alpha-Keto heterocycle inhibitors of fatty acid amide hydrolase: carbonyl group modification and alpha-substitution.
Two sets of novel analogues of the recently disclosed alpha-keto heterocycle inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for regulation of endogenous oleamide and anandamide, were synthesized and evaluated in order to clarify a role of the electrophilic carbonyl group and structural features important for their activity. Both the electrophilic carbonyl and the degree of alpha-substitution markedly affect inhibitor potency.
Boger
D L
DL
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. boger@scripps.edu
Miyauchi
H
H
Hedrick
M P
MP
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D007659:Ketones / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000648:ultrastructure; D009829:Oleic Acids / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D007659:Ketones; D009829:Oleic Acids; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C029407:oleylamide; C078814:anandamide