2(S)-<(2-benzoylphenyl)amino>-3-<4-<2-(5-methyl-2-phenyl-3H-imidazol-4-yl)ethoxy>phenyl>propionic acid | 196808-45-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2(S)-<(2-benzoylphenyl)amino>-3-<4-<2-(5-methyl-2-phenyl-3H-imidazol-4-yl)ethoxy>phenyl>propionic acid
• 英文别名: N-(2-benzoylphenyl)-O-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yI)ethyl]-L-tyrosine；(2S)-2-(2-benzoylanilino)-3-[4-[2-(5-methyl-2-phenyl-1H-imidazol-4-yl)ethoxy]phenyl]propanoic acid
• CAS: 196808-45-4
• 化学式: C₃₄H₃₁N₃O₄
• 分子量: 545.638
• InChiKey: SCFHGNMHMPSWDS-HKBQPEDESA-N

物化性质

• 熔点：
  148-150 °C
• 沸点：
  793.7±70.0 °C(Predicted)
• 密度：
  1.257±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  41
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  6

制备方法与用途

法格列他扎尔是一种PPARγ激动剂，对2型糖尿病患者的血糖控制有显著的治疗益处。

反应信息

• 作为产物：
  描述：

  methyl (2S)-2-(2-benzoylanilino)-3-[4-[2-[5-methyl-2-phenyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethoxy]phenyl]propanoate 在 lithium hydroxide 、 三氟化硼乙醚 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 2.5h， 生成 2(S)-<(2-benzoylphenyl)amino>-3-<4-<2-(5-methyl-2-phenyl-3H-imidazol-4-yl)ethoxy>phenyl>propionic acid
  参考文献：
  名称：

  N-(2-Benzoylphenyl)-l-tyrosine PPARγ Agonists. 2. Structure−Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety

  摘要：

  We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic (2) (PPAR gamma pK(i) = 8.94, PPAR gamma, pEC(50) = 9.47) as a potent and selective PPAR gamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPAR gamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid (16) (PPAR gamma pK(i) = 8.85, PPAR gamma pEC(50) = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-{2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}pheynyl)propionic acid (24) (PPAR gamma pK(i) = 8.6, PPAR gamma pEC(50) = 8.89) provided two potent and selective PPAR gamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPAR gamma ligands (PPAR gamma pK(i)'s 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPAR gamma binding, functional activity, selectivity, and aqueous solubility.

  DOI：

  10.1021/jm980413z

文献信息

• SYSTEMS AND METHODS FOR ENHANCING VACCINE EFFICACY
  申请人：Phipps Richard P.

  公开号：US20110300129A1

  公开（公告）日：2011-12-08

  Pharmaceutical compositions of the invention include an antigen or a nucleic acid molecule encoding the antigen; one or both of a PPAR ligand and an RxR ligand; and a pharmaceutically suitable carrier. The pharmaceutical composition can optionally include a mitogen or other additives. Also disclosed are methods of inducing B cell differentiation and promoting an immune response against an antigen.
• [EN] SYSTEMS AND METHODS FOR ENHANCING VACCINE EFFICACY<br/>[FR] SYSTÈMES ET PROCÉDÉS POUR AMÉLIORER L'EFFICACITÉ DE VACCINS
  申请人：UNIV ROCHESTER

  公开号：WO2010075037A1

  公开（公告）日：2010-07-01

  Pharmaceutical compositions of the invention include an antigen or a nucleic acid molecule encoding the antigen; one or both of a PPAR ligand and an RxR ligand; and a pharmaceutically suitable carrier. The pharmaceutical composition can optionally include a mitogen or other additives. Also disclosed are methods of inducing B cell differentiation and promoting an immune response against an antigen.
• <i>N</i>-(2-Benzoylphenyl)-<scp>l</scp>-tyrosine PPARγ Agonists. 2. Structure−Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety
  作者：Jon L. Collins、Steven G. Blanchard、G. Evan Boswell、Paul S. Charifson、Jeff E. Cobb、Brad R. Henke、Emily A. Hull-Ryde、Wieslaw M. Kazmierski、Debra H. Lake、Lisa M. Leesnitzer、Jürgen Lehmann、James M. Lenhard、Lisa A. Orband-Miller、Yolanda Gray-Nunez、Derek J. Parks、Kelli D. Plunkett、Wei-Qin Tong

  DOI：10.1021/jm980413z

  日期：1998.12.1

  We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic (2) (PPAR gamma pK(i) = 8.94, PPAR gamma, pEC(50) = 9.47) as a potent and selective PPAR gamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPAR gamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-4-[2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid (16) (PPAR gamma pK(i) = 8.85, PPAR gamma pEC(50) = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}pheynyl)propionic acid (24) (PPAR gamma pK(i) = 8.6, PPAR gamma pEC(50) = 8.89) provided two potent and selective PPAR gamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPAR gamma ligands (PPAR gamma pK(i)'s 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPAR gamma binding, functional activity, selectivity, and aqueous solubility.