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Research ArticleDrug Discovery and Translational Medicine

Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain

Kay Ahn, Sarah E. Smith, Marya B. Liimatta, David Beidler, Nalini Sadagopan, David T. Dudley, Tim Young, Paul Wren, Yanhua Zhang, Steven Swaney, Keri Van Becelaere, Jacqueline L. Blankman, Daniel K. Nomura, Shobha N. Bhattachar, Cory Stiff, Tyzoon K. Nomanbhoy, Eranthie Weerapana, Douglas S. Johnson and Benjamin F. Cravatt
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 114-124; DOI: https://doi.org/10.1124/jpet.111.180257
Kay Ahn
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Sarah E. Smith
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Marya B. Liimatta
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David Beidler
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Nalini Sadagopan
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David T. Dudley
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Tim Young
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Paul Wren
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Yanhua Zhang
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Steven Swaney
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Keri Van Becelaere
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Jacqueline L. Blankman
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Daniel K. Nomura
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Shobha N. Bhattachar
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Cory Stiff
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Tyzoon K. Nomanbhoy
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Eranthie Weerapana
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Douglas S. Johnson
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Benjamin F. Cravatt
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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 (kinact/Ki = 40,300 M−1s−1; IC50 = 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.

Footnotes

  • This work was supported by Pfizer Worldwide Research and Development; the National Institutes of Health National Institute on Drug Abuse [Grants DA017259, F31-DA026261, K99-DA030908] (to B.F.C., J.L.B., and D.K.N., respectively); and a Pfizer Postdoctoral Fellowship (to E.W.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.180257.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    FAAH
    fatty acid amide hydrolase
    hFAAH
    human FAAH
    rFAAH
    rat FAAH
    ABPP
    activity-based protein profiling
    AEA
    anandamide
    CB1
    CB1 cannabinoid receptor
    CB2
    CB2 cannabinoid receptor
    CC
    click chemistry
    CFA
    complete Freund's adjuvant
    FP
    fluorophosphonate
    FP-rhodamine
    FP-carboxytetramethylrhodamine
    MIA
    monosodium iodoacetate
    NAE
    N-acyl ethanolamine
    OEA
    N-oleoyl ethanolamine
    PEA
    N-palmitoyl ethanolamine
    PWT
    paw withdrawal threshold
    PAGE
    polyacrylamide gel electrophoresis
    PBS
    phosphate-buffered saline
    DMSO
    dimethyl sulfoxide
    COX2
    cyclooxygenase 2
    OL-135
    1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-phenylheptane
    URB597
    (3′-carbamolybiphenyl-3-yl cyclohexylcarbamate
    PF-750
    N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide
    PF-3845
    N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)piperidine-1-carboxamide
    PF-04457845
    N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide
    PF-04457845yne
    4-(3-((5-(pent-4-yn-1-yloxy)pyridin-2-yl)oxy)benzylidene)-N-(pyridazin-3-yl)piperidine-1-carboxamide
    JP104
    3′-carbamoylbiphenyl-3-yl undec-10-ynylcarbamate
    SR141716
    5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide
    SR144528
    5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide
    WIN 55,212-2
    (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone.

  • Received February 2, 2011.
  • Accepted April 14, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleDrug Discovery and Translational Medicine

Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain

Kay Ahn, Sarah E. Smith, Marya B. Liimatta, David Beidler, Nalini Sadagopan, David T. Dudley, Tim Young, Paul Wren, Yanhua Zhang, Steven Swaney, Keri Van Becelaere, Jacqueline L. Blankman, Daniel K. Nomura, Shobha N. Bhattachar, Cory Stiff, Tyzoon K. Nomanbhoy, Eranthie Weerapana, Douglas S. Johnson and Benjamin F. Cravatt
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 114-124; DOI: https://doi.org/10.1124/jpet.111.180257

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Research ArticleDrug Discovery and Translational Medicine

Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain

Kay Ahn, Sarah E. Smith, Marya B. Liimatta, David Beidler, Nalini Sadagopan, David T. Dudley, Tim Young, Paul Wren, Yanhua Zhang, Steven Swaney, Keri Van Becelaere, Jacqueline L. Blankman, Daniel K. Nomura, Shobha N. Bhattachar, Cory Stiff, Tyzoon K. Nomanbhoy, Eranthie Weerapana, Douglas S. Johnson and Benjamin F. Cravatt
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 114-124; DOI: https://doi.org/10.1124/jpet.111.180257
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