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Research ArticleDrug Discovery and Translational Medicine

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Kent T. Symons, Phan M. Nguyen, Mark E. Massari, John V. Anzola, Lena M. Staszewski, Li Wang, Nahid Yazdani, Steven Dorow, Jerry Muhammad, Marciano Sablad, Natasha Rozenkrants, Celine Bonefous, Joseph E. Payne, Peter J. Rix, Andrew K. Shiau, Stewart A. Noble, Nicholas D. Smith, Christian A. Hassig, Yan Zhang and Tadimeti S. Rao
Journal of Pharmacology and Experimental Therapeutics February 2011, 336 (2) 468-478; DOI: https://doi.org/10.1124/jpet.110.172817
Kent T. Symons
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Phan M. Nguyen
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Mark E. Massari
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John V. Anzola
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Lena M. Staszewski
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Li Wang
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Nahid Yazdani
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Steven Dorow
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Jerry Muhammad
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Marciano Sablad
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Natasha Rozenkrants
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Celine Bonefous
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Joseph E. Payne
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Peter J. Rix
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Andrew K. Shiau
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Stewart A. Noble
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Nicholas D. Smith
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Christian A. Hassig
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Yan Zhang
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Tadimeti S. Rao
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Abstract

Nitric oxide (NO) derived from neuronal nitric-oxide synthase (nNOS) and inducible nitric-oxide synthase (iNOS) plays a key role in various pain and inflammatory states. KLYP961 (4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one) inhibits the dimerization, and hence the enzymatic activity of human, primate, and murine iNOS and nNOS (IC50 values 50–400 nM), with marked selectivity against endothelial nitric-oxide synthase (IC50 >15,000 nM). It has ideal drug like-properties, including excellent rodent and primate pharmacokinetics coupled with a minimal off-target activity profile. In mice, KLYP961 attenuated endotoxin-evoked increases in plasma nitrates, a surrogate marker of iNOS activity in vivo, in a sustained manner (ED50 1 mg/kg p.o.). KLYP961 attenuated pain behaviors in a mouse formalin model (ED50 13 mg/kg p.o.), cold allodynia in the chronic constriction injury model (ED50 25 mg/kg p.o.), or tactile allodynia in the spinal nerve ligation model (ED50 30 mg/kg p.o.) with similar efficacy, but superior potency relative to gabapentin, pregabalin, or duloxetine. Unlike morphine, the antiallodynic activity of KLYP961 did not diminish upon repeated dosing. KLYP961 also attenuated carrageenin-induced edema and inflammatory hyperalgesia and writhing response elicited by phenylbenzoquinone with efficacy and potency similar to those of celecoxib. In contrast to gabapentin, KLYP961 did not impair motor coordination at doses as high as 1000 mg/kg p.o. KLYP961 also attenuated capsaicin-induced thermal allodynia in rhesus primates in a dose-related manner with a minimal effective dose (≤10 mg/kg p.o.) and a greater potency than gabapentin. In summary, KLYP961 represents an ideal tool with which to probe the physiological role of NO derived from iNOS and nNOS in human pain and inflammatory states.

Footnotes

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

    doi:10.1124/jpet.110.172817.

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

  • ABBREVIATIONS:

    NOS
    nitric-oxide synthase
    iNOS
    inducible NOS
    eNOS
    endothelial NOS
    nNOS
    neuronal NOS
    CCI
    chronic constrictive nerve injury
    PBQ
    phenylbenzoquinone
    BBS-4
    (R)-1-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)pyrrolidine-2-carboxamide
    HEK
    human embryonic kidney
    SEITU
    2-ethyl-2-thiopseudourea hydrobromide
    LPS
    lipopolysaccharide
    MK-801
    (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
    ANOVA
    analysis of variance
    AUC
    areas under the curve
    DMSO
    dimethyl sulfoxide
    KLYP956
    N-(3-chlorophenyl)-N-((8-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-4-methylthiazole-5-carboxamide
    HA
    hemagglutinin
    CI
    confidence interval
    KLYP961
    (4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one
    GW274150
    ([2-[(1-iminoethyl) amino]ethyl]-L-homocysteine).

  • Received July 12, 2010.
  • Accepted October 21, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 372 (1)
Journal of Pharmacology and Experimental Therapeutics
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1 Jan 2020
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Research ArticleDrug Discovery and Translational Medicine

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Kent T. Symons, Phan M. Nguyen, Mark E. Massari, John V. Anzola, Lena M. Staszewski, Li Wang, Nahid Yazdani, Steven Dorow, Jerry Muhammad, Marciano Sablad, Natasha Rozenkrants, Celine Bonefous, Joseph E. Payne, Peter J. Rix, Andrew K. Shiau, Stewart A. Noble, Nicholas D. Smith, Christian A. Hassig, Yan Zhang and Tadimeti S. Rao
Journal of Pharmacology and Experimental Therapeutics February 1, 2011, 336 (2) 468-478; DOI: https://doi.org/10.1124/jpet.110.172817

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Research ArticleDrug Discovery and Translational Medicine

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Kent T. Symons, Phan M. Nguyen, Mark E. Massari, John V. Anzola, Lena M. Staszewski, Li Wang, Nahid Yazdani, Steven Dorow, Jerry Muhammad, Marciano Sablad, Natasha Rozenkrants, Celine Bonefous, Joseph E. Payne, Peter J. Rix, Andrew K. Shiau, Stewart A. Noble, Nicholas D. Smith, Christian A. Hassig, Yan Zhang and Tadimeti S. Rao
Journal of Pharmacology and Experimental Therapeutics February 1, 2011, 336 (2) 468-478; DOI: https://doi.org/10.1124/jpet.110.172817
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