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Research ArticleArticle

E6130, a Novel CX3C Chemokine Receptor 1 (CX3CR1) Modulator, Attenuates Mucosal Inflammation and Reduces CX3CR1+ Leukocyte Trafficking in Mice with Colitis

Hisashi Wakita, Tatsuya Yanagawa, Yoshikazu Kuboi and Toshio Imai
Molecular Pharmacology November 2017, 92 (5) 502-509; DOI: https://doi.org/10.1124/mol.117.108381
Hisashi Wakita
Eisai Co., Ltd., Tsukuba Research Laboratories, Ibaraki (H.W., T.Y., Y.K.) and KAN Research Institute Inc., Hyogo (T.I.), Japan
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Tatsuya Yanagawa
Eisai Co., Ltd., Tsukuba Research Laboratories, Ibaraki (H.W., T.Y., Y.K.) and KAN Research Institute Inc., Hyogo (T.I.), Japan
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Yoshikazu Kuboi
Eisai Co., Ltd., Tsukuba Research Laboratories, Ibaraki (H.W., T.Y., Y.K.) and KAN Research Institute Inc., Hyogo (T.I.), Japan
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Toshio Imai
Eisai Co., Ltd., Tsukuba Research Laboratories, Ibaraki (H.W., T.Y., Y.K.) and KAN Research Institute Inc., Hyogo (T.I.), Japan
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Abstract

The chemokine fractalkine (CX3C chemokine ligand 1; CX3CL1) and its receptor CX3CR1 are involved in the pathogenesis of several diseases, including inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, rheumatoid arthritis, hepatitis, myositis, multiple sclerosis, renal ischemia, and atherosclerosis. There are no orally available agents that modulate the fractalkine/CX3CR1 axis. [(3S,4R)-1-[2-Chloro-6-(trifluoromethyl)benzyl]-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetic acid (2S)-hydroxy(phenyl)acetate (E6130) is an orally available highly selective modulator of CX3CR1 that may be effective for treatment of inflammatory bowel disease. We found that E6130 inhibited the fractalkine-induced chemotaxis of human peripheral blood natural killer cells (IC50 4.9 nM), most likely via E6130-induced down-regulation of CX3CR1 on the cell surface. E6130 had agonistic activity via CX3CR1 with respect to guanosine 5′-3-O-(thio)triphosphate binding in CX3CR1-expressing Chinese hamster ovary K1 (CHO-K1) membrane and had no antagonistic activity. Orally administered E6130 ameliorated several inflammatory bowel disease–related parameters in a murine CD4+CD45RBhigh T-cell-transfer colitis model and a murine oxazolone-induced colitis model. In the CD4+CD45RBhigh T-cell transfer model, E6130 inhibited the migration of CX3CR1+ immune cells and decreased the number of these cells in the gut mucosal membrane. These results suggest that E6130 is a promising therapeutic agent for treatment of inflammatory bowel disease.

Footnotes

    • Received February 1, 2017.
    • Accepted August 16, 2017.
  • This work was funded by Eisai Co., Ltd.

  • https://doi.org/10.1124/mol.117.108381.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 92 (5)
Molecular Pharmacology
Vol. 92, Issue 5
1 Nov 2017
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Research ArticleArticle

Characterization of a Modulator of Chemokine Receptor CX3CR1

Hisashi Wakita, Tatsuya Yanagawa, Yoshikazu Kuboi and Toshio Imai
Molecular Pharmacology November 1, 2017, 92 (5) 502-509; DOI: https://doi.org/10.1124/mol.117.108381

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Research ArticleArticle

Characterization of a Modulator of Chemokine Receptor CX3CR1

Hisashi Wakita, Tatsuya Yanagawa, Yoshikazu Kuboi and Toshio Imai
Molecular Pharmacology November 1, 2017, 92 (5) 502-509; DOI: https://doi.org/10.1124/mol.117.108381
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