2-(6-(2-(7-phenylheptanoyl)-1,3-oxazol-5-yl)pyridin-3-yl)acetonitrile | 1429771-02-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(6-(2-(7-phenylheptanoyl)-1,3-oxazol-5-yl)pyridin-3-yl)acetonitrile
• 英文别名: 2-(6-(2-(7-phenylheptanol)oxazol-5-yl)pyridin-3-yl)acetonitrile；2-[6-[2-(7-Phenylheptanoyl)-1,3-oxazol-5-yl]pyridin-3-yl]acetonitrile；2-[6-[2-(7-phenylheptanoyl)-1,3-oxazol-5-yl]pyridin-3-yl]acetonitrile
• CAS: 1429771-02-7
• 化学式: C₂₃H₂₃N₃O₂
• 分子量: 373.455
• InChiKey: MDHSRBKWWXIDHJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  28
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  79.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(6-(2-(7-phenylheptanoyl)-1,3-oxazol-5-yl)pyridin-3-yl)acetonitrile 在 盐酸 、 水 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以60%的产率得到2-(6-(2-(7-phenylheptanoyl)oxazol-5-yl)pyridin-3-yl)acetic acid
  参考文献：
  名称：

  Design, Synthesis, and Characterization of α-Ketoheterocycles That Additionally Target the Cytosolic Port Cys269 of Fatty Acid Amide Hydrolase

  摘要：

  A series of alpha-ketooxazoles incorporating electrophiles at the C5 position of the pyridyl ring of 2 (OL-135) and related compounds were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH) that additionally target the cytosolic port Cys269. From this series, a subset of the candidate inhibitors exhibited time-dependent FAAH inhibition and noncompetitive irreversible inactivation of the enzyme, consistent with the targeted Cys269 covalent alkylation or addition, and maintained or enhanced the intrinsic selectivity for FAAH versus other serine hydrolases. A preliminary in vivo assessment demonstrates that these inhibitors raise endogenous brain levels of anandamide and other FAAH substrates upon intraperitoneal (i.p.) administration to mice, with peak levels achieved within 1.5-3 h, and that the elevations of the signaling lipids were maintained >6 h, indicating that the inhibitors effectively reach and remain active in the brain, inhibiting FAAH for a sustained period.

  DOI：

  10.1021/jm401820q
• 作为产物：
  描述：

  2-氯-5-吡啶乙腈 在 四(三苯基膦)钯 、 四丁基氟化铵 、 戴斯-马丁氧化剂 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 20.0h， 生成 2-(6-(2-(7-phenylheptanoyl)-1,3-oxazol-5-yl)pyridin-3-yl)acetonitrile
  参考文献：
  名称：

  Design, Synthesis, and Characterization of α-Ketoheterocycles That Additionally Target the Cytosolic Port Cys269 of Fatty Acid Amide Hydrolase

  摘要：

  A series of alpha-ketooxazoles incorporating electrophiles at the C5 position of the pyridyl ring of 2 (OL-135) and related compounds were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH) that additionally target the cytosolic port Cys269. From this series, a subset of the candidate inhibitors exhibited time-dependent FAAH inhibition and noncompetitive irreversible inactivation of the enzyme, consistent with the targeted Cys269 covalent alkylation or addition, and maintained or enhanced the intrinsic selectivity for FAAH versus other serine hydrolases. A preliminary in vivo assessment demonstrates that these inhibitors raise endogenous brain levels of anandamide and other FAAH substrates upon intraperitoneal (i.p.) administration to mice, with peak levels achieved within 1.5-3 h, and that the elevations of the signaling lipids were maintained >6 h, indicating that the inhibitors effectively reach and remain active in the brain, inhibiting FAAH for a sustained period.

  DOI：

  10.1021/jm401820q

文献信息

• Rational Design of Fatty Acid Amide Hydrolase Inhibitors That Act by Covalently Bonding to Two Active Site Residues
  作者：Katerina Otrubova、Monica Brown、Michael S. McCormick、Gye W. Han、Scott T. O’Neal、Benjamin F. Cravatt、Raymond C. Stevens、Aron H. Lichtman、Dale L. Boger

  DOI：10.1021/ja4014997

  日期：2013.4.24

  The design and characterization of α-ketoheterocycle fatty acid amide hydrolase (FAAH) inhibitors are disclosed that additionally and irreversibly target a cysteine (Cys269) found in the enzyme cytosolic port while maintaining the reversible covalent Ser241 attachment responsible for their rapid and initially reversible enzyme inhibition. Two α-ketooxazoles (3 and 4) containing strategically placed

  公开了 α-酮杂环脂肪酸酰胺水解酶 (FAAH) 抑制剂的设计和表征，其额外且不可逆地靶向酶胞质端口中发现的半胱氨酸 (Cys269)，同时保持可逆共价 Ser241 附着，负责其快速且最初可逆的酶抑制. 制备了两种 α-酮恶唑（3 和 4），它们在 2 的吡啶基取代基的 C5 位置（OL-135）含有策略性放置的亲电子试剂，并作为 FAAH 抑制剂进行检测。与观察到的时间依赖性非竞争性抑制一致，与大鼠 FAAH 人源化变体结合的 3 的共晶 X 射线结构显示，3 不仅与活性位点催化亲核试剂 Ser241 作为去质子化的半缩酮共价结合，而且还与 Cys269 共价结合通过吡啶基C5-取代基，从而提供在酶活性位点具有双共价连接的抑制剂。小鼠原型抑制剂的体内表征表明，与可逆抑制剂 2 相比，它们在更大程度上提高脑内源性 FAAH 底物水平（> 6 小时），表明抑制剂在脑中积累并持续存在长时间完