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Research ArticleInflammation, Immunopharmacology, and Asthma

Pharmacology of AM211, a Potent and Selective Prostaglandin D2 Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Gretchen Bain, Daniel S. Lorrain, Karin J. Stebbins, Alex R. Broadhead, Angelina M. Santini, Pat Prodanovich, Janice Darlington, Christopher D. King, Catherine Lee, Christopher Baccei, Brian Stearns, Yen Troung, John H. Hutchinson, Peppi Prasit and Jilly F. Evans
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 290-301; DOI: https://doi.org/10.1124/jpet.111.180430
Gretchen Bain
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Daniel S. Lorrain
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Karin J. Stebbins
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Alex R. Broadhead
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Angelina M. Santini
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Pat Prodanovich
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Janice Darlington
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Christopher D. King
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Catherine Lee
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Christopher Baccei
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Brian Stearns
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Yen Troung
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John H. Hutchinson
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Peppi Prasit
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Jilly F. Evans
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Abstract

The prostaglandin D2 (PGD2) receptor type 2 (DP2) is a G protein-coupled receptor that has been shown to be involved in a variety of allergic diseases, including allergic rhinitis, asthma, and atopic dermatitis. In this study, we describe the preclinical pharmacological and pharmacokinetic properties of the small-molecule DP2 antagonist [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (AM211). We determine that AM211 has high affinity for human, mouse, rat, and guinea pig DP2 and it shows selectivity over other prostanoid receptors and enzymes. Antagonist activity of AM211 at the DP2 receptor was confirmed by inhibition of PGD2-stimulated guanosine 5′-O-[γ-thio]triphosphate binding to membranes expressing human DP2. A basophil activation assay and a whole-blood assay of eosinophil shape change were used to demonstrate the ability of AM211 to potently antagonize PGD2-stimulated functional responses in relevant human cells and in the context of a physiologically relevant environment. AM211 exhibits good oral bioavailability in rats and dogs and dose-dependently inhibits 13,14-dihydro-15-keto-PGD2-induced leukocytosis in a guinea pig pharmacodynamic assay. AM211 demonstrates efficacy in two animal models of allergic inflammation, including an ovalbumin-induced lung inflammation model in guinea pigs and an ovalbumin-induced mouse model of allergic rhinitis. AM211 represents a potent and selective antagonist of DP2 that may be used clinically to evaluate the role of DP2 in T helper 2-driven allergic inflammatory diseases.

Footnotes

  • This work was supported by Amira Pharmaceuticals.

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

    doi:10.1124/jpet.111.180430.

  • ABBREVIATIONS:

    PGD2
    prostaglandin D2
    DP2
    PGD2 receptor type 2
    DP1
    PGD2 receptor type 1
    DK-PGD2
    13,14-dihydro-15-keto-PGD2
    AM211
    [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid
    Th2
    T helper 2
    COPD
    chronic obstructive pulmonary disease
    BALF
    bronchoalveolar lavage fluid
    TP
    thromboxane A2 receptor
    IP
    prostacyclin receptor
    FP
    prostaglandin F2α receptor
    PBS
    phosphate-buffered saline
    ESC
    eosinophil shape change
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    GTPγS
    guanosine 5′-O-[γ-thio]triphosphate
    COX
    cyclooxygenase
    OVA
    ovalbumin
    DMSO
    dimethylsulfoxide
    ANOVA
    analysis of variance
    CHO
    Chinese hamster ovary
    HEK
    human embryonic kidney
    AUC
    area under the curve
    IL
    interleukin
    Veh
    vehicle
    TB
    total binding
    PPAR
    peroxisome proliferator-activated receptor
    FSC
    forward light scatter
    SSC
    side scatter
    FACS
    fluorescence-activated cell sorting
    BAY u3405
    (+)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid
    BW A868C
    3-[(2-cyclohexyl-2-hydroxyethyl)amino]-2,5-dioxo-1-(phenylmethyl)-4-imidazolidineheptanoic acid
    SQ 29,548
    [1S-[1α,2α(Z),3α,4α]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
    GW7647
    2-methyl-2-[[4-[2-[[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methylpropanoic acid
    GW0742
    [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy] acetic acid
    MK-7246
    {(7R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl}acetic acid.

  • Received February 10, 2011.
  • Accepted April 8, 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 ArticleInflammation, Immunopharmacology, and Asthma

Pharmacology of AM211, a Potent and Selective Prostaglandin D2 Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Gretchen Bain, Daniel S. Lorrain, Karin J. Stebbins, Alex R. Broadhead, Angelina M. Santini, Pat Prodanovich, Janice Darlington, Christopher D. King, Catherine Lee, Christopher Baccei, Brian Stearns, Yen Troung, John H. Hutchinson, Peppi Prasit and Jilly F. Evans
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 290-301; DOI: https://doi.org/10.1124/jpet.111.180430

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Research ArticleInflammation, Immunopharmacology, and Asthma

Pharmacology of AM211, a Potent and Selective Prostaglandin D2 Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Gretchen Bain, Daniel S. Lorrain, Karin J. Stebbins, Alex R. Broadhead, Angelina M. Santini, Pat Prodanovich, Janice Darlington, Christopher D. King, Catherine Lee, Christopher Baccei, Brian Stearns, Yen Troung, John H. Hutchinson, Peppi Prasit and Jilly F. Evans
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 290-301; DOI: https://doi.org/10.1124/jpet.111.180430
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