title: Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, Groton, CT 06340, USA. kay.ahn@pfizer.com
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Mauro
authors.initials: M
authors.lastname: Mileni
authors.forename: David
authors.initials: D
authors.lastname: Beidler
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Michele K
authors.initials: MK
authors.lastname: McKinney
authors.forename: Eranthie
authors.initials: E
authors.lastname: Weerapana
authors.forename: Nalini
authors.initials: N
authors.lastname: Sadagopan
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Smith
authors.forename: Scott
authors.initials: S
authors.lastname: Lazerwith
authors.forename: Cory
authors.initials: C
authors.lastname: Stiff
authors.forename: Satwik
authors.initials: S
authors.lastname: Kamtekar
authors.forename: Keshab
authors.initials: K
authors.lastname: Bhattacharya
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Stephen
authors.initials: S
authors.lastname: Swaney
authors.forename: Keri
authors.initials: K
authors.lastname: Van Becelaere
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: 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
chemical_list: 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