公开号：WO2010138901A1

  公开（公告）日：2010-12-02

  Compounds that modulate gamma secretase (e.g., alter the cleavage pattern of gamma secretase) are described herein. Also disclosed are pharmaceutical compositions, methods of modulating the activity of gamma secretase, and methods of treating Alzheimer's Disease using the compounds described herein.

  本文件描述了调节γ-分泌酶（例如，改变γ-分泌酶的切割模式）的化合物。还公开了包含这些化合物的药物组合物、调节γ-分泌酶活性的方法，以及使用本文件描述的化合物治疗阿尔茨海默病的方法。
• Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator
  作者：Hairuo Peng、Tina Talreja、Zhili Xin、J. Hernan Cuervo、Gnanasambandam Kumaravel、Michael J. Humora、Lin Xu、Ellen Rohde、Lawrence Gan、Mi-young Jung、Melanie N. Shackett、Sowmya Chollate、Anthone W. Dunah、Pamela A. Snodgrass-belt、H. Moore Arnold、Arthur G. Taveras、Kenneth J. Rhodes、Robert H. Scannevin

  DOI：10.1021/ml200175q

  日期：2011.10.13

  We have investigated a novel series of acid-derived gamma-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent gamma-secretase modulator, which lowered A beta 42, increased A beta 38, but had little to no effect on A beta 40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain A beta 42 levels in CF-1 mice and Fischer rats, as well as plasma A beta 42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.