6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinic acid
• 英文别名: 6-[2-(7-phenylheptanoyl)-1,3-oxazol-5-yl]pyridine-3-carboxylic acid
• 化学式: C₂₂H₂₂N₂O₄
• 分子量: 378.428
• InChiKey: SHWZOKMNLUJQPA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  28
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  93.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinic acid 、 甲硫醇 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以67%的产率得到methyl 6-(2-(7-phenylheptanoyl)oxazol-5-yl)-pyridine-3-carbothioate
  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：

  6-氯烟酸甲酯 在 lithium hydroxide 、 四丁基氟化铵 、 叔丁基锂 、 戴斯-马丁氧化剂 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 30.0h， 生成 6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinic acid
  参考文献：
  名称：

  基于强力和选择性的基于α-酮杂环的抑制剂，用于安南酰胺和油酰胺分解代谢酶，脂肪酸酰胺水解酶。

  摘要：

  针对2f（OL-135）（一种有效的脂肪酸酰胺水解酶（FAAH）抑制剂）的结构-活性关系（SAR）进行了详细研究，其目标是恶唑的5位。对一系列取代苯衍生物（12-14）的研究表明，最佳取代位置是间位，所选成员的效价接近或超过2f。与这些研究同时，还研究了取代对2f的吡啶环的影响。还研究了一系列小的非芳香族C5取代基，发现K（i）与Hammett sigma（p）常数（rho = 3.01，R2 = 0.91）具有明确定义的相关性，吸电子取代基增强效力，导致抑制剂的K（i）s低至400 pM（20n）。

  DOI：

  10.1021/jm0611509
• 作为试剂：
  描述：

  methyl 6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinate 在 6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinic acid 作用下， 以 Ethyl acetate acetate 为溶剂， 生成 6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinic acid
  参考文献：
  名称：

  Oxazole ketones as modulators of fatty acid amide hydrolase

  摘要：

  某些噁唑酮类化合物可用作FAAH抑制剂。这些化合物可用于药物组合物和治疗由脂肪酸酰胺水解酶（FAAH）活性介导的疾病状态，紊乱和病况的方法。因此，这些化合物可用于治疗焦虑、疼痛、炎症、睡眠障碍、进食障碍或运动障碍（如多发性硬化）等病症。

  公开号：

  US20070203156A1

文献信息

• OXAZOLE KETONES AS MODULATORS OF FATTY ACID AMIDE HYDROLASE
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：EP1983994A2

  公开（公告）日：2008-10-29
• US7915270B2
  申请人：——

  公开号：US7915270B2

  公开（公告）日：2011-03-29
• [EN] OXAZOLE KETONES AS MODULATORS OF FATTY ACID AMIDE HYDROLASE<br/>[FR] OXAZOLE-CÉTONES EN TANT QUE MODULATEURS DE L'AMIDE D'ACIDE GRAS HYDROLASE
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2007098142A2

  公开（公告）日：2007-08-30

  [EN] Certain oxazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS).
  [FR] Certains composés de type oxazole-cétone peuvent être employés en tant qu'inhibiteurs de FAAH. De tels composés peuvent être employés dans des compositions pharmaceutiques et des méthodes de traitement d'états pathologiques, de troubles et de maladies faisant intervenir l'activité de l'amide d'acide gras hydrolase (FAAH). Ainsi, les composés peuvent être administrés dans le traitement de l'anxiété, de la douleur, de l'inflammation, des troubles du sommeil, des troubles de l'alimentation, ou des troubles du mouvement (par exemple SEP).
• Design, Synthesis, and Characterization of α-Ketoheterocycles That Additionally Target the Cytosolic Port Cys269 of Fatty Acid Amide Hydrolase
  作者：Katerina Otrubova、Benjamin F. Cravatt、Dale L. Boger

  DOI：10.1021/jm401820q

  日期：2014.2.13

  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.
• Potent and Selective α-Ketoheterocycle-Based Inhibitors of the Anandamide and Oleamide Catabolizing Enzyme, Fatty Acid Amide Hydrolase
  作者：F. Anthony Romero、Wu Du、Inkyu Hwang、Thomas J. Rayl、F. Scott Kimball、Donmienne Leung、Heather S. Hoover、Richard L. Apodaca、J. Guy Breitenbucher、Benjamin F. Cravatt、Dale L. Boger

  DOI：10.1021/jm0611509

  日期：2007.3.1

  with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituents was also explored and revealed that the K(i) follows a well-defined correlation with the Hammett sigma(p) constant (rho = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K(i)s as low as 400 pM (20n). Proteomic-wide

  针对2f（OL-135）（一种有效的脂肪酸酰胺水解酶（FAAH）抑制剂）的结构-活性关系（SAR）进行了详细研究，其目标是恶唑的5位。对一系列取代苯衍生物（12-14）的研究表明，最佳取代位置是间位，所选成员的效价接近或超过2f。与这些研究同时，还研究了取代对2f的吡啶环的影响。还研究了一系列小的非芳香族C5取代基，发现K（i）与Hammett sigma（p）常数（rho = 3.01，R2 = 0.91）具有明确定义的相关性，吸电子取代基增强效力，导致抑制剂的K（i）s低至400 pM（20n）。