Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.
Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.
Ahn
Kay
K
Pfizer Global Research and Development, Groton, CT 06340, USA. kay.ahn@pfizer.com
Johnson
Douglas S
DS
Mileni
Mauro
M
Beidler
David
D
Long
Jonathan Z
JZ
McKinney
Michele K
MK
Weerapana
Eranthie
E
Sadagopan
Nalini
N
Liimatta
Marya
M
Smith
Sarah E
SE
Lazerwith
Scott
S
Stiff
Cory
C
Kamtekar
Satwik
S
Bhattacharya
Keshab
K
Zhang
Yanhua
Y
Swaney
Stephen
S
Van Becelaere
Keri
K
Stevens
Raymond C
RC
Cravatt
Benjamin F
BF
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D000077489:Piperazine; D010879:Piperazines; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C032727:piperidine; C078814:anandamide