Sulfonyl fluoride inhibitors of fatty acid amide hydrolase.
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.
Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, USA.
Shakiru O
SO
Alapafuja
Spyros P
SP
Nikas
Indu T
IT
Bharathan
Vidyanand G
VG
Shukla
Mahmoud L
ML
Nasr
Anna L
AL
Bowman
Nikolai
N
Zvonok
Jing
J
Li
Xiaomeng
X
Shi
John R
JR
Engen
Alexandros
A
Makriyannis
D000476:Alkanesulfonates / Q000494:pharmacology*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010168:Palmitates / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000476:Alkanesulfonates; D000581:Amidohydrolases; D010168:Palmitates; D010636:Phenols; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases; C556520:AM 3506; C104963:AM 374