Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, USA.
J Med Chem. 2012 Nov 26;55(22):10074-89. doi: 10.1021/jm301205j. Epub 2012 Nov 2.
Sulfonyl fluorides are known to inhibit esterases. Early work from our laboratory has identified hexadecyl sulfonylfluoride (AM374) as a potent in vitro and in vivo inhibitor of fatty acid amide hydrolase (FAAH). We now report on later generation sulfonyl fluoride analogs that exhibit potent and selective inhibition of FAAH. Using recombinant rat and human FAAH, we show that 5-(4-hydroxyphenyl)pentanesulfonyl fluoride (AM3506) has similar inhibitory activity for both the rat and the human enzyme, while rapid dilution assays and mass spectrometry analysis suggest that the compound is a covalent modifier for FAAH and inhibits its action in an irreversible manner. Our SAR results are highlighted by molecular docking of key analogs.
磺酰氟化物是众所周知的酯酶抑制剂。我们实验室的早期工作已经确定了十六烷基磺酰氟（AM374）是一种有效的体外和体内脂肪酸酰胺水解酶（FAAH）抑制剂。现在我们报告了后来一代的磺酰氟类似物，它们对 FAAH 表现出有效的选择性抑制。使用重组大鼠和人 FAAH，我们表明 5-(4-羟苯基)戊烷磺酰氟（AM3506）对大鼠和人酶都具有相似的抑制活性，而快速稀释测定和质谱分析表明该化合物是 FAAH 的共价修饰物，并以不可逆的方式抑制其作用。我们的 SAR 结果突出了关键类似物的分子对接。
