Discovery of a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics.
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.
Boger
Dale L
DL
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
Miyauchi
Hiroshi
H
Du
Wu
W
Hardouin
Christophe
C
Fecik
Robert A
RA
Cheng
Heng
H
Hwang
Inkyu
I
Hedrick
Michael P
MP
Leung
Donmienne
D
Acevedo
Orlando
O
Guimarães
Cristiano R W
CR
Jorgensen
William L
WL
Cravatt
Benjamin F
BF
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
D000581:Amidohydrolases; D000700:Analgesics; D007659:Ketones; D010080:Oxazoles; D011725:Pyridines; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D000099252:Fatty Acid Amide Hydrolases