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.