PF-04457845

Description: PF-04457845 is a novel, highly potent and selective FAAH (fatty acid amide hydrolase) inhibitor with IC50 values of 7.2+/-0.63 nM and 7.4+/-0.62 nM for hFAAH and rFAAH, respectively. 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. 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.

References: J Pharmacol Exp Ther. 2011 Jul; 338(1):114-24; J Med Chem. 2018 May 24; 61(10):4476-4504.