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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.

SUBMITTER: Ahn K

PROVIDER: S-EPMC3126636 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.

Ahn Kay K Smith Sarah E SE Liimatta Marya B MB Beidler David D Sadagopan Nalini N Dudley David T DT Young Tim T Wren Paul P Zhang Yanhua Y Swaney Steven S Van Becelaere Keri K Blankman Jacqueline L JL Nomura Daniel K DK Bhattachar Shobha N SN Stiff Cory C Nomanbhoy Tyzoon K TK Weerapana Eranthie E Johnson Douglas S DS Cravatt Benjamin F BF

The Journal of pharmacology and experimental therapeutics 20110419 1

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 ...[more]

PMID: 21505060

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Project description:Although cannabinoids are efficacious in laboratory animal models of inflammatory pain, their established cannabimimetic actions diminish enthusiasm for their therapeutic development. Conversely, fatty acid amide hydrolase (FAAH), the chief catabolic enzyme regulating the endogenous cannabinoid N-arachidonoylethanolamine (anandamide), has emerged as an attractive target for treating pain and other conditions. Here, we tested WIN 55212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de)-1,4-benzoxazin-6-yl]-1-napthalenylmethanone], a cannabinoid receptor agonist, and genetic deletion or pharmacological inhibition of FAAH in the lipopolysaccharide (LPS) mouse model of inflammatory pain. WIN 55212-2 significantly reduced edema and hot-plate hyperalgesia caused by LPS infusion into the hind paws, although the mice also displayed analgesia and other central nervous system effects. FAAH(-/-) mice exhibited reduced paw edema and hyperalgesia in this model without apparent cannabimimetic effects. Transgenic mice expressing FAAH exclusively on neurons continued to display the antiedematous, but not the antihyperalgesic, phenotype. The CB(2) cannabinoid receptor (CB(2)) antagonist SR144528 [N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide] blocked this non-neuronal, anti-inflammatory phenotype, and the CB(1) cannabinoid receptor (CB(1)) antagonist rimonabant [SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] blocked the antihyperalgesic phenotype. The FAAH inhibitor URB597 [cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester] attenuated the development of LPS-induced paw edema and reversed LPS-induced hyperalgesia through the respective CB(2) and CB(1) mechanisms of action. However, the transient receptor potential vanilloid type 1 antagonist capsazepine did not affect either the antihyperalgesic or antiedematous effects of URB597. Finally, URB597 attenuated levels of the proinflammatory cytokines interleukin-1beta and tumor necrosis factor alpha in LPS-treated paws. These findings demonstrate that simultaneous elevations in non-neuronal and neuronal endocannabinoid signaling are possible through inhibition of a single enzymatic target, thereby offering a potentially powerful strategy for treating chronic inflammatory pain syndromes that operate at multiple levels of anatomical integration.

Project description:Endocannabinoids act as analgesic agents in a number of headache models. However, their effectiveness varies with the route of administration and the type of pain. In this study, we assessed the role of the fatty acid amide hydrolase inhibitor URB597 in an animal model of orofacial pain based on tooth pulp stimulation. More specifically, we assessed the effects of intracerbroventricular (i.c.v.) and intraperitoneal (i.p.) administration of URB597 on the amplitude of evoked tongue jerks (ETJ) in rats. The levels of the investigated mediators anandamide (AEA), 2-arachidonyl glycerol (2-AG), Substance P (SP), calcitonin-gene-related peptide (CGRP), endomorphin-2 (EM-2) and fatty acid amide hydrolase (FAAH) inhibitor by URB597 and receptors cannabinoid type-1 receptors (CB1R), cannabinoid type-2 receptors (CB2R) and µ-opioid receptors (MOR) were determined in the mesencephalon, thalamus and hypothalamus tissues. We have shown that increasing endocannabinoid AEA levels by both central and peripheral inhibition of FAAH inhibitor by URB597 has an antinociceptive effect on the trigemino-hypoglossal reflex mediated by CB1R and influences the activation of the brain areas studied. On the other hand, URB597 had no effect on the concentration of 2-AG in the examined brain structures and caused a significant decrease in CB2R mRNA expression in the hypothalamus only. Tooth pulp stimulation caused in a significant increase in SP, CGRP and EM-2 gene expression in the midbrain, thalamus and hypothalamus. In contrast, URB597 administered peripherally one hour before stimulation decreased the mRNA level of these endogenous neuropeptides in comparison with the control and stimulation in all examined brain structures. Our results show that centrally and peripherally administered URB597 is effective at preventing orofacial pain by inhibiting AEA catabolism and reducing the level of CGRP, SP and EM-2 gene expression and that AEA and 2-AG have different species and model-specific regulatory mechanisms. The data presented in this study may represent a new promising therapeutic target in the treatment of orofacial pain.

Dataset Information

Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.

Publications

Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.

Similar Datasets

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