Sulfonyl Fluoride Inhibitors of Fatty Acid Amide Hydrolase

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• 作者：Shakiru O. Alapafuja ; Spyros P. Nikas ; Indu T. Bharathan ; Vidyanand G. Shukla ; Mahmoud L. Nasr ; Anna L. Bowman ; Nikolai Zvonok ; Jing Li ; Xiaomeng Shi ; John R. Engen ; Alexandros Makriyannis
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10074-10089
• 全文大小：558K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

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.