Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide.
The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid), and anandamide (an endogenous ligand for cannabinoid receptors) is detailed. The inhibitors may serve as useful tools to clarify the role of endogenous oleamide and anandamide and may prove to be useful therapeutic agents for the treatment of sleep disorders or pain. The combination of several features-an optimal C12-C8 chain length, pi-unsaturation introduction at the corresponding arachidonoyl Delta(8,9)/Delta(11,12) and oleoyl Delta(9,10) location, and an alpha-keto N4 oxazolopyridine with incorporation of a second weakly basic nitrogen provided FAAH inhibitors with K(i)s that drop below 200 pM and are 10(2)-10(3) times more potent than the corresponding trifluoromethyl ketones.
Boger
D L
DL
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. boger@scripps.edu
Sato
H
H
Lerner
A E
AE
Hedrick
M P
MP
Fecik
R A
RA
Miyauchi
H
H
Wilkie
G D
GD
Austin
B J
BJ
Patricelli
M P
MP
Cravatt
B F
BF
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000493:pharmacokinetics*; D019556:COS Cells; D002186:Cannabinoids / Q000493:pharmacokinetics; D002462:Cell Membrane / Q000201:enzymology; D002554:Cerebrosides / Q000378:metabolism; D015195:Drug Design; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D009829:Oleic Acids / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014162:Transfection; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D002186:Cannabinoids; D002554:Cerebrosides; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D009829:Oleic Acids; D053284:Polyunsaturated Alkamides; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases; C029407:oleylamide; C078814:anandamide