title: Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.
abstract: The endogenous cannabinoid (endocannabinoid) anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH). Pharmacological blockade of FAAH has emerged as a potentially attractive strategy for augmenting endocannabinoid signaling and retaining the beneficial effects of cannabinoid receptor activation, while avoiding the undesirable side effects, such as weight gain and impairments in cognition and motor control, observed with direct cannabinoid receptor 1 agonists. Here, we report the detailed mechanistic and pharmacological characterization of N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide (PF-04457845), a highly efficacious and selective FAAH inhibitor. Mechanistic studies confirm that PF-04457845 is a time-dependent, covalent FAAH inhibitor that carbamylates FAAH's catalytic serine nucleophile. PF-04457845 inhibits human FAAH with high potency (k(inact)/K(i) = 40,300 M(-1)s(-1); IC(50) = 7.2 nM) and is exquisitely selective in vivo as determined by activity-based protein profiling. Oral administration of PF-04457845 produced potent antinociceptive effects in both inflammatory [complete Freund's adjuvant (CFA)] and noninflammatory (monosodium iodoacetate) pain models in rats, with a minimum effective dose of 0.1 mg/kg (CFA model). PF-04457845 displayed a long duration of action as a single oral administration at 1 mg/kg showed in vivo efficacy for 24 h with a concomitant near-complete inhibition of FAAH activity and maximal sustained elevation of anandamide in brain. Significantly, PF-04457845-treated mice at 10 mg/kg elicited no effect in motility, catalepsy, and body temperature. Based on its exceptional selectivity and in vivo efficacy, combined with long duration of action and optimal pharmacokinetic properties, PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA. kay.ahn@pfizer.com
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Smith
authors.forename: Marya B
authors.initials: MB
authors.lastname: Liimatta
authors.forename: David
authors.initials: D
authors.lastname: Beidler
authors.forename: Nalini
authors.initials: N
authors.lastname: Sadagopan
authors.forename: David T
authors.initials: DT
authors.lastname: Dudley
authors.forename: Tim
authors.initials: T
authors.lastname: Young
authors.forename: Paul
authors.initials: P
authors.lastname: Wren
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Steven
authors.initials: S
authors.lastname: Swaney
authors.forename: Keri
authors.initials: K
authors.lastname: Van Becelaere
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.forename: Shobha N
authors.initials: SN
authors.lastname: Bhattachar
authors.forename: Cory
authors.initials: C
authors.lastname: Stiff
authors.forename: Tyzoon K
authors.initials: TK
authors.lastname: Nomanbhoy
authors.forename: Eranthie
authors.initials: E
authors.lastname: Weerapana
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D010880:Piperidines; D011724:Pyridazines; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C560620:N-pyridazin-3-yl-4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxamide