| Sulfonyl fluoride inhibitors of fatty acid amide hydrolase. | |
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MedLine Citation:
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PMID: 23083016 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural Date: 2012-11-02 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 55 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-26 Completed Date: 2013-02-05 Revised Date: 2013-06-12 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 10074-89 Citation Subset: IM |
Affiliation:
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Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alkanesulfonates
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pharmacology* Amidohydrolases / antagonists & inhibitors*, metabolism Animals Brain / drug effects*, metabolism Humans Male Mice Models, Molecular Molecular Structure Palmitates / pharmacology* Phenols / pharmacology* Radioligand Assay Rats Recombinant Proteins / antagonists & inhibitors*, metabolism Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Structure-Activity Relationship |
| Grant Support | |
ID/Acronym/Agency:
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DA003801/DA/NIDA NIH HHS; DA007215/DA/NIDA NIH HHS; DA009158/DA/NIDA NIH HHS; R01 DA007215/DA/NIDA NIH HHS; R01 GM086507/GM/NIGMS NIH HHS; R01 GM101135/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/AM 3506; 0/AM 374; 0/Alkanesulfonates; 0/Palmitates; 0/Phenols; 0/Recombinant Proteins; EC 3.5.-/Amidohydrolases; EC 3.5.1.-/fatty-acid amide hydrolase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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