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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleCellular and Molecular

Identification and Characterization of INCB9471, an Allosteric Noncompetitive Small-Molecule Antagonist of C-C Chemokine Receptor 5 with Potent Inhibitory Activity against Monocyte Migration and HIV-1 Infection

Niu Shin, Kim Solomon, Naiming Zhou, Kathy He Wang, Vasudha Garlapati, Beth Thomas, Yanlong Li, Maryanne Covington, Frederic Baribaud, Susan Erickson-Viitanen, Phil Czerniak, Nancy Contel, Phillip Liu, Timothy Burn, Gregory Hollis, Swamy Yeleswaram, Kris Vaddi, Chu-Biao Xue, Brian Metcalf, Steve Friedman, Peggy Scherle and Robert Newton
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 228-239; DOI: https://doi.org/10.1124/jpet.111.179531
Niu Shin
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Kim Solomon
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Naiming Zhou
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Kathy He Wang
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Vasudha Garlapati
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Beth Thomas
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Yanlong Li
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Maryanne Covington
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Frederic Baribaud
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Susan Erickson-Viitanen
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Phil Czerniak
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Nancy Contel
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Phillip Liu
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Timothy Burn
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Gregory Hollis
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Swamy Yeleswaram
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Kris Vaddi
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Chu-Biao Xue
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Abstract

C-C chemokine receptor 5 (CCR5) is a clinically proven target for inhibition of HIV-1 infection and a potential target for various inflammatory diseases. In this article, we describe 5-[(4-{(3S)-4-[(1R,2R)-2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride (INCB9471), a potent and specific inhibitor of human CCR5 that has been proven to be safe and efficacious in viral load reduction in phase I and II human clinical trails. INCB9471 was identified using a primary human monocyte-based radioligand competition binding assay. It potently inhibited macrophage inflammatory protein-1β-induced monocyte migration and infection of peripheral blood mononuclear cells by a panel of R5-HIV-1 strains. The results from binding and signaling studies using incremental amounts of INCB9471 demonstrated INCB9471 as a noncompetitive CCR5 inhibitor. The CCR5 residues that are essential for interaction with INCB9471 were identified by site-specific mutagenesis studies. INCB9471 rapidly associates with but slowly dissociates from CCR5. When INCB9471 was compared with three CCR5 antagonists that had been tested in clinical trials, the potency of INCB9471 in blocking CCR5 ligand binding was similar to those of 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R0–2-(methyloxy)-1-[4-(trifluoromethyl) phenyl]ethyl}-1-piperazingyl)-1-piperidinyl]carbonyl}pyrimidine (SCH-D; vicriviroc), 4-{[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxyl)methyl]-2, 5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140; aplaviroc), and 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)cyclohexanecarboxamide (UK427857; maraviroc). Its inhibitory activity against CCR5-mediated Ca2+ mobilization was also similar to those of SCH-D and 873140. Further analysis suggested that INCB9471 and UK427857 may have different binding sites on CCR5. The significance of two CCR5 antagonists with different binding sites is discussed in the context of potentially overcoming drug-resistant HIV-1 strains.

Footnotes

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

    doi:10.1124/jpet.111.179531.

  • ABBREVIATIONS:

    CCR5
    C-C chemokine receptor 5
    CXCR4
    C-X-C chemokine receptor 4
    CXCR3
    C-X-C chemokine receptor 3
    DMEM
    Dulbecco's modified Eagle's medium
    FACS
    fluorescence-activated cell sorting
    HEK
    human embryonic kidney
    MCP-1
    monocyte chemoattractant protein-1
    MIP
    macrophage inflammatory protein
    PBMC
    peripheral blood mononuclear cell
    PE
    phycoerythrin
    RANTES
    regulated on activation, normal T cell expressed and secreted
    rhIL-10
    recombinant human interleukin-10
    TM
    transmembrane domain
    SCH-D
    4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R0–2-(methyloxy)-1-[4-(trifluoromethyl) phenyl]ethyl}-1-piperazingyl)-1-piperidinyl]carbonyl}pyrimidine
    UK 427857
    4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)cyclohexanecarboxamide
    873140
    4-{[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxyl)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride
    INCB9471
    5-[(4-{(3S)-4-[(1R,2R)-2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride
    TAK779
    N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride
    SCH-C
    4-[(Z)-(4-bromophenyl)-(ethoxyimino)methyl]-1'-[2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide
    AD101
    (2,4-dimethylpyridin-3-yl)-[4-methyl-4[(3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazin-1-yl]-1-piperidyl]methanone.

  • Received January 20, 2011.
  • Accepted March 24, 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 ArticleCellular and Molecular

Identification and Characterization of INCB9471, an Allosteric Noncompetitive Small-Molecule Antagonist of C-C Chemokine Receptor 5 with Potent Inhibitory Activity against Monocyte Migration and HIV-1 Infection

Niu Shin, Kim Solomon, Naiming Zhou, Kathy He Wang, Vasudha Garlapati, Beth Thomas, Yanlong Li, Maryanne Covington, Frederic Baribaud, Susan Erickson-Viitanen, Phil Czerniak, Nancy Contel, Phillip Liu, Timothy Burn, Gregory Hollis, Swamy Yeleswaram, Kris Vaddi, Chu-Biao Xue, Brian Metcalf, Steve Friedman, Peggy Scherle and Robert Newton
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 228-239; DOI: https://doi.org/10.1124/jpet.111.179531

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Research ArticleCellular and Molecular

Identification and Characterization of INCB9471, an Allosteric Noncompetitive Small-Molecule Antagonist of C-C Chemokine Receptor 5 with Potent Inhibitory Activity against Monocyte Migration and HIV-1 Infection

Niu Shin, Kim Solomon, Naiming Zhou, Kathy He Wang, Vasudha Garlapati, Beth Thomas, Yanlong Li, Maryanne Covington, Frederic Baribaud, Susan Erickson-Viitanen, Phil Czerniak, Nancy Contel, Phillip Liu, Timothy Burn, Gregory Hollis, Swamy Yeleswaram, Kris Vaddi, Chu-Biao Xue, Brian Metcalf, Steve Friedman, Peggy Scherle and Robert Newton
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 228-239; DOI: https://doi.org/10.1124/jpet.111.179531
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