1-[(tert-butyldimethylsilyl)oxy]-1-(5-tributylstannyloxazol-2-yl)-7-phenylheptane

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-[(tert-butyldimethylsilyl)oxy]-1-(5-tributylstannyloxazol-2-yl)-7-phenylheptane
• 英文别名: 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole；tert-butyl-dimethyl-[7-phenyl-1-(5-tributylstannyl-1,3-oxazol-2-yl)heptoxy]silane
• 化学式: C₃₄H₆₁NO₂SiSn
• 分子量: 662.659
• InChiKey: XUUBEONIIXLAOP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.99
• 重原子数：
  39
• 可旋转键数：
  21
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  35.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-[(tert-butyldimethylsilyl)oxy]-1-(5-tributylstannyloxazol-2-yl)-7-phenylheptane 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 6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinonitrile
  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

• Discovery of a Potent, Selective, and Efficacious Class of Reversible α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Effective as Analgesics
  作者：Dale L. Boger、Hiroshi Miyauchi、Wu Du、Christophe Hardouin、Robert A. Fecik、Heng Cheng、Inkyu Hwang、Michael P. Hedrick、Donmienne Leung、Orlando Acevedo、Cristiano R. W. Guimarães、William L. Jorgensen、Benjamin F. Cravatt

  DOI：10.1021/jm049614v

  日期：2005.3.1

  Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic

  脂肪酸酰胺水解酶 (FAAH) 在其作用部位降解神经调节脂肪酸酰胺，包括 anandamide（内源性大麻素激动剂）和油酰胺（睡眠诱导脂质），并密切参与其调节。在这里，我们报告了在动物模型中发现了一种有效的、选择性的和有效的可逆 FAAH 抑制剂，它们可以产生镇痛作用，从而验证了疼痛干预的新治疗靶点。发现有用抑制剂的关键是常规实施针对丝氨酸水解酶超家族的蛋白质组学选择性筛选，确保对 FAAH 的选择性，并结合候选抑制剂的系统体内检查。
• Oxazole ketones as modulators of fatty acid amide hydrolase
  申请人：Boger L. Dale

  公开号：US20070203156A1

  公开（公告）日：2007-08-30

  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).

  某些噁唑酮类化合物可用作FAAH抑制剂。这些化合物可以用于制备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、紊乱和病情的方法。因此，这些化合物可以用于治疗焦虑、疼痛、炎症、睡眠障碍、进食障碍或运动障碍（如MS）。
• 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
• Optimization of α-Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase
  作者：F. Scott Kimball、F. Anthony Romero、Cyrine Ezzili、Joie Garfunkle、Thomas J. Rayl、Dustin G. Hochstatter、Inkyu Hwang、Dale L. Boger

  DOI：10.1021/jm701210y

  日期：2008.2.1

  A series of alpha-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain of 2 (OL-135) and representative oxazole C5 substituents were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH). Exceptionally potent and selective FAAH inhibitors emerged from the series (e.g., 6, K-i = 200 and 260 pM for rat and rhFAAH). With simple and small C5 oxazole substituents, each series bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl C2 side chain was found to follow a well-defined linear relationship between -log K-i and Hammett sigma(p) of a magnitude (rho = 2.7-3.0) that indicates that the substituent electronic effect dominates, confirming its fundamental importance to the series and further establishing its predictive value. Just as significantly, the nature of the C5 oxazole substituent substantially impacts the selectivity of the inhibitors whereas the effect of the C2 acyl chain was more subtle but still significant even in the small series examined. Combination of these independent features, which display generalized trends across a range of inhibitor series, simultaneously improves FAAH potency and selectivity and can provide exquisitely selective and potent FAAH inhibitors.
• 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.