title: Discovery of a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics.
abstract: Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.
authors.affiliation: Department of Chemistry, Cell Biology, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. boger@scripps.edu
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyauchi
authors.forename: Wu
authors.initials: W
authors.lastname: Du
authors.forename: Christophe
authors.initials: C
authors.lastname: Hardouin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fecik
authors.forename: Heng
authors.initials: H
authors.lastname: Cheng
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hedrick
authors.forename: Donmienne
authors.initials: D
authors.lastname: Leung
authors.forename: Orlando
authors.initials: O
authors.lastname: Acevedo
authors.forename: Cristiano R W
authors.initials: CR
authors.lastname: Guimarães
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D040901:Proteomics; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases / Q000737:chemistry; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D007659:Ketones; D010080:Oxazoles; D011725:Pyridines; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D000099252:Fatty Acid Amide Hydrolases