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Sulfonyl fluoride inhibitors of fatty acid amide hydrolase.

ABSTRACT: 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.

SUBMITTER: Alapafuja SO

PROVIDER: S-EPMC3678964 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Sulfonyl fluoride inhibitors of fatty acid amide hydrolase.

Alapafuja Shakiru O SO Nikas Spyros P SP Bharathan Indu T IT Shukla Vidyanand G VG Nasr Mahmoud L ML Bowman Anna L AL Zvonok Nikolai N Li Jing J Shi Xiaomeng X Engen John R JR Makriyannis Alexandros A

Journal of medicinal chemistry 20121102 22

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 ...[more]

PMID: 23083016

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